Article

Associations between maternal phthalate exposure and cord sex hormones in human infants

May 2011
Chemosphere 83(8):1192-9

DOI:10.1016/j.chemosphere.2010.12.079

Source
PubMed

Authors:

Shu-Li Wang

National Health Research Institutes

Po-Chin Huang

National Health Research Institutes

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Exposure to Synthetic Endocrine-Disrupting Chemicals in Relation to Maternal and Fetal Sex Steroid Hormones: A Scoping Review

Article

Full-text available

Jul 2024

Purpose of Review Many synthetic endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment and highly detected among pregnant people. These chemicals may disrupt maternal and/or fetal sex steroid hormones, which are critical to pregnancy maintenance and fetal development. Here, we review the epidemiological literature examining prenatal exposure to common synthetic EDCs in relation to maternal and fetal sex steroid hormones. Recent Findings We performed a literature search using PubMed, SCOPUS, and Embase, ultimately identifying 29 articles for full review. Phenols, parabens, and persistent organic pollutants generally showed inverse associations with androgens, estrogens, and progesterone. Phthalates and per-and polyfluoroalkyl substances tended to be inversely associated with progesterone, while evidence regarding androgens and estrogens was mixed. Inconsistent, but noteworthy, differences by fetal sex and timing of exposure/outcome were observed. Summary Overall, the literature suggests EDCs may disrupt maternal and fetal sex steroid activity, though findings are mixed. Given the pervasive, high-volume production of these synthetic chemicals and the critical functions sex steroid hormones play during gestation, additional research is warranted.

Phthalate Metabolites in Maternal and Cord Plasma and Their Relations to Other Selected Endocrine Disruptors and Steroids

Article

Full-text available

Nov 2018

Endocrine disruptors (EDs) are known to have harmful effects on the human endocrine system; special effort is actually given to the exposure during pregnancy. Humans are usually exposed to a mixture of EDs, which may potentiate or antagonize each other, and the combined effect may be difficult to estimate. The main phthalate monoesters monoethyl-, mono-n-butyl-, monoisobutyl-, monobenzyl-, mono-(2-ethylhexyl)-, mono-(2-ethyl-5-hydroxyhexyl)- and mono-(2-ethyl-5-oxohexyl) phthalate were determined in 18 maternal (37th week of pregnancy) and cord plasma samples using liquid chromatography-tandem mass spectrometry. Previously determined levels of selected bisphenols, parabens and steroids were also considered in this study. In cord blood, there were significantly higher mono-n-butyl phthalate levels than in maternal blood (p=0.043). The results of multiple regression models showed that maternal plasma phthalates were negatively associated with cord plasma androstenedione, testosterone and dehydroepiandrosterone and positively associated with estradiol and estriol. For estriol, a cumulative association was also observed for Σbisphenols. To the best of our knowledge, this is the first pilot study evaluating the effect of prenatal exposure by multiple EDs on newborn steroidogenesis. Our results confirmed phthalate accumulation in the fetal area and disruption of fetal steroidogenesis. This preliminary study highlights the negative impacts of in utero EDs exposure on fetal steroidogenesis.

Prenatal exposure to common plasticizers: a longitudinal study on phthalates, brain volumetric measures, and IQ in youth

Article

Full-text available

Aug 2023

Exposure to phthalates, used as plasticizers and solvents in consumer products, is ubiquitous. Despite growing concerns regarding their neurotoxicity, brain differences associated with gestational exposure to phthalates are understudied. We included 775 mother-child pairs from Generation R, a population-based pediatric neuroimaging study with prenatal recruitment, who had data on maternal gestational phthalate levels and T1-weighted magnetic resonance imaging in children at age 10 years. Maternal urinary concentrations of phthalate metabolites were measured at early, mid-, and late pregnancy. Child IQ was assessed at age 14 years. We investigated the extent to which prenatal exposure to phthalates is associated with brain volumetric measures and whether brain structural measures mediate the association of prenatal phthalate exposure with IQ. We found that higher maternal concentrations of monoethyl phthalate (mEP, averaged across pregnancy) were associated with smaller total gray matter volumes in offspring at age 10 years (β per log10 increase in creatinine adjusted mEP = −10.7, 95%CI: −18.12, −3.28). Total gray matter volumes partially mediated the association between higher maternal mEP and lower child IQ (β for mediated path =−0.31, 95%CI: −0.62, 0.01, p = 0.05, proportion mediated = 18%). An association of higher monoisobutyl phthalate (mIBP) and smaller cerebral white matter volumes was present only in girls, with cerebral white matter volumes mediating the association between higher maternal mIBP and lower IQ in girls. Our findings suggest the global impact of prenatal phthalate exposure on brain volumetric measures that extends into adolescence and underlies less optimal cognitive development.

Health effects associated with phthalate activity on nuclear receptors

Article

Sep 2021

Phthalates are endocrine disruptors, widely used as plasticizers to impart flexibility in plastics, and as solvents in personal care products. Due to their nearly ubiquitous use in consumer products, most humans are exposed to phthalates daily. There has been extensive research on the reproductive health effects associated with phthalate exposure, but less attention has been paid to other actions. This review aims to summarize the known action of phthalates on different nuclear receptors. Some phthalates bind to and activate the estrogen receptor, making them weakly estrogenic. However, other phthalates antagonize androgen receptors. Some high molecular weight phthalates antagonize thyroid receptors, affecting metabolism. Several phthalates activate and interfere with the normal function of different peroxisome proliferator-activated receptors (PPARs), receptors that have critical roles in lipid metabolism and energy homeostasis. Some phthalates activate the aryl hydrocarbon receptor, which is critical for xenobiotic metabolism. Although phthalates have a short half-life in vivo , because people are continuously exposed, studies should examine the health effects of phthalates associated with long-term exposure. There is limited research on the effects of phthalates on health outcomes aside from reproductive function, particularly concerning are childhood adiposity, behavior, and learning. There is also limited information on actions of phthalates not mediated via nuclear receptors. Humans are exposed to multiple chemicals simultaneously, and how chemical mixtures act on nuclear receptor activity needs study. Although we know a great deal about phthalates, there is still much that remains uncertain. Future studies need to further examine their other potential health effects.

Association of Maternal-Neonatal Steroids With Early Pregnancy Endocrine Disrupting Chemicals and Pregnancy Outcomes

Article

Dec 2020

Context Steroids play an important role in fetal development and parturition. Gestational exposures to endocrine disrupting chemicals (EDCs) affect steroidal milieu and pregnancy outcomes, raising the possibility of steroids serving as biomarkers. Most studies have not addressed the impact of EDC mixtures, which are reflective of real life scenarios. Objective Assess the association of maternal and neonatal steroids with pregnancy outcomes and early pregnancy EDC levels. Design Prospective analysis of mother-infant dyads. Setting University hospital. Participants 121 mother-infant dyads. Main Outcome Measures The associations of maternal and neonatal steroidal hormones from 121 dyads with pregnancy outcomes, the associations of first trimester EDCs individually and as mixtures with maternal and neonatal steroids in a sub-set of 56 dyads and the influence of BMI, age and offspring sex in modulating the EDC associations with steroids were determined. Results (1) Steroid-specific positive or negative associations with pregnancy measures were evident; (2) many maternal first trimester EDCs were negatively associated with estrogens and positively with androgen/estrogen ratios; (3) EDC-steroid associations were influenced by maternal age, pre-pregnancy BMI, and fetal sex and (4) EDCs individually and as mixtures showed direct and inverse fetal sex-dependent associations with maternal and neonatal steroids. Conclusions This proof-of-concept study indicates association of steroids with pregnancy outcomes depending on maternal age, pre-pregnancy BMI, and fetal sex, with the effects of EDCs differing when considered individually or as mixtures. These findings suggest that steroidal hormonal measures have potential to serve as biomarkers of impact of EDC exposures and pregnancy outcome.

DNA Methylation at Birth is Associated with Childhood Serum Immunoglobulin E Levels

Article

Full-text available

Apr 2021

Immunoglobulin E (IgE) is known to play an important role in allergic diseases. Epigenetic traits acquired due to modification of deoxyribonucleic acid (DNA) methylation (DNAm) in early life may have phenotypic consequences through their role in transcriptional regulation with relevance to the developmental origins of diseases including allergy. However, epigenome-scale studies on the longitudinal association of cord blood DNAm with IgE over time are lacking. Our study aimed to examine the association of DNAm at birth with childhood serum IgE levels during early life. Genome-scale DNAm and total serum IgE measured at birth, 5, 8, and 11 years of children in the Taiwan Maternal and Infant Cohort Study were included in the study in the discovery stage. Linear mixed models were implemented to assess the association between cord blood DNAm at ~310K 5′-cytosine-phosphate-guanine-3′ (CpG) sites with repeated IgE measurements, adjusting for cord blood IgE. Identified statistically significant CpGs (at a false discovery rate, FDR, of 0.05) were further tested in an independent replication cohort, the Isle of Wight (IoW) birth cohort. We mapped replicated CpGs to genes and conducted gene ontology analysis using ToppFun to identify significantly enriched pathways and biological processes of the genes. Cord blood DNAm of 273 CpG sites were significantly (FDR = 0.05) associated with IgE levels longitudinally. Among the identified CpGs available in both cohorts (184 CpGs), 92 CpGs (50%) were replicated in the IoW in terms of consistency in direction of associations between DNA methylation and IgE levels later in life, and 16 of the 92 CpGs showed statistically significant associations ( P

The Endocrine Disruption of Prenatal Phthalate Exposure in Mother and Offspring

Article

Full-text available

Aug 2020

Phthalates are a group of ubiquitous synthetic endocrine-disrupting chemicals. Fetal and neonatal periods are particularly susceptible to endocrine disorders, which prenatal exposure to phthalates causes. There is increasing evidence concerning the potential endocrine disrupting for phthalate exposure during pregnancy. This article aims to review the endocrine impairment and potential outcomes of prenatal phthalate exposure. Prenatal exposure phthalates would disrupt the levels of thyroid, sex hormone, and 25-hydroxyvitamin D in pregnant women or offspring, which results in preterm birth, preeclampsia, maternal glucose disorders, infant cryptorchidism, infant hypospadias, and shorter anogenital distance in newborns, as well as growth restriction not only in infants but also in early adolescence and childhood. The relationship of prenatal phthalate exposure with maternal and neonatal outcomes in human beings was often sex-specific associations. Because of the potentially harmful influence of prenatal phthalate exposure, steps should be taken to prevent or reduce phthalate exposure during pregnancy.

Maternal phthalate exposure and BMI trajectory in children—an 18-year birth cohort follow-up study

Article

Full-text available

Jun 2024
J EXPO SCI ENV EPID

Background Obesity is a major health concern worldwide. Previous studies have suggested that phthalate plasticizers are obesogens. However, the relationship between early-life phthalate exposure and long-term obesity development remains unknown. Objective We investigated the association between prenatal phthalate exposure and children’s body mass index (BMI) patterns in an 18-year birth cohort follow-up study in Taiwan. Methods Our analytical lab quantified seven phthalate metabolites in maternal urine during pregnancy using quantitative liquid chromatography-tandem mass spectrometry. In addition, we calculated BMI z scores for participated children at each follow-up, utilized trajectory analysis to describe children’s BMI z-score patterns at 2–18 years of age, and adopted generalized estimating equations (GEE) and multivariate logistic regression models to assess the association between prenatal phthalate exposure and BMI z scores in children. Results A total of 208 mother-child pairs were included in the analysis. Maternal urinary diethyl phthalate (DEP) metabolites were associated with the increase of BMI z scores in children aged 2–18 years in the GEE model. Doubled maternal urinary ∑mDEHP (3 mono hexyl-metabolites of di-ethyl-hexyl phthalate (DEHP) increased the risk of children being in the stable-high BMI trajectory group until the age of eighteen. Impact statement We observed that BMI trajectories of children remained stable after the age of 5 years. During each follow-up, a higher frequency of overweight or obese was observed in children, ranging from 15.9% to 35.6% for girls and 15.2–32.0% for boys, respectively. Prenatal phthalate exposure was associated with increasing BMI z scores in children. Prenatal DEHP exposure was associated with a stable-high BMI trajectory in children up to the age of 18 years.

Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections

Article

Full-text available

Jan 2024

Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study’s objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal–child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath’s pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed.

Effect of prenatal exposure to phthalates on birth weight of offspring: A meta-analysis

Article

Jan 2024
REPROD TOXICOL

Evidence of the ability of endocrine disrupting compounds to induce testicular germ cell cancer in humans

Preprint

Full-text available

Dec 2023

Testicular cancer is an increasing burden in modern societies and the most common malignancy among young adult males. Environment contaminants, especially endocrine disrupting compounds (EDC), may play a significant role in the development of these cancers through epigenetic alterations occurring during fetal and neonatal development. As long-term studies in humans and suitable experimental models with the potential to develop testicular cancer are lacking, no causal link can be established between endocrine disruptor exposure and testicular cancer incidence. Therefore, we developed an experimental model that recapitulates the differentiation of germ cells from primordial germ cells (pluripotency) into spermatocytes (meiosis) by using xenografted human fetal testis combined with germ cell transplantation into adult testis compartments. Using this model, we demonstrate that long-term fetal exposure (until 12 weeks) to a mixture of Di-2-ethylhexylphthalate (DEHP) and Bisphenol A (BPA), two most prevalent plasticizers, could interfere with fetal germ cell differentiation, leading to carcinogenesis and seminomas. Transcriptome, methylome, and histological analyses reveal that BPA/DEHP exposure induced some significant hallmarks of germ cell tumors to occur: persistent pluripotent and proliferative germ cells, global hypomethylation of CpGs in germ cells, abnormal expression of meiotic markers and fibrotic signatures in fetal testis. Additionally, we found that EDC-exposed fetal germ cells were more likely to develop seminoma in a context that allows spermatogenesis to begin. This study proposes the first experimental evidence that EDC exposure can cause long-term, irreversible lesions in fetal germ cells, which then lead to testicular tumorigenesis in adults.

Worldwide risk assessment of phthalates and bisphenol A in humans: The need for updating guidelines

Article

Full-text available

Oct 2023
ENVIRON INT

Association between prenatal androgens and cord blood androgens, a path analysis

Article

Full-text available

Jan 2023

To determine association paths between prenatal androgens and cord blood androgens. The concentrations of T, FT, DHT, DHEA and SHBG in prenatal venous blood and cord blood were measured in 342 pregnant women and their neonates. The association paths between these hormones in prenatal and cord blood were revealed using Pearson correlation, multiple linear regression and path analysis. CB-T, CB-FT and CB-DHT in male neonates were higher than those in female neonates. In male and female neonates, P-FT was lower than CB-FT; however, P-DHT and P-SHBG were higher than CB-DHT and CB-SHBG, respectively. P-DHEA was lower than CB-DHEA in female newborns. In male neonates, there were association paths of P-T → CB-T → CB-FT → CB-DHT, P-T → CB-FT → CB-DHT, P-T → P-FT → CB-FT → CB-DHT, P-T → P-DHT, CB-DHEA → CB-DHT, CB-DHEA → P-DHT, and CB-DHEA → P-DHEA. In female neonates, there were association paths of P-T → CB-T → CB-FT → CB-DHT, P-T → P-FT → CB-FT → CB-DHT, P-T → P-FT → P-DHT, P-T → P-DHT, P-DHEA → P-DHT, CB-DHEA → P-DHEA, and CB-DHEA → CB-FT. There were differences in the T, FT and DHT concentrations in cord blood between male and female neonates and in the FT, DHT, DHEA, and SHBG concentrations between prenatal and cord blood. P-T and P-FT concentrations were positively associated with CB-T and CB-FT concentrations, while CB-DHEA concentration was positively associated with P-DHEA concentration.

Urinary phthalates, phenols, and parabens in relation to sleep health markers among a cohort of Mexican adolescents

Article

Dec 2022
SCI TOTAL ENVIRON

Introduction Emerging research has shed light on the potential impact of environmental toxicants on sleep health, however, it remains unclear if these associations exist during adolescence and whether associations differ by sex. This study aimed to examine associations between phthalates, parabens, and phenols on adolescent sleep health using cross-sectional data from 470 participants from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study. Material and methods In 2015, spot urine samples were analyzed for exposure biomarkers of 13 phthalate metabolites, ten phenol, and four paraben analytes. Over seven consecutive days, sleep duration, midpoint, and fragmentation were assessed with wrist-actigraphy. We examined associations between summary phthalates, individual phthalate metabolites, and phenol and paraben analytes with mean weekday sleep duration, midpoint, and fragmentation using linear regression models adjusted for specific-gravity and sex, age, pubertal status, smoking and alcohol behavior, physical activity, and screen time. Results Mean (SD) age was 13.8 (2.1) years; 53.5 % were female. Σ Plastic - summary measure for toxicants from plastic sources - and Σ DEHP and its metabolites, were associated with longer sleep duration in the unstratified sample. To illustrate, every 1-unit log increase in Σ DEHP was associated with 7.7 min (95 % CI: 0.32, 15.1; p < 0.05) longer duration. Summary measures of toxicants from plastic sources, personal care products, anti-androgenic toxicants, and multiple individual phthalates, phenols, and parabens were associated with later midpoint. The midpoint associations were largely female-specific. There were no associations with sleep fragmentation. Conclusions Higher EDC exposure may be related to longer sleep duration and later sleep timing during adolescence, and associations may vary by toxicant and according to sex.

Association between Phthalate Metabolites in Cord Blood and Preterm Birth, a Nested Case-Control Study in Tianjin, China

Preprint

Full-text available

Aug 2022

The influences of maternal exposure to endocrine disrupting chemicals on birth outcomes are not well understood. To assess phthalates exposure levels in utero and investigate their associations with preterm birth (PTB)，we performed a case-control study of 30 PTB newborns and 60 matched control newborns from a prospective mother-baby cohort. Control subjects were matched to case subjects by maternal age (+/- 3 years) and birth date. We quantified concentrations of MBP, MBzP, MMP, MEP and MEHP in cord blood. Compared with control infants, the concentrations of MMP, MEP and MEHP in cord blood were significantly higher in preterm newborns. With or without adjusting for potential confounders, MMP, MEHP and high molecular weight phthalate metabolites concentrations above the median levels were observed to be associated with an increased risk of PTB. In our study, prenatal phthalates exposure was related to preterm birth and may be a risk factor.

Reproductive toxicity of maternal exposure to di(2‐ethylhexyl)phthalate and butyl paraben (alone or in association) on both male and female Wistar offspring

Article

Aug 2022

Parabens and phthalates are commonly found as contaminants in human fluids and are able to provoke reproductive toxicity, being considered endocrine disruptors. To evaluate the effects of phthalate and paraben, alone or in combination, on reproductive development of the offspring, female pregnant Wistar rats were allocated in six experimental groups: three control groups [gavage (CG), subcutaneous (CS) and gavage+subcutaneous)] received corn oil as vehicle; the remaining groups were exposed to DEHP (500mg/kg, gavage), BP (100mg/kg, subcutaneously) or MIX (DEHP+ BP), from gestational day 12 until post-natal day (PND) 21. The following parameters were assessed on the offspring: anogenital distance and weight at PND1, nipple counting at PND13, puberty onset, estrous cycle, weights of reproductive and detoxifying organs, histological evaluation of reproductive organs and sperm evaluations (counts, morphology and motility). Female pups from MIX group presented reduced body weight at PND1, lower AGD and decreased endometrium thickness. Male animals showed decreased body weight at PND1 and lower number of Sertoli cells on DEHP and MIX groups; MIX group revealed increased of abnormal seminiferous tubules; DEHP animals presented delayed preputial separation and higher percentage of immotile sperms; BP males presented diminished number of Leydig cells. In conclusion, the male offspring was more susceptible to DEHP toxicity; even when mixed to paraben, the main negative effects observed seem to be due to anti-androgenic phthalate action. On the other hand, DEHP seems to be necessary to improve the effects of BP on reducing estrogenic and increasing androgenic dependent events.

Exposure to phthalates and female reproductive health: A literature review

Article

Mar 2022
REPROD TOXICOL

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that have been known for their ability to interfere with the action of hormones and affect endocrine pathways, including the ones involved in the development and function of both male and female reproductive systems. EDCs comprise a wide class of compounds, such as pesticides, bisphenol A, phthalates and, parabens, that are present in the environment and in several daily use products. Phthalate esters, compounds commonly used as plasticizers and additives in many industrial applications, have attracted special attention because of the widespread human exposure and the potential for disruption of androgen-dependent development in males. Although phthalates are rapidly metabolized and excreted, their ubiquitous presence ensures continuous exposures throughout different life stages from conception to adult life, as documented by a number of human biomonitoring studies worldwide. Although most research efforts have been placed on the impact of phthalates on male reproductive development and functions, there is a large body of recent experimental and observational data indicating that phthalates can negatively affect female reproductive health, and in particular alter ovarian and uterine functions, potentially contributing to disorders like polycystic ovarian syndrome, endometriosis, and other common female reproductive problems. This review summarizes the most recent experimental and epidemiologic literature on the potential effects of phthalate exposures on female reproductive health and their impact on female fertility.

Assessment of metabolic perturbations associated with exposure to phthalates among pregnant African American women

Article

Nov 2021
SCI TOTAL ENVIRON

Background Phthalates have been linked with numerous harmful health effects. Limited data are available on the molecular mechanism underlying phthalate toxicity on human health. In this study, we measured urinary phthalate metabolites and used high-resolution metabolomics (HRM) to identify biological perturbations associated with phthalate exposures among pregnant African American (AA) women, who are disproportionately exposed to high phthalates levels. Methods We used untargeted HRM profiling to characterize serum samples collected during early (8–14 weeks gestation) and late (24–30 weeks gestation) pregnancy from 73 participants from the Atlanta AA Maternal-Child cohort. We measured eight urinary phthalate metabolites in early and late pregnancy, including Monoethyl phthalate (MEP), Mono(2-ethlyhexyl) phthalate (MEHP), and Mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), to assess maternal exposures to phthalates. Metabolite and metabolic pathway perturbation were evaluated using an untargeted HRM workflow. Results Geometric mean creatinine-adjusted levels of urinary MEP, MEHP, and MEHHP were 67.3, 1.4, and 4.1 μg/g creatinine, respectively, with MEP and MEHP higher than the mean levels of non-Hispanic blacks in the general US population (2015–2016). There were 73 and 1435 metabolic features significantly associated with at least one phthalate metabolite during early and late pregnancy (p < 0.005), respectively. Pathway enrichment analysis revealed perturbations in four inflammation- and oxidative-stress-related pathways associated with phthalate metabolite levels during both early and late pregnancy, including glycerophospholipid, urea cycle, arginine, and tyrosine metabolism. We confirmed 10 metabolites with level-1 evidence, which are associated with urinary phthalates, including thyroxine and thiamine, which were negatively associated with MEP, as well as tyramine and phenethylamine, which were positively associated with MEHP and MEHHP. Conclusion Our results demonstrated that urinary phthalate levels were associated with perturbations in biological pathways connected with inflammation, oxidative stress, and endocrine disruption. The findings support future targeted investigations on molecular mechanisms underlying the impact of maternal phthalates exposure on adverse health outcomes.

Direct and non-direct transfer of phthalate esters from indoor sources to settled dust: Model analysis

Article

Jun 2021
BUILD ENVIRON

Phthalate esters (PAEs), as a group of typical semi-volatile organic compounds (SVOCs) with excellent performance as plasticizers, are widely used in indoor products and have been found to harm human health. There are two migration pathways for phthalates from the source to settled dust, namely: direct and non-direct contact with the sources. Therefore, concentrations of phthalates in settled dust have exhibited significant differences in the source and non-source surfaces in past literature. In this study, a porous media model is proposed to characterise the mass transfer mechanism of phthalates from the source into settled dust via two migration pathways. We compared the simulation data with the experimental data in the literature to validate the model, and the simulation results were consistent with the experimental results within an acceptable degree. Based on the model, a certain thickness of settled dust was selected to simulate the dust-phase concentration change of DEHP within 500 days and the concentration difference between source (value of 21,687.33 μg/g) and non-source surfaces (value of 150.32 μg/g) was compared. Then, the difference in the concentration distribution in the dust layer of different mass transfer pathways was visually demonstrated. Dust loading can dominate the mass transfer of phthalates and influence the concentration in dust by affecting the characteristics of the dust layer (porosity and thickness of settled dust). In addition, the solid diffusion coefficient and Koa values of phthalates have a significant influence on the dust-phase concentration and time to reach a steady state.

Phthalate Exposure Pattern in Breast Milk within a Six-Month Postpartum Time in Southern Taiwan

Article

Full-text available

May 2021
Int J Environ Res Publ Health

Di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, has been detected in breast milk in many countries; however, whether phthalate metabolite concentration and the detection rate in breast milk change postpartum is still unknown. We measured phthalate metabolite concentrations in breast milk in the first 6 months postpartum in women enrolled in the E-Da hospital from January to July 2017. A total of 56 breastfeeding mothers and 66 samples were included in this study. We analyzed the samples’ concentration of eight phthalate metabolites using liquid chromatography mass spectrometry. The concentration of mono-2-ethylhexyl phthalate (MEHP) was significantly higher in the first month, and then decreased over time. The detection rate of ono-isobutyl phthalate (MiBP) and mono-n-butyl phthalate (MBP) was low in the first month and then increased over time. Compared with a previous study published in 2011, the levels of MEHP and MiBP in breast milk were much lower in the present study, suggesting an increased awareness of the health risks of phthalate exposure after a food scandal occurred in Taiwan. This study provides information for evaluating newborns’ exposure to different kinds of phthalate through human milk in the postpartum period.

Phthalate mixtures in pregnancy, autistic traits, and adverse childhood behavioral outcomes

Article

Full-text available

Feb 2021
ENVIRON INT

Background Prenatal exposure to multiple phthalates is ubiquitous, and yet few studies have evaluated these exposures as a mixture in relation to child autistic traits and behavioral problems. Objectives To assess cumulative associations between prenatal phthalate mixtures and child behaviors, including effect modification by exposure timing and child sex. Methods Analyses included 501 mother/child pairs from the multicenter pregnancy cohort The Infant Development and Environment Study (TIDES). Nine maternal urinary phthalate metabolites were measured in early and late pregnancy, and behavior was assessed at ages 4–5 years using composite T scores for the Behavioral Assessment System for Children (BASC-2), which measures several dimensions of child behavior, and the Social Responsiveness Scale (SRS-2), which measures social impairment consistent with autistic traits. We utilized weighted quantile sum (WQS) regressions to examine pregnancy period-specific associations between phthalate mixtures and behavioral outcomes. Full-sample 95% WQS confidence intervals are known to be anti-conservative, so we calculated a confirmatory p-value using a permutation test. Effect modification by sex was examined with stratified analyses. Results A one-quintile increase in the early pregnancy phthalate mixture was associated with increased SRS-2 total score (coefficient = 1.0, confirmatory p = 0.01) and worse adaptive skills (coefficient = −1.0, confirmatory p = 0.06) in both sexes. In sex-stratified analyses, the early pregnancy phthalate mixture was associated with increased SRS-2 total score in boys (coefficient = 1.2, confirmatory p = 0.04) and girls (coefficient = 1.0, confirmatory p = 0.10) and worse BASC-2 adaptive skills score in girls (coefficient = −1.5, confirmatory p = 0.06), while the late pregnancy phthalate mixture was associated with increased BASC-2 externalizing score in boys (coefficient = 1.3, confirmatory p = 0.03). Conclusion Our results suggest cumulative adverse associations between prenatal phthalate mixtures and multiple facets of childhood behavior.

Meconium Exposure to Phthalates, Sex and Thyroid Hormones, Birth Size and Pregnancy Outcomes in 251 Mother–Infant Pairs from Shanghai

Article

Full-text available

Oct 2020
Int J Environ Res Publ Health

Phthalates are hormonally active pollutants. In-utero exposure to phthalates has been reported to be associated with birth size parameters and pregnancy outcomes. However, previous reports were inconsistent. We examined the associations between meconium exposure to phthalates and the effects on birth size parameters, pregnancy outcomes and sex and thyroid hormones in 251 mother–infant pairs from a Shanghai hospital. We measured 10 metabolites of phthalates in meconium samples collected during the first 24h after delivery. Information on seven birth size parameters (birth weight, birth length, abdominal circumference, head circumference, femur length, biparietal diameter and anogenital distance) and three pregnancy outcomes (gestational diabetes, premature rupture of membrane, and premature birth) was available from the birth record. Concentrations of free testosterone, estradiol (E2), thyroid stimulating hormone, concentrations of total and free thyroxine and triiodothyronine were measured from cord blood. Multivariate linear regression and logistic regression were used to estimate associations between phthalate exposure and health outcomes. mono-iso-butylphthalate (MiBP), mono-n-butylphthalate (MnBP) and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) were positively associated with birth length and femur length which seemed more obvious in female newborn; MiBP, MnBP and mono-2-ethylhexylphthalate (MEHP) were positively associated with gestational diabetes mellitus (GDM) only in mothers with male newborns; monomethyl phthalate (MMP), MiBP and MEOHP were positively associated with E2 in male newborns. This study indicates that meconium exposure to phthalates may adversely affect some fetal growth parameters and GDM with a potential gender effect.

Prenatal and childhood exposure to phthalic acid esters and vaccination antibodies in children: A 15-year follow-up birth cohort study

Article

Full-text available

Dec 2020

Phthalic acid esters (PAE) are widely used during chemical synthesis and do not form covalent linkages with products. It has been reported that exposure to PAE affects the immune response. However, their effect on antibody concentrations in children is still under investigation. We aimed to examine the association between early-life phthalate exposure and antibody concentrations in children in a longitudinal birth cohort established in 2000–2001. We recruited 398 neonates in central Taiwan and followed them up every 2–3 years, with various antibody-related studies at 11- and 14-year follow-ups. Seven urinary phthalate metabolites were quantified in mothers during pregnancy and children aged 11 years. Four antibody concentrations were analyzed in children aged 11 and 14 years. The percent change in antibody concentrations from ages 11 to 14 years was calculated and its association with phthalate exposure was evaluated via multivariate regression analysis. Eighty-one followed-up children were with sufficient data. After adjusting for prenatal exposure and other confounders, double concentrations of the urinary sum of di-2-ethylhexyl phthalate (ΣDEHPm) and mono-n-butyl phthalate (MnBP) were associated with a 18.06% (95% CI = 3.34%, 32.78%) and 22.53% decrease (95% CI = 3.39%, 41.66%) in antibody concentration against hepatitis B, respectively. Phthalate exposure was found to be related to decreased antibody concentrations against hepatitis B (DEHP, DBnP) in the early teens. This exposure is suggested to be considered for clinical re-booster vaccines among junior high school students. Further verification with additional cohorts and studies on the underlying mechanisms of phthalate exposure are warranted.

The Age Distribution among Children Seeking Medical Treatment for Precocious Puberty in Taiwan

Article

Full-text available

Sep 2020
Int J Environ Res Publ Health

Objective: Children with precocious puberty (PP) may have increased physiological and psychological problems. In this study, we aimed to explore the trend of parents seeking medical care for their children with precocious puberty. Methods: The Taiwan National Health Insurance Research Dataset (NHIRD) was used to estimate the prevalence (2000-2013) and incidence (2002-2013) of PP (ICD-9 code: 259.1) among boys aged 0-11 years and girls aged 0-10 years. The proportions of PP management within 1 year from the date of first diagnosis were also compared between two periods (2002-2007 and 2008-2012). The trends of PP prevalence or incidence were determined by join-point regression. Results: In 2000, 309 boys and 2706 girls had at least one visit for PP, the crude prevalence rates (per 10,000 persons) were 0.99 (95% confidence interval, 95% CI 0.87-1.14) and 13.56 (95% CI 13.01-14.13) in boys and girls, respectively. In 2013, the crude prevalence rates increased to 7.01 (95% CI 6.56-7.84) and 110.95 (95% CI 108.97-112.96) in boys and girls, respectively. A total of 2584 girls and 207 boys with incident PP cases were identified in 2002, and 7498 girls and 739 boys were identified in 2013. For girls, the incidence rates (per 10,000 person-years) were 16.17 (95% CI 15.55-16.80) and 70.23 (95% CI 68.65-71.83) in 2002 and 2013, respectively. For boys, the incidence rates were 1.09 (95% CI 0.95-1.24) and 5.72 (95% CI 5.32-6.15) in 2002 and 2013, respectively. The sex ratio (F:M) of the incidence of PP cases was 14.89 in 2002 and 12.28 in 2013. Conclusion: In this study, from 2000 to 2013, the frequency of visiting pediatric endocrinology outpatient clinics for precocious puberty increased in both genders. We advocate that it is important to pay increased attention to children's health, environmental hormones, and diet. Researchers should consider how to survey precocious puberty and offer parents more education to avoid the waste of medical resources or delays in seeking medical care.

Autophagy role in environmental pollutants exposure

Chapter

Feb 2020
Prog Mol Biol Transl Sci

During the last decades, the potential harmfulness derived from the exposure to environmental pollutants has been largely demonstrated, with associated damages ranging from geno- and cyto-toxicity to tissue malfunction and alterations in organism physiology. Autophagy is an evolutionarily-conserved cellular mechanism essential for cellular homeostasis, which contributes to protect cells from a wide variety of intracellular and extracellular stressors. Due to its pivotal importance, its correct functioning is directly linked to cell, tissue and organismal fitness. Environmental pollutants, particularly industrial compounds, are able to impact autophagic flux, either by increasing it as a protective response, by blocking it, or by switching its protective role toward a pro-cell death mechanism. Thus, the understanding of the effects of chemicals exposure on autophagy has become highly relevant, offering new potential approaches for risk assessment, protection and preventive measures to counteract the detrimental effects of environmental pollutants on human health.

Phthalates

Chapter

Dec 2019

Phthalate esters (PAE) are widely used plasticizers and solvents that are added to many consumer products used in our daily life. PAEs are not chemically bound to the polymer, and therefore are easily released or migrate into the environment including air, drink, foodstuffs, or furniture. Humans can be exposed to PAE through inhalation, ingestion, dermal absorption, or contact with medical devices. Approximately 70% of the oral dose is excreted in urine. Urinary monoesters are the major urinary metabolites of PAEs and commonly used as internal exposure indexes. Infants and children are more prone to expose to certain PAE than adolescents and adults due to their hand-to-mouth behavior. Adverse effects of PAE exposure have been observed in human studies, and verified in animal experiments. Prenatal PAE exposure is related to decreased levels of testosterone (TT), free TT, progesterone, triiodothyronine, and thyroxine in children. PAE exposure is also associated with developing allergic disease and obesity, decreasing intelligence quotient scores, and affecting psychological behaviors and renal function in children. Higher PAE exposure is also associated with endometriosis, leiomyoma, spontaneous abortion, fertility, and breast cancer in women and semen quality in men. More data are necessary for cancers of the breast, endometrial tissue, ovary, and/or prostate to understand the potential risk related to sex hormone sensitive neoplasms. In summary, phthalates exposure was found to be associated with various adverse effects related to altered functions of systems including the endocrine, immune, nervous, and reproduction, particularly at critical development windows during fetal, fast growing, and pubertal stages. Future research is directed to multiple generation approach in humans and/or testing animals, and considerations of psychological parameters (i.e., stress) to provide a further wide observational window for the conclusion.

Endocrine-Distributing Chemicals and Reproductive Function

Chapter

Dec 2019

Exposures to environmental chemicals affecting androgen action (endocrine-disrupting chemicals (EDCs)) are suspected to have a negative impact on male reproductive function by disrupting normal differentiation and development. In this chapter, the literature on the impact of exposure to endocrine-disrupting chemicals on male reproduction will be reviewed. We will specifically address the effects of exposure to organochlorine compounds, perfluorinated alkylate substances (PFAS), phthalates, and phenols on anogenital distance, reproductive hormones in childhood, puberty onset, and semen quality, focusing on prenatal or early exposures during vulnerable time points of development. Generally, anogenital distance (AGD) appears to be a promising, easily obtainable marker of male reproductive health. Maternal exposure to phthalates has consistently been associated with shorter AGD in male offspring, but no consistent associations between PFAS or bisphenol A exposure and AGD have been found. Prenatal exposure to organochlorine pesticides (OCPs) appears to lower children’s testosterone concentrations and increase aromatase activity after birth. In addition, prenatal exposure to dioxins and OCPs may delay puberty, whereas exposure to polychlorinated biphenyls (PCBs) accelerates the onset of puberty in boys. Maternal, childhood, or adult phthalate exposure has been associated with lower reproductive hormone concentrations, changed onset of puberty and semen quality. No consistent associations between PFAS or phenol exposure and AGD, reproductive hormones, puberty onset, or semen quality have been found. We suggest that more research is urgently needed focusing on birth cohort studies addressing the adverse effects of exposures during vulnerable time windows during development, e.g., in utero, during early childhood, and puberty. The cohorts should have the necessary size, include biological material, focus on multiple exposures, and have long-term follow-up with repeated clinical examinations.

Prenatal and childhood phthalate exposure and attention deficit hyperactivity disorder traits in child temperament: A 12-year follow-up birth cohort study

Article

Aug 2019
SCI TOTAL ENVIRON

Temperamental tendencies may form the basis of personality development, and specific personality constellations are associated with increased incidences of behavioural problems. Phthalic acid ester (PAE) has been associated with symptoms of attention deficit hyperactivity disorder (ADHD) in cross-sectional studies. We hypothesised that early-life exposure to PAE affects the temperaments of children, particularly ADHD traits. In this study, we analysed the temperament evaluations completed at least once by maternal-infant pairs (n = 208) when the child was aged 2, 5, and/or 11 years between 2000 and 2012. We measured seven PAE metabolites in the urine of the mothers during pregnancy and their children using liquid chromatography-electrospray ionisation-tandem mass spectrometry. These metabolites included mono-methyl phthalate, mono-ethyl phthalate, mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), and three metabolites of di (2-ethylhexyl) phthalate. The phthalate metabolite levels in pregnant women were significantly associated with a decreased threshold of responsiveness (coefficients from -0.21 to -0.46) and increased distractibility (coefficients from 0.23 to 0.46) in pre-school children. After adjustment for maternal exposure, the phthalate metabolite concentrations of the children exhibited significantly increased odds ratios (ORs) with respect to the ADHD symptom traits. Specifically, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), the sum of the DEHP metabolites, and MBzP yielded ORs and 95% confidence intervals of 2.98 (1.05-8.48), 3.28 (1.15-9.35), and 9.12 (1.07-78.06), respectively, for every log10 creatinine unit (g/g creatinine) increase. Thus, early-life phthalate exposure was found to be associated with the behavioural characteristics of children, particularly temperamental traits associated with ADHD.

Fetal growth in environmental epidemiology: Mechanisms, limitations, and a review of associations with biomarkers of non-persistent chemical exposures during pregnancy

Article

Full-text available

May 2019
ENVIRON HEALTH-GLOB

Background: Non-persistent chemicals, such as phthalates, environmental phenols, organophosphate pesticides, and others, are challenging to study because of their ubiquity in the environment, diverse exposure routes, and high temporal variability of biomarkers. Nonetheless, there is interest in understanding how gestational exposure to these chemicals may affect fetal growth, as perturbations to normal fetal growth are related to a plethora of adverse health outcomes in childhood and adulthood. Methods: The purpose of this review is to describe the state of the science on this topic. We searched PubMed for studies that included both 1) biomarkers of non-persistent chemicals collected during pregnancy and 2) fetal growth outcomes measured at birth (e.g., birth weight) or by ultrasound in utero (e.g., estimated fetal weight). Results: The bulk of the literature we found uses biomarkers measured at a single time point in pregnancy and birth weight as the primary measure of fetal growth. There is a small, but growing, body of research that uses ultrasound measures to assess fetal growth during pregnancy. In addition to summarizing the findings of the publications we identified, we describe inconsistencies in methodology, areas for improvement, and gaps in existing knowledge that can be targeted for improvement in future work. This literature is characterized by variability in methodology, likely contributing to the inconsistency of results reported. We further discuss maternal, placental, and fetal pathways by which these classes of chemicals may affect fetal growth. Conclusions: To improve understanding of how everyday chemical exposures affect fetal growth, and ultimately lifelong health outcomes, mechanisms of toxicant action should be considered alongside improved study designs for future hypothesis-driven research.

Nutritional Changes to Improve Female Fertility: Role of Obesity, Hormones, Dietary Patterns and Endocrine Disrupting Chemicals

Article

Jan 2025
OBSTET GYNECOL SURV

Importance Infertility affects around 180 million people in the world and can be influenced by a number of nutritional factors. Objective The idea of a pretreatment optimization including beneficial weight loss, adequate physical activity, and good lifestyle habits could enhance fertility for many couples who want to conceive a baby. Results There are different aspects related to nutrition, such as obesity (affecting 23%–30% of reproductive-aged women), dietary patterns (type of diet, good or bad habits, and physical activity), nutrients (vitamins or minerals), hormones (adipokines, among others), and endocrine-disrupting chemicals (phytoestrogens and bisphenol A, among others) that have a clear impact on women’s fertility. Evidence Acquisition Findings have shown that a Mediterranean or balanced diet with an adequate weight loss in case of obesity and an appropriate serum concentration of different nutrients with low endocrine-disrupting exposure could improve female fertility. In addition, the context is quite important, as there are many differences between overweight and low-weight women, and both can encounter difficulties conceiving. Conclusions and Relevance The aim of this review is to elucidate the impact of obesity and hormones in women’s fertility. In addition, how dietary patterns could help people to increase probability of conception and birth using less fertility treatments cycles will be also analyzed. Moreover, the role of endocrine-disrupting chemicals, pollutants, and contaminants will be discussed. Target Audience Obstetricians and gynecologists, family physicians. Learning objectives After completing this activity, the learner will be better able to discuss how obesity and hormones impact fertility; explain the role of dietary patterns regarding conception and birth; and describe the effect of endocrine-disrupting chemicals, pollutants, and contaminants.

DEHP-mediated oxidative stress leads to impaired testosterone synthesis in Leydig cells through the cAMP/PKA/SF-1/StAR pathway

Article

Dec 2024
ENVIRON POLLUT

Temporal and Geographic Variability of Urinary Phthalates Metabolite Levels in Humans: A Systematic Review and Meta-Analysis of International Biomonitoring Data

Preprint

Full-text available

Nov 2024

Phthalates are endocrine-disrupting chemicals (EDCs) that alter hormone functions throughout the lifespan. Growing awareness of the adverse health effects of phthalate exposure has led to regulating certain phthalates in the United States, Canada, and Europe. However, international comparisons of urinary phthalate metabolite concentrations as biomarkers of exposure are sparse, and few studies have controlled for cohort-specific variables like pregnancy. We aimed to examine trends in urinary phthalate monoester metabolite concentrations in non-occupationally exposed populations globally, excluding locations where representative data are already available at the country level. We systematically reviewed studies published between 2000 and 2023 that reported urinary phthalate monoester concentrations. We examined changes in metabolite concentrations across time, controlling for region, age, and pregnancy status, using mixed-effects meta-regression models with and without a quadratic term for time. We identified heterogeneity using Cochran's Q-statistic and I2 index, adjusting for it with the trim-and-fill method. The final analytic sample consisted of 216 studies. Significant differences in phthalate metabolite concentrations were observed across regions, age groups, and between pregnant and non-pregnant cohorts. Our meta-regression identified a significant non-linear trend with time for Mono-n-butyl phthalate and Mono-isononyl phthalate concentration internationally and in Eastern and Pacific Asia (EPA). We also observed significant non-linear associations between time and Mono(2-ethyl-5-hydroxyhexyl) phthalate, Mono(2-carboxymethylhexyl) phthalate, and Mono(3-carboxypropyl) phthalate concentration internationally and/or in EPA, along with Mono(2-ethylhexyl) phthalate, Mono-carboxy-isononyl phthalate, and Mono-ethyl phthalate. Additionally, Mono-ethyl phthalate concentration showed a significant negative linear association with time in Latin America and Africa. Heterogeneity was high, indicating potential bias in our results. Our findings indicate the need for increased awareness of phthalate exposure. Further analysis of the attributable disease burden and cost at regional and international levels, especially in low- and middle-income countries, is essential to understanding these and other EDCs impact on population health and the economy.

Associations between mycoestrogen exposure and sex steroid hormone concentrations in maternal serum and cord blood in the UPSIDE pregnancy cohort

Article

Full-text available

Jun 2024

Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet. Because the chemical structure of ZEN and metabolites closely resembles 17β-estradiol (E2), they interact with estrogen receptors α/β earning their designation as ‘mycoestrogens’. In animal models, gestational exposure to mycoestrogens disrupts estrogen activity and impairs fetal growth. Here, our objective was to evaluate relationships between mycoestrogen exposure and sex steroid hormone concentrations in maternal circulation and cord blood for the first time in humans. In each trimester, pregnant participants in the UPSIDE study (n = 297) provided urine for mycoestrogen analysis and serum for hormone analysis. At birth, placental mycoestrogens and cord steroids were measured. We fitted longitudinal models examining log-transformed mycoestrogen concentrations in relation to log-transformed hormones, adjusting for covariates. Secondarily, multivariable linear models examined associations at each time point (1st, 2nd, 3rd trimesters, delivery). We additionally considered effect modification by fetal sex. ZEN and its metabolite, α-zearalenol (α-ZOL), were detected in >93% and >75% of urine samples; >80% of placentas had detectable mycoestrogens. Longitudinal models from the full cohort exhibited few significant associations. In sex-stratified analyses, in pregnancies with male fetuses, estrone (E1) and free testosterone (fT) were inversely associated with ZEN (E1 %Δ: −6.68 95%CI: −12.34, −0.65; fT %Δ: −3.22 95%CI: −5.68, −0.70); while α-ZOL was positively associated with E2 (%Δ: 5.61 95%CI: −1.54, 9.85) in pregnancies with female fetuses. In analysis with cord hormones, urinary mycoestrogens were inversely associated with androstenedione (%Δ: 9.15 95%CI: 14.64, −3.30) in both sexes, and placental mycoestrogens were positively associated with cord fT (%Δ: 37.13, 95%CI: 4.86, 79.34) amongst male offspring. Findings support the hypothesis that mycoestrogens act as endocrine disruptors in humans, as in animal models and livestock. Additional work is needed to understand impacts on maternal and child health.

Endocrine Disruptors

Chapter

Dec 2023

Endocrine disruption is a relatively new field of study, as endocrine disruptors were not formally acknowledged by regulatory agencies until 1996. Over the years, many federal and international regulatory agencies and professional associations have provided varying terminology and classifications; however, in general, exposure to endocrine disruptors, or endocrine‐disrupting chemicals (EDCs), at environmentally relevant doses results in adverse effects consequent to interfering with endocrine function. Apart from minor nomenclature disagreements, there are challenges and limitations to this field, as EDC classification criteria can vary substantially in considering evidence for a biologically plausible causal relationship between the endocrine activity and the induced adverse effect. Accordingly, international consensus for unambiguous designation of EDCs is lacking. Therefore, this chapter will not attempt to resoundingly identify all known or suspected EDCs; rather, the objective of this chapter is to first provide historical context to chemical regulation, including on endocrine disruption and its development as a field, and then follow with a review of the health implications, which highlights some fundamental concepts of endocrine disruption and incorporates a tale of the infamous public health disaster resulting from prescribing pregnant women diethylstilbestrol (DES), a potent synthetic estrogen. The current testing guidelines and standards for EDCs are also reviewed, demonstrating the restricted focus on canonical endocrine disruption that is characterized by nuclear hormone receptor‐based activity and the estrogenic, androgenic, thyroidal, and steroidogenic (EATS) modalities. To end, some of the more recently regulated EDCs, particularly bisphenol A and phthalates, as well as other ubiquitous EDCs, like phytoestrogens and flame retardants, are reviewed.

Plastic packaging-associated chemicals and their hazards – An overview of reviews

Article

Apr 2023
CHEMOSPHERE

Plastic packaging contains residues from substances used during manufacturing, such as solvents, along with non-intentionally added substances (NIAS), such as impurities, oligomers, or degradation products. By searching peer-reviewed literature, we found that at least 10,259 chemicals were related to plastic packaging materials, which include chemicals used during manufacturing and/or present in final packaging items. We then summarized and discussed their chemical structures, analytical instruments, migration characteristics, and hazard categories where possible. For plastic packaging chemicals, examination of the literature reveals gas and liquid chromatography hyphenated to a variety of accurate mass analyzers based on the use of high-resolution mass spectrometry is usually used for the identification of unknown migrants coming from plastic packaging. Chemical migration from food packaging is affected by several parameters, including the nature and complexity of the food, contact time, temperature of the system, type of packaging contact layer, and properties of the migrants. A review of the literature reveals that information on adverse effects is only available for approximately 1600 substances. Among them, it appears that additives are more toxic than monomers to wildlife and humans. Neurotoxicity accounted for the highest proportion of toxicity of all types of chemicals, while benzenoids, organic acids, and derivatives were the most toxic types of chemicals. Furthermore, studies have demonstrated that hydrocarbon derivatives, organic nitrogen compounds, and organometallic compounds have the highest proportions of dermatotoxicity, and organohalogen compounds have the highest proportions of hepatotoxicity. The main contributors to skin sensitization are organic salts. This study provides a basis for comprehensively publicizing information on chemicals in plastics, and could be helpful to better understand their potential risks to the environment and humans.

Effect of dust formation on the fate of indoor phthalates: Model analysis

Article

Dec 2022
BUILD ENVIRON

The effect of phthalates exposure during pregnancy on asthma in infants aged 0 to 36 months: a birth cohort study

Article

Full-text available

Jun 2022
ENVIRON GEOCHEM HLTH

This cohort study sought to investigate the effects of phthalates exposure during pregnancy on offspring asthma and its association with placental stress and inflammatory factor mRNA expression levels. A total of 3474 pregnant women from the China Ma’anshan birth cohort participated in this study. Seven phthalate metabolites were detected in urine samples during pregnancy by solid phase extraction–high-performance liquid chromatography tandem mass spectrometry. Placenta stress and inflammation mRNA expression were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Early pregnancy may be the critical period when phthalates exposure increases the risk of asthma in infants and young children, and there is a certain gender difference in the risk of asthma in infants and young children. Moreover, through the placenta stress and inflammatory factor associated with infant asthma found anti-inflammatory factor of interleukin-10 (IL-10) mRNA expression will reduce the risk of 36-month-old male infant asthma. The expression of interleukin-4(IL-4) and macrophage (M2) biomarker cluster of differentiation 206(CD206) mRNA reduced the risk of asthma in 18-month-old female infants. Placental stress and inflammatory response were analyzed using mediating effects. Tumor necrosis factor-α (TNFα) showed a complete mediating effect between mono-benzyl phthalate (MBzP) exposure in early pregnancy and asthma in 12-month-old males, and IL-10 also showed a complete mediating effect between mono-n-butyl phthalate (MBP) exposure in early and late pregnancy and asthma in 36-month-old males. In summary, exposure to phthalates during pregnancy may contribute to the development of asthma in infants, which may be associated with placental stress and inflammation.

Prenatal Exposure to Emerging Plasticizers and Synthetic Antioxidants and Their Potency to Cross Human Placenta

Article

Jun 2022

Gestational exposure to environmental chemicals and subsequent permeation through the placental barrier represents potential health risks to both pregnant women and their fetuses. In the present study, we explored prenatal exposure to a suite of 46 emerging plasticizers and synthetic antioxidants (including five transformation products of 2,6-di-tert-butyl-4-hydroxytoluene, BHT) and their potency to cross human placenta based on a total of 109 maternal and cord serum pairs. Most of these chemicals have rarely or never been investigated for prenatal exposure and associated health risks. Eleven of them exhibited detection frequency greater than 50% in maternal blood, including dibutyl fumarate (DBF), 2,6-di-tert-butylphenol (2,4-DtBP), 1,3-diphenylguanidine (DPG), methyl-2-(benzoyl)benzoate (MBB), triethyl citrate (TEC), BHT, and its five metabolites, with a median concentration from 0.05 to 3.1 ng/mL. The transplacental transfer efficiency (TTE) was determined for selected chemicals with valid measurements in more than 10 maternal/cord blood pairs, and the mean TTEs exhibited a large variation (i.e., 0.29-2.14) between chemicals. The determined TTEs for some of the target chemicals were comparable to the predicted values by our previously proposed models developed from molecular descriptors, indicating that their transplacental transfer potency could be largely affected by physicochemical properties and molecular structures. However, additional biological and physiological factors may influence the potency of environmental chemicals to cross human placenta. Overall, our study findings raise concern on human exposure to an increasing list of plastic additives during critical life stages (e.g., pregnancy) and potential health risks.

Environmental Phthalate Exposure in Relation to Reproduction Outcomes and Health Endpoints

Chapter

May 2022

Environmental pollutants, like xenobiotic substances released as byproducts of anthropogenic actions, naturally lead to pollution of the environment. They negatively affect the environment through unfavorable impacts on growth, development, and reproduction of organisms including humans. One of the outstanding examples of xenobiotics is endocrine disrupting compounds (EDCs) such as phthalate esters (PEs), which have the efficacy to disturb numerous biological systems including the invertebrate, reptilian, avian, aquatic, and also the mammalian systems. Phthalates are family of xenobiotic hazardous compounds amalgamating in plastics to intensify their plasticity, flexibility, longevity, versatility, and durability. Ignoring the rising issue on the hazardous nature of various phthalates and their metabolites, ruthless usage of phthalates as plasticizer in plastics and as additives in innumerable consumer products continues due to their low eminent properties, their cost-effectiveness, and lack of suitable alternatives. Globally epidemiological human studies showed various phthalates and their metabolites ingested passively by man from the general environment, foods, drinks, breathing air, and routine household products cause various dysfunctions. This comprehensive chapter on the hazards of phthalates would benefit the general population, academia, scientists, clinicians, environmentalists, and law or policymakers to decide upon whether usage of phthalates to be continued swiftly without sufficient deceleration or regulated by law or to be phased out from earth forever.

The mediating role of plasma microRNAs in the association of phthalates exposure with arterial stiffness: A panel study

Article

May 2022
ENVIRON RES

Phthalates exposure has been reported to be linked with arterial stiffness. However, the biological mechanisms underlying this association remain unclear. We conducted a panel study using 338 paired urine-blood samples by repeated measurements of 123 adults across 3 seasons to assess the potential mediating role of plasma microRNAs (miRNAs) in the association of phthalates exposure with arterial stiffness. We measured 10 urinary phthalate metabolites by gas chromatography-tandem mass spectrometry (GC-MS/MS) and 5 candidate arterial stiffness-related miRNAs (miR-146a, miR-222, miR-125 b, miR-126, and miR-21) in plasma by real-time PCR. Arterial stiffness parameters including brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) were determined in health examinations during each visit. Linear mixed-effect (LME) models revealed that mono-methyl phthalate (MMP), mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MBP), mono-n-octyl phthalate (MOP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) were significantly associated with one or more of the 5 plasma miRNAs (all P FDR < 0.05). Based on weighted quantile sum (WQS) regression, we found positive associations of phthalate metabolites mixture with miR-146a, miR-125 b, and miR-222, and individual MMP and MBP were the major contributors. Additionally, miR-146a was inversely related to ABI. Mediation analysis further indicated that miR-146a mediated 31.6% and 21.3% of the relationships of MMP and MiBP with ABI, respectively. Our findings suggested that certain phthalates exposure was related to plasma miRNAs alterations in a dose-response manner and miR-146a might partly mediate phthalate-associated ABI reduction.

Simultaneous determination of eight β-adrenergic agonists in human urine by an isotope dilution-online clean-up system coupled with liquid chromatography-tandem mass spectrometry

Article

Apr 2022
CHEMOSPHERE

β-Adrenergic agonist compounds are medicines that open up the lung's medium and large airways. β-Adrenergic agonist compounds have been illegally or legally used to increase lean muscle mass in meat animals, bodybuilding, weight-loss programs, and athletes. Developing a rapid analytical approach for determining β-adrenergic agonist compounds in biological samples is crucial for individual exposure assessment. This study established an analytical method for simultaneously measuring eight β-adrenergic agonist compounds in human urine, including clenbuterol, terbutaline, salbutamol, ractopamine, zilpaterol, cimaterol, tulobuterol, and fenoterol. Two hundred microliters of a urine sample were added to eight deuterium-labeled internal standard mixtures and glucuronidase/arylsulfatase for enzymatic hydrolysis, and were then analyzed using an online clean-up system coupled with a liquid chromatography-tandem mass spectrometry system (LC–MS/MS). The limit of quantiﬁcation ranged from 0.03 to 0.12 ng/mL urine for the eight β-adrenergic agonist compounds. The relative standard deviations (RSD) of the within-run and between-run precisions were less than 10%, and the relative accuracy errors were less than 17% in the three-level spiked artiﬁcial urine samples. Two hundred eighty human urine samples collected from the general population in Taiwan were assessed to demonstrate the capability and feasibility of this method. The detection frequencies were 33% for clenbuterol, 5% for ractopamine, and less than 5% for the others. We concluded that the isotope dilution-online clean-up system coupled with LC–MS/MS method is a valuable analytical method for investigating urinary β-adrenergic agonist compounds in humans and is valuable for human biomonitoring studies.

Exploration of long-term exposure markers for phthalate esters in human hair using liquid chromatography-tandem mass spectrometry

Article

Feb 2022
ANAL CHIM ACTA

Phthalate esters are a group of synthetic industrial chemicals that are widely used in plastics. Urinary phthalate metabolites are short-term exposure markers frequently used to represent exposure levels in environmental epidemiology studies. Human hair is an alternative matrix for recording long-term exposure, but there are still analytical challenges that need to be addressed. In this study, an analytical method was established for simultaneously measuring nine major phthalate metabolites in human hair and successfully applied to measure phthalate metabolites in 30 hair samples collected from 30 individual human volunteers without known occupational exposure to phthalates. Two portions of 25 mg of hair samples were extracted by acidified methanol and water in 240 min of ultrasonication and then analyzed using a liquid chromatography-tandem mass spectrometry system. The limit of quantification ranged from 0.72 to 10.7 ng/g hair for nine phthalate metabolites. All nine phthalate metabolites were detected in more than 70% of the 30 individual human hair samples. The measured levels of hair phthalate metabolites were (in descending order): MEHP > MMP ≫ MEP > MBP (MnBP + MiBP) > MiNP > MEHHP ≈ MEOHP ≈ MECPP. The primary metabolite, MEHP (692 ± 582 ng/g), is the major DEHP metabolite in hair. This result is consistent with the findings in blood but not in urine, in which the secondary metabolites are the major DEHP metabolites. This method is easy to foresee with a clinical application and applies to human biomonitoring studies to assess long-term environmental phthalate exposure.

Endocrine-Disrupting Chemicals and Child Health

Article

Jan 2022

While definitions vary, endocrine-disrupting chemicals (EDCs) have two fundamental features: their disruption of hormone function and their contribution to disease and disability. The unique vulnerability of children to low-level EDC exposures has eroded the notion that only the dose makes the thing a poison, requiring a paradigm shift in scientific and policy practice. In this review, we discuss the unique vulnerability of children as early as fetal life and provide an overview of epidemiological studies on programming effects of EDCs on neuronal, metabolic, and immune pathways as well as on endocrine, reproductive, and renal systems. Building on this accumulating evidence, we dispel and address existing myths about the health effects of EDCs with examples from child health research. Finally, we provide a list of effective actions to reduce exposure, and subsequent harm that are applicable to individuals, communities, and policy-makers. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Associations of prenatal exposure to phthalates and one phthalate substitute with anthropometric measures in early life: Results from the German LIFE Child cohort study

Article

May 2021
BEST PRACT RES CL EN

Exposure to phthalates is widespread and especially early life stages represent a critical window of exposure. In the present study, we investigated the effect of prenatal exposure to phthalates on birth outcomes and weight development in early life. In 130 mother-child pairs, we estimated the association of concentrations of 13 phthalates in spot-urine samples collected during pregnancy and birth outcomes and weight gain in the first two years of life using robust linear regression. High molecular weight phthalates were inversely associated with birth weight in girls but not in boys. Thus, prenatal exposure to phthalates may affect birth weight in a sex-specific manner.

Trimester-specific and sex-specific effects of prenatal exposure to di(2-ethylhexyl) phthalate on fetal growth, birth size, and early-childhood growth: A longitudinal prospective cohort study

Article

Feb 2021
SCI TOTAL ENVIRON

Prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) may cause adverse health outcomes. However, trimester-specific impacts of DEHP exposure on offspring growth from fetal to early childhood stage have not been thoroughly evaluated. In this sudy, participants who provided a full series of urine spicemens at three trimesters were selected from a birth cohort conducted at Wuhan, China from 2014 to 2015. 814 mother-offspring pairs were included in the study. Urinary concentrations of DEHP metabolites were determined using liquid chromatography-tandem mass spectrometry. Z-scores for ultrasound-measured fetal growth parameters at 14.0–18.9, 22.6–27.0, and 29.0–33.9 weeks of gestation, were caculated. Weight, height, and body mass index (BMI) at 6, 12, and 24 months were standardized to z-scores using sex-specific and age-specific WHO child growth standards. Linear regressions with generalized estimating equations were used to assess the relationships of DEHP levels per trimester to fetal growth, birth size, and growth at 6, 12, and 24 months to explore the trimester-specific impacts of DEHP exposure on offspring development. Among males, the1st-trimester DEHP was negatively related to fetal growth (β < 0, p < 0.05), but positively related to 24-month BMI. The 2nd-trimester DEHP was negatively related to birth weight and birth length, but positively related to weight gain rates from birth to 24 months old. The 3rd-trimester DEHP was positively (β > 0, p < 0.05) associated with birth weight and BMI at 6 and 12 months. Among females, the 1st-trimester DEHP was associated with increased birth length, while the 2nd-trimester DEHP was negatively associated with BMI at 6 and 12 months. A negative association between DEHP and weight gain rates at 6 months was noted among females. This prospective cohort revealed the sex-specific and trimester-specific relationships of DEHP exposure to offspring growth from fetal to early-childhood stage.

Effects and Mechanisms of Phthalates' Action on Reproductive Processes and Reproductive Health: A Literature Review

Article

Full-text available

Sep 2020
Int J Environ Res Publ Health

The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.

Prenatal Exposure to a Phthalate Mixture Leads to Multigenerational and Transgenerational Effects on Uterine Morphology and Function in Mice

Article

Feb 2020
REPROD TOXICOL

Phthalates are commonly used plasticizers and additives that are found in plastic containers, children’s toys and medical equipment. Phthalates are classified as endocrine-disrupting chemicals and exposure to phthalates has been associated with several human health risks including reproductive defects. Most studies focus on a single phthalate; however, humans are exposed to a mixture of phthalates daily. We hypothesized that prenatal exposure to an environmentally relevant phthalate mixture would lead to changes in uterine morphology and function in mice in a multi-generational manner. To test this hypothesis, pregnant CD-1 dams were orally dosed with vehicle or a phthalate mixture (20 μg/kg/day, 200 μg/kg/day, 200 mg/kg/day, and 500 mg/kg/day) from gestational day 10.5 to parturition. The mixture contained 35% diethyl phthalate, 21% di-(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. The F1 pups were maintained and mated to produce two more generations (F2 and F3). At the age of 13 months, all females were euthanized and tissue samples were collected in diestrus. Our results showed that exposure to a phthalate mixture caused a decrease in progesterone levels in the treated groups in the F2 generation. The 200 mg/kg/day treatment group showed a decreased and increased luminal epithelial cell proliferation in the F1 and F2 generations respectively. In addition, these mice in the F2 generation had reduced Hand2 expression in the sub-epithelial stroma compared to the controls. A higher incidence of multilayered luminal epithelium and large dilated endometrial glands were observed in the phthalate mixture exposed groups in all generations. The mixture also caused a higher incidence of smooth muscle actin expression and collagen deposition in the endometrium compared to controls. Collectively, our results demonstrate that prenatal exposure to an environmentally relevant phthalate mixture can have adverse effects on female reproductive functions.

Strategies employed by viruses to manipulate autophagy

Chapter

Jan 2020

Autophagy, originally described as a conserved bulk degradation pathway important to maintain cellular homeostasis during starvation, has also been implicated in playing a central role in multiple physiological processes. For example, autophagy is part of our innate immunity by targeting intracellular pathogens to lysosomes for degradation in a process called xenophagy. Coevolution and adaptation between viruses and autophagy have armed viruses with a multitude of strategies to counteract the antiviral functions of the autophagy pathway. In addition, some viruses have acquired mechanisms to exploit specific functions of either autophagy or the key components of this process, the autophagy-related (ATG) proteins, to promote viral replication and pathogenesis. In this chapter, we describe several examples where the strategy employed by a virus to subvert autophagy has been described with molecular detail. Their stratagems positively or negatively target practically all the steps of autophagy, including the signaling pathways regulating this process. This highlights the intricate relationship between autophagy and viruses and how by commandeering autophagy, viruses have devised ways to fine-tune their replication.

Plasticizer Exposure and Reproductive Health: Phthalates and Bisphenol A

Chapter

Nov 2019

Phthalates and bisphenol A are among the most popular plasticizers used today, which are ubiquitous environmental chemical pollutants with endocrine disruption. In this chapter, we summarize the basic characteristics of phthalates and bisphenol A and their effects on male and female reproductive health. We focus on the effects of phthalates exposure on testosterone level, anogenital distance, semen quality and hypospadias incidence in the male, as well as on precocious puberty, endometriosis, abnormalities of pregnancy in the female. Moreover, the effects of bisphenol A exposure on male semen quality, reproductive cells, sex hormones and female steroid hormone levels, reproductive organ diseases, and adverse birth outcomes are discussed. Results indicate that exposure to phthalates and bisphenol can adversely affect male and female reproductive health. However, evidence is still controversial. More large-scale prospective cohort studies are needed to verify the effects of plasticizer exposure on reproductive health in humans.

Prenatal and ancestral exposure to di(2-ethylhexyl) phthalate alters gene expression and DNA methylation in mouse ovaries

Article

Jun 2019

Di(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer and known endocrine disrupting chemical, which causes transgenerational reproductive toxicity in female rodents. However, the mechanisms of action underlying the transgenerational toxicity of DEHP are not understood. Therefore, this study determined the effects of prenatal and ancestral DEHP exposure on various ovarian pathways in the F1, F2, and F3 generations of mice. Pregnant CD-1 dams were orally exposed to corn oil (vehicle control) or DEHP (20 μg/kg/day-750 mg/kg/day) from gestation day 10.5 until birth. At postnatal day 21 for all generations, ovaries were removed for gene expression analysis of various ovarian pathways and for 5-methyl cytosine (5-mC) quantification. In the F1 generation, prenatal DEHP exposure disrupted the expression of cell cycle regulators, the expression of peroxisome-proliferator activating receptors, and the percentage of 5-mC compared to control. In the F2 generation, exposure to DEHP decreased the expression of steroidogenic enzymes, apoptosis factors, and ten-eleven translocation compared to controls. It also dysregulated the expression of phosphoinositide 3-kinase (PI3K) factors. In the F3 generation, ancestral DEHP exposure decreased the expression of steroidogenic enzymes, PI3K factors, cell cycle regulators, apoptosis factors, Esr2, DNA methylation mediators, and the percentage of 5-mC compared to controls. Overall, the data show that prenatal and ancestral DEHP exposure greatly suppress gene expression of pathways required for folliculogenesis and steroidogenesis in the ovary in a transgenerational manner and that gene expression may be influenced by DNA methylation. These results provide insight into some of the mechanisms of DEHP-mediated toxicity in the ovary across generations.

Title: Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: Altered fetal steroid hormones and genes. Running title: Dose additive effects of two phthalates

Article

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Association between phthalate exposure and glutathione S-transferase M1 polymorphism in adenomyosis, leiomyoma and endometriosis

Article

Full-text available

Feb 2010
HUM REPROD

Phthalates are known to have estrogenic effects in cell models and experimental animals. However, the evidence regarding the effects of phthalates on human reproduction is still limited. We conducted a case-control study to determine whether estrogen-dependent diseases are associated with phthalate exposure and how the glutathione S-transferase M1 (GSTM1; a major detoxification enzyme) genotype modulates the risk. We recruited subjects who underwent laparotomy and had pathologic confirmation of endometriosis (EN) (n = 28), adenomyosis (AD) (n = 16) and leiomyoma (LEI) (n = 36) from the Department of Obstetrics and Gynecology at a medical center in Taiwan between 2005 and 2007. Controls (n = 29) were patients without any of the three aforementioned gynecologic conditions. Urine samples were collected before surgery and analyzed for seven phthalate metabolites using liquid chromatography-tandem mass spectrometry. Peripheral lymphocytes were used for GSTM1 genotype determination. Patients with LEIs had significantly higher levels of total urinary mono-ethylhexyl phthalate (SigmaMEHP; 52.1 versus 18.9 microg/g creatinine, P < 0.05) than the controls, whereas patients with EN had an increased level of urinary mono-n-butyl phthalate (94.1 versus 58.0 microg/g creatinine, P < 0.05). Subjects with GSTM1 null genotype had significantly increased odds for AD relative to those with GSTM1 wild genotype [odds ratio (OR) = 5.30; 95% CI, 1.22-23.1], even after adjustment for age and phthalate exposure. Subjects who carried the GSTM1 null genotype and had a high urinary level of SigmaMEHP showed a significantly increased risk for AD (OR = 10.4; 95% CI, 1.26-85.0) and LEIs (OR = 5.93; 95% CI, 1.10-31.9) after adjustment for age, compared with those with GSTM1 wild-type and low urinary level of SigmaMEHP. These results suggest that both GSTM1 null and phthalate exposure are associated with AD and LEI. Larger studies are warranted to investigate potential interaction between GSTM1 null and phthalate exposure in the etiology of estrogen-dependent gynecologic conditions.

Phthalate Exposure in Girls During Early Puberty

Article

Full-text available

Feb 2009

The aim of this study was to determine the levels of phthalate ester metabolites in girls in early puberty, and the associated environmental factors for phthalate exposure. A case-control study was conducted in which we recruited girls in early puberty, including 30 girls with premature thelarche (PT) and 26 with central precocious puberty (CPP), and 33 normal controls. The mean urine levels of monomethyl phthalate (MMP) were significantly higher in the PT group (96.5 +/- 134.0 ng/ml) than in the control group (26.4 +/- 30.0 ng/ml; p = 0.005). The levels of monobutyl phthalate (MBuP) correlated with the intake of seafood, drink and the use of plastic cups. The levels of mono-(2-ethylhexyl) phthalate (MEHP) correlated with the intake of seafood and meat and exposure plastic handi-wrap. Significantly higher MMP in the PT girls revealed that phthalate may be one of the environmental causes of early puberty in Taiwanese girls.

Abnormalities of Sexual Development in Male Rats with in Utero and Lactational Exposure to the Antiandrogenic Plasticizer Di(2-Ethylhexyl) Phthalate

Article

Full-text available

Apr 2001

Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP), on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens.

Correlation of serum hormone concentrations in maternal and umbilical cord samples

Article

Full-text available

Jun 2003

Evidence suggests that adult cancer risk of hormonally related tumors may be influenced by the in utero environment, and most speculation on the biological mechanism has focused on the hormonal component. Epidemiological studies investigating the biological nature of pregnancy and maternal factors associated with offspring's cancer risk have relied on maternal hormone measurements. The degree to which maternal hormone levels represent the fetal environment, however, is not widely known. Pregnancy estrogen, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate concentrations were measured in maternal and mixed umbilical cord sera from 86 singleton pregnancies. Spearman correlations between maternal and cord hormone levels generally ranged between 0.2 and 0.3. The correlation was 0.26 for estriol, the estrogen of highest concentration in pregnancy, and 0.27 for estradiol, the most biologically active estrogen. The correlations between mother and offspring for the estrogens and DHEA appeared similar for males and females, whereas there was a suggestion that the maternal-umbilical cord correlations for other androgens varied in magnitude by fetal sex, and all correlations appeared higher in pregnancies lasting <38 weeks compared with longer gestational lengths, although these stratified findings may have been attributable to chance. These data show a moderate degree of correlation in hormone concentrations between the maternal and fetal circulation. Studies using maternal hormone concentrations as a proxy for the fetal environment should consider the misclassification resulting with the use of this marker.

In Utero Exposure to Di-(2-ethylhexyl)phthalate and Duration of Human Pregnancy

Article

Full-text available

Dec 2003

Di-(2-ethylhexyl)phthalate (DEHP), the most commonly used plasticizer in flexible polyvinylchloride formulations, is a ubiquitous environmental contaminant. To date, no information exists on the potential health hazards from exposure to DEHP and/or its main metabolite, mono-(2-ethylhexyl)phthalate (MEHP), in high-risk conditions, such as pregnancy and during the neonatal period. The aim of this study was to evaluate prenatal exposure to DEHP and/or MEHP and its possible biologic effects. We measured serum DEHP and MEHP concentrations in the cord blood of 84 consecutive newborns by high-performance liquid chromatography. Relationships between DEHP/MEHP and infant characteristics were tested using Fisher's exact test, unpaired t-tests, and univariate linear regression analyses, and significant differences on univariate analysis were evaluated using multiple logistic regression analysis. We found detectable cord blood DEHP and/or MEHP concentrations in 88.1% of the samples. Either DEHP or MEHP was present in 65 of 84 (77.4%) of the examined samples. Mean concentrations of DEHP and MEHP were 1.19 +/- 1.15 microg/mL [95% confidence interval (CI), 0.93-1.44, range = 0-4.71] and 0.52 +/- 0.61 microg/mL (95% CI, 0.39-0.66, range = 0-2.94), respectively. MEHP-positive newborns showed a significantly lower gestational age compared with MEHP-negative infants (p = 0.033). Logistic regression analysis results indicated a positive correlation between absence of MEHP in cord blood and gestational age at delivery (odds ratio = 1.50, 95% CI, 1.013-2.21; p = 0.043). These findings confirm that human exposure to DEHP can begin in utero and suggest that phthalate exposure is significantly associated with a shorter pregnancy duration.

Prenatal Exposures to Phthalates among Women in New York City and Krakow, Poland

Article

Full-text available

Nov 2003

Experimental evidence has shown that certain phthalates can disrupt endocrine function and induce reproductive and developmental toxicity. However, few data are available on the extent of human exposure to phthalates during pregnancy. As part of the research being conducted by the Columbia Center for Children's Environmental Health, we have measured levels of phthalates in 48-hr personal air samples collected from parallel cohorts of pregnant women in New York, New York, (n = 30) and in Krakow, Poland (n = 30). Spot urine samples were collected during the same 48-hr period from the New York women (n = 25). The following four phthalates or their metabolites were measured in both personal air and urine: diethyl phthalate (DEP), dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), and butyl benzyl phthalate (BBzP). All were present in 100% of the air and urine samples. Ranges in personal air samples were as follows: DEP (0.26-7.12 microg/m3), DBP (0.11-14.76 microg/m3), DEHP (0.05-1.08 microg/m3), and BBzP (0.00-0.63 microg/m3). The mean personal air concentrations of DBP, di-isobutyl phthalate, and DEHP are higher in Krakow, whereas the mean personal air concentration of DEP is higher in New York. Statistically significant correlations between personal air and urinary levels were found for DEP and monoethyl phthalate (r = 0.42, p < 0.05), DBP and monobutyl phthalate (r = 0.58, p < 0.01), and BBzP and monobenzyl phthalate (r = 0.65, p < 0.01). These results demonstrate considerable phthalate exposures during pregnancy among women in these two cohorts and indicate that inhalation is an important route of exposure.

Di(n-Butyl) Phthalate Impairs Cholesterol Transport and Steroidogenesis in the Fetal Rat Testis through a Rapid and Reversible Mechanism

Article

Full-text available

Apr 2004

In utero exposure to di(n-butyl) phthalate (DBP) leads to a variety of male reproductive abnormalities similar to those caused by androgen receptor antagonists. DBP demonstrates no affinity for the androgen receptor, but rather leads to diminished testosterone production by the fetal testis. The purpose of this study was to determine the onset and reversibility of DBP effects on the fetal testis and to determine at a functional level the points in the cholesterol transport and steroidogenesis pathways affected by DBP. Starting at gestational day (gd) 12, pregnant rats were gavaged daily with 500 mg/kg DBP or corn oil control. Significant decreases in testosterone production and mRNA expression of scavenger receptor B1, P450(SCC), steroidogenic acute regulatory protein, and cytochrome p450c17 were observed as early as gd 17. Testosterone, mRNA, and protein levels remained low 24 h after withdrawal of DBP treatment but increased 48 h after cessation of DBP exposure. In another experiment, pregnant dams were treated with DBP until gd 19, with the start of DBP treatment moved 1 d later into gestation for each treatment group, with the final group dosed only on gd 19. Significant decreases in testosterone, mRNA expression, and protein expression were evident as early as 3 h after treatment with DBP, with full repression apparent 24 h after treatment. Using a testis explant system, we determined that DBP treatment led to diminished transport of cholesterol across the mitochondrial membrane as well as diminished function at each point in the testosterone biosynthesis pathway except 17 beta-hydroxysteroid dehydrogenase. The transcriptional repression caused by DBP does not appear to be mediated via interference with steroidogenic factor-1 as determined by reporter assays. We conclude that high-dose DBP exposure leads to rapid and reversible diminution of the expression of several proteins required for cholesterol transport and steroidogenesis in the fetal testis, resulting in decreased testosterone synthesis and consequent male reproductive maldevelopment.

Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure

Article

Full-text available

Sep 2005

Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2-36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02). We defined the anogenital index (AGI) as AGD divided by weight at examination [AGI = AGD/weight (mm/kg)] and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85). Urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP)] were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2). The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05). We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009). The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans.

In Utero Exposure to Dioxins and Polychlorinated Biphenyls and Its Relations to Thyroid Function and Growth Hormone in Newborns

Article

Full-text available

Nov 2005

The aim of this study is to examine the association between transplacental exposure to dioxins/polychlorinated biphenyls (PCBs) and thyroid and growth hormones in newborns. We recruited 118 pregnant women, between 25 and 34 years of age, at the obstetric clinic. Personal data collected included reproductive and medical histories and physical factors. Clinicians gathered placental and umbilical cord serum upon delivery and carefully scored the 118 newborns, making both structural and functional assessments. We analyzed placentas for 17 polychlorinated dibenzo-p-dioxins and dibenzofurans and 12 dioxin-like PCB congeners with the World Health Organization-defined toxic equivalent factors, and six indicator PCBs by high-resolution gas chromatography and high-resolution mass spectrometry. We analyzed thyroid and growth hormones from cord serum using radioimmunoassay. Insulin-like growth factor (IGF)-1, IGF-binding globulin-3, and thyroxine x thyroid-stimulating hormone (T4 x TSH) were significantly associated with increased placental weight and Quetelet index (in kilograms per square meter; correlation coefficient r = 0.2-0.3; p < 0.05). Multivariate analyses showed independently and significantly decreased free T4 (FT4) x TSH with increasing non-ortho PCBs (r = -0.2; p < 0.05). We suggest that significant FT4 feedback alterations to the hypothalamus result from in utero exposure to non-ortho PCBs. Considering the vast existence of bioaccumulated dioxins and PCBs and the resultant body burden in modern society, we suggest routine screening of both thyroid hormone levels and thyroid function in newborns.

Human Breast Milk Contamination with Phthalates and Alterations of Endogenous Reproductive Hormones in Infants Three Months of Age

Article

Full-text available

Feb 2006

Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.

Phthalate affect the reproductive function and sexual behavior of male Wistar rats

Article

Full-text available

Jun 2006
HUM EXP TOXICOL

Phthalates are chemicals used in many industrial products (plastic toys, shampoos, soaps), and are suspected of inducing adverse effects on the male reproductive system. In the present study, we evaluated the effects of the plasticizer di-(2-ethylhexyl)-phthalate (DEHP) on the reproductive function and sexual behavior of male offspring rats, exposed in utero and during lactation (0, 20, 100 and 500 mg/kg per day by gavage). The effects produced clearly demonstrate the ability of DEHP to disrupt the androgen-regulated development of the male reproductive tract. Absolute and relative weights of androgen-dependent tissue organs (ventral prostate and seminal vesicle) were significantly reduced at the highest dose level tested (500 mg/kg per day). Impairment of male sexual behavior (500 mg/kg per day) was also observed. Moreover, the reduction in daily sperm production and epididymal sperm counts observed after administration of the highest dose suggests an impairment of the spermatogenic processes. Most of the adverse effects reported here were observed both during puberty and during adulthood, indicating permanent effects of in utero and lactational DEHP exposure.

Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP): a cross-sectional study in China

Article

Full-text available

Nov 2006

Observations of adverse developmental and reproductive effects in laboratory animals and wildlife have fueled increasing public concern regarding the potential for various chemicals to impair human fertility. Our objective in this study was to assess the effect of occupational exposure to high levels of phthalate esters on the balance of gonadotropin and gonadal hormones including luteinizing hormone, follicle-stimulating hormone, free testosterone (fT), and estradiol. We examined urine and blood samples of 74 male workers at a factory producing unfoamed polyvinyl chloride flooring exposed to di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) and compared them with samples from 63 male workers from a construction company, group matched for age and smoking status. Compared to the unexposed workers, the exposed workers had substantially and significantly elevated concentrations of mono-n-butyl phthalate (MBP; 644.3 vs. 129.6 microg/g creatinine, p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; 565.7 vs. 5.7 microg/g creatinine, p < 0.001). fT was significantly lower (8.4 vs. 9.7 microg/g creatinine, p = 0.019) in exposed workers than in unexposed workers. fT was negatively correlated to MBP (r = -0.25, p = 0.03) and MEHP (r = -0.19, p = 0.095) in the exposed worker group. Regression analyses revealed that fT decreases significantly with increasing total phthalate ester score (the sum of quartiles of MBP and MEHP; r = -0.26, p = 0.002). We observed a modest and significant reduction of serum fT in workers with higher levels of urinary MBP and MEHP compared with unexposed workers.

Cumulative Effects of Dibutyl Phthalate and Diethylhexyl Phthalate on Male Rat Reproductive Tract Development: Altered Fetal Steroid Hormones and Genes

Article

Full-text available

Sep 2007

Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that coadministered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production, and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague Dawley rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP+DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production and processed for gene expression by quantitative real-time PCR. The DBP+DEHP dose increased the incidence of many reproductive malformations by >or=50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and cyp11a were cumulatively decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose-additive effects when administered as a mixture.

Correlation of umbilical cord blood hormones and growth factors with stem cell potential: Implications for the prenatal origin of breast cancer hypothesis

Article

Full-text available

May 2007

Prenatal levels of mitogens may influence the lifetime breast cancer risk by driving stem cell proliferation and increasing the number of target cells, and thereby increasing the chance of mutation events that initiate oncogenesis. We examined in umbilical cord blood the correlation of potential breast epithelial mitogens, including hormones and growth factors, with hematopoietic stem cell concentrations serving as surrogates of overall stem cell potential. We analyzed cord blood samples from 289 deliveries. Levels of hormones and growth factors were correlated with concentrations of stem cell and progenitor populations (CD34+ cells, CD34+CD38- cells, CD34+c-kit+ cells, and granulocyte-macrophage colony-forming units). Changes in stem cell concentration associated with each standard deviation change in mitogens and the associated 95% confidence intervals were calculated from multiple regression analysis. Cord blood plasma levels of insulin-like growth factor-1 (IGF-1) were strongly correlated with all the hematopoietic stem and progenitor concentrations examined (one standard-deviation increase in IGF-1 being associated with a 15-19% increase in stem/progenitor concentrations, all P < 0.02). Estriol and insulin-like growth factor binding protein-3 levels were positively and significantly correlated with some of these cell populations. Sex hormone-binding globulin levels were negatively correlated with these stem/progenitor pools. These relationships were stronger in Caucasians and Hispanics and were weaker or not present in Asian-Americans and African-Americans. Our data support the concept that in utero mitogens may drive the expansion of stem cell populations. The correlations with IGF-1 and estrogen are noteworthy, as both are crucial for mammary gland development.

Environmental exposure to dioxins and polychlorinated biphenyls reduce levels of gonadal hormones in newborns: Results from the Duisburg cohort study

Article

Full-text available

Apr 2008
INT J HYG ENVIR HEAL

Endocrine dysfunction related to the hypothalamic-pituitary-thyroid (HPT) and/or the hypothalamic-pituitary-gonadal axis (HPG) is being discussed as underlying developmental adversity of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs). This study was done to evaluate effects related to the HPG axis. A birth-cohort study was initiated in the year 2000. Healthy mother-infant pairs were recruited in the industrialized city of Duisburg, Germany. Dioxins, dioxin-like PCBs and six indicator PCBs were measured in maternal blood during pregnancy and in maternal milk. Testosterone and estradiol levels were measured in maternal and cord serum of 104 mother-infant pairs representing a subsample with a complete data set of the total basic sample of 232 participants. Linear regression analysis was used to describe the association of PCDD/Fs or PCB in maternal blood or milk with sex steroid concentrations after adjustment for confounding. Median concentrations for PCDD/Fs in maternal blood fat and milk fat in terms of WHO-TEq were 15.3 and 13.1pg WHO-TEq/g, respectively, and for the sum of the indicator PCBs (#28, #52, #101, #138, #153, #180) 149 and 177ng/g. The adjusted ratio of geometric means when doubling the concentration of PCDD/Fs in maternal blood fat was 0.86, 95% confidence interval (95% CI): 0.72-1.03 for testosterone and 0.73 (0.61-0.87) for estradiol in cord serum. Typically, testosterone reduction was more pronounced in cord serum of female and estradiol reduction in that of male babies. Reduction of hormone levels was generally more pronounced for dioxins than for indicator PCBs. The hypothalamic-pituitary-gonadal axis of newborn babies is influenced by prenatal exposure to PCDD/Fs and PCBs in a manner suggestive of AhR-mediation. The clinical relevance of this finding remains to be established, however.

Associations between urinary phthalate monoesters and thyroid hormones in pregnant women

Article

Full-text available

Oct 2007

Maternal hypothyroidism during pregnancy can cause adverse effects in the fetus. Scientific evidence has shown that probable thyroid-like function of some phthalates in vitro and in vivo, and phthalates exposure, can begin in utero. This study investigated the association between phthalate exposure and thyroid hormones in pregnant women. Serum and spot urine samples were collected from 76 Taiwanese pregnant women at second trimester. Thyroid hormones, including thyroid-stimulating hormone (TSH), triiodothyronine (T(3)), thyroxine (T(4)) and free T(4) (FT(4)) were analysed in serum samples, and five urinary phthalate monoesters, including mono butyl phthalate (MBP), monoethyl phthalate (MEP) and mono ethylhexyl phthalate (MEHP), were measured. Urinary MBP, MEP and MEHP, the median levels of which were 81.8, 27.7 and 20.6 ng/ml, respectively, were the predominant substances in the urinary phthalate monoesters. Significant mild negative correlations were found between T(4) and urinary MBP (R = -0.248, P < 0.05), and between FT(4) and urinary MBP (R = -0.368, P < 0.05). After adjusting for age, BMI and gestation, urinary MBP levels showed negative associations with FT(4) and T(4) (FT(4): beta = -0.110, P < 0.001; T(4): beta=-0.112, P = 0.003). Exposure to di-n-butyl phthalate (DBP) may affect thyroid activity in pregnant women, but how DBP affects thyroid function is unclear. Further studies are needed to elucidate the mechanism of action and to investigate whether any other factors related to DBP exposure alter the thyroid function.

Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects

Article

Jan 2009

World Medical Association (WMA

Published research in English-language journals are increasingly required to carry a statement that the study has been approved and monitored by an Institutional Review Board in conformance with 45 CFR 46 standards if the study was conducted in the United States. Alternative language attesting conformity with the Helsinki Declaration is often included when the research was conducted in Europe or elsewhere. The Helsinki Declaration was created by the World Medical Association in 1964 (ten years before the Belmont Report) and has been amended several times. The Helsinki Declaration differs from its American version in several respects, the most significant of which is that it was developed by and for physicians. The term "patient" appears in many places where we would expect to see "subject." It is stated in several places that physicians must either conduct or have supervisory control of the research. The dual role of the physician-researcher is acknowledged, but it is made clear that the role of healer takes precedence over that of scientist. In the United States, the federal government developed and enforces regulations on researcher; in the rest of the world, the profession, or a significant part of it, took the initiative in defining and promoting good research practice, and governments in many countries have worked to harmonize their standards along these lines. The Helsinki Declaration is based less on key philosophical principles and more on prescriptive statements. Although there is significant overlap between the Belmont and the Helsinki guidelines, the latter extends much further into research design and publication. Elements in a research protocol, use of placebos, and obligation to enroll trials in public registries (to ensure that negative findings are not buried), and requirements to share findings with the research and professional communities are included in the Helsinki Declaration. As a practical matter, these are often part of the work of American IRBs, but not always as a formal requirement. Reflecting the socialist nature of many European counties, there is a requirement that provision be made for patients to be made whole regardless of the outcomes of the trial or if they happened to have been randomized to a control group that did not enjoy the benefits of a successful experimental intervention.

Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters - discussion

Article

Jan 2006

Decreased Serum Free Testosterone in Workers Exposed to High Levels of Din-butyl Phthalate (DBP) and Di2-ethylhexyl Phthalate (DEHP), A Cross-Sectional Study in China

Article

Nov 2006

BACKGROUND: Observations of adverse developmental and reproductive effects in laboratory animals and wildlife have fueled increasing public concern regarding the potential for various chemicals to impair human fertility. OBJECTIVE: Our objective in this study was to assess the effect of occupational exposure to high levels of phthallate esters on the balance of gonadotropin and gonadal hormones including luteinizing hormone, follicle-stimulating hormone, free testosterone (fT), and estradiol. METHODS: We examined urine and blood samples of 74 male workers at a factory producing unfoamed polyvinyl chloride flooring exposed to di-n-butyl phthalate (DBP) and di-2-ethythexyl phthalate (DEHP) and compared them with samples from 63 male workers from a construction company, group matched for age and smoking status. RESULTS: Compared to the unexposed workers, the exposed workers had substantially and significantly elevated concentrations of mono-n-butyl phthalate (MBP; 644.3 vs. 129.6 mu g/g creatinine, p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; 565.7 vs. 5.7 mu g/g creatinine, p < 0.001). fT was significantly lower (8.4 vs. 9.7 mu g/g creatinine, p = 0.019) in exposed workers than in unexposed workers. fT was negatively correlated to MBP (r = -0.25, p = 0.03) and MEHP (r = -0.19, p = 0.095) in the exposed worker group. Regression analyses revealed that fT decreases significantly with increasing total phthalate ester score (the sum of quartiles of MBP and MEHP; r = -0.26, p = 0.002). CONCLUSION: We observed a modest and significant reduction of serum fT in workers with higher levels of urinary MBP and MEHP compared with unexposed workers.

A quantitative comparison of interval type-2 and type-1 fuzzy logic systems: First results

Conference Paper

Aug 2010

Jerry M Mendel

The question “When will an IT2 FLS outperform a T1 FLS?” has been asked by many, and is acknowledged by many experts to be arguably the most important unanswered question in the T2 field. As a research problem, this question turns into: Establish when and by how much a type-2 fuzzy logic system (T2 FLS) will outperform a type-1 (T1) FLS. This paper provides first results on solving this problem. Its approach is novel because it does not focus immediately on a specific application, but instead focuses on the common component to all performance analyses, thereby providing results that can be used by others in their application-based performance comparisons. The Wu-Mendel minimax uncertainty bounds, which in the past have been used to approximate the type-reduced set, and to also act as a starting point for designs of IT2 FLSs, play the key role in this paper. Although comparing an IT2 FLS to a T1 FLS seems like a daunting task, because of the complicated nature of the equations that describe them, this paper shows that when an IT2 FLS is expanded about a T1 FLS-itself a new concept-, surprisingly, very simple first results are obtained.

Association between prenatal exposure to phthalates and the health of newborns

Article

Jan 2009

Phthalates are developmental and reproductive toxicants for the fetus in pregnant rodents, and the ability of phthalates to penetrate the placenta have been reported. The aims of this study were to evaluate the association between maternal urine excretion, the exposure of fetus to phthalates in amniotic fluid, and the health of newborns. Amniotic fluid and urine samples from pregnant women were collected to measure five phthalate monoesters using liquid chromatography/tandem mass spectrometry (LC/MS-MS) and the newborns' birth weight, gestational age, and anogenital distance (AGD) were collected. The median levels of three phthalate monoesters in urine and amniotic fluid were 78.4 and 85.2 ng/mL monobutyl phthalate (MBP); 24.9 and 22.8 ng/mL mono-(2-ethylhexyl) phthalate (MEHP); 19.8 and Not Detected monoethyl phthalate (MEP). We found a significant positive correlation only between creatinine adjusted urinary MBP and amniotic fluid MBP (R(2)=0.156, p<0.05) in all infants and, only in female infants, a significantly negative correlation between amniotic fluid MBP, AGD (R=-0.31, p<0.06), and the anogenital index adjusted by birth weight (AGI-W) (R=-0.32, p<0.05). Although the influence of prenatal di-n-butyl phthalate (DBP) exposure on the endocrinology and physiology of the fetus is still a puzzle, our data clearly show that in utero exposure to phthalates in general has anti-androgenic effects on the fetus.

Associations between urinary metabolites of di(2‐ethylhexyl) phthalate and reproductive hormones in fertile men

Article

Aug 2011
INT J ANDROL

Widely used man-made chemicals, including phthalates, can induce hormonal alterations through a variety of cellular and molecular mechanisms. A number of rodent and observational studies have consistently demonstrated the anti-androgenic effect of several phthalates. However, there are only limited data on the relationship between exposure to these chemicals and reproductive hormone levels in men. All men (n=425) were partners of pregnant women who participated in the Study for Future Families in five US cities and provided urine and serum samples on the same day. Eleven phthalate metabolites were measured in urine and serum samples were analysed for reproductive hormones, including follicle-stimulating hormone, luteinizing hormone, testosterone, inhibin B and oestradiol and sex hormone-binding globulin (SHBG). Pearson correlations and parametric tests were used for unadjusted analyses, and multiple linear regression analysis was performed controlling for appropriate covariates. We observed weak or no associations with urinary phthalates other than di(2-ethylhexyl) phthalate (DEHP). All measures of testosterone [total, calculated free testosterone and the free androgen index (FAI)] were inversely correlated with the urinary concentrations of four DEHP metabolites. After adjustment by appropriate covariates, there was no longer an association between urinary DEHP metabolite concentrations and total testosterone levels; however, FAI was significantly associated with the urinary concentrations of several DEHP metabolites. SHBG was positively related to the urinary concentrations of mono(2-ethylhexyl) phthalate, but not with other DEHP metabolites, an association that was attenuated after adjustment. Our results suggest that DEHP exposure of fertile men is associated with minor alterations of markers of free testosterone.

Urinary Metabolites of Di(2-ethylhexyl) Phthalate Are Associated With Decreased Steroid Hormone Levels in Adult Men

Article

May 2009
J ANDROL

Experimental animal studies have demonstrated that exposure to some phthalates may be associated with altered endocrine function and adverse effects on male reproductive development and function, but human studies are limited. In the present study, urine and serum samples were collected from 425 men recruited through a US infertility clinic. Urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP), and other phthalate monoester metabolites were measured, along with serum levels of testosterone, estradiol, sex hormone-binding globulin (SHBG), follicle-stimulating hormone, luteinizing hormone, inhibin B, and prolactin. Two oxidized urinary metabolites of DEHP were also measured in urine from 221 of the men. In multiple regression models adjusted for potential confounders, MEHP was inversely associated with testosterone, estradiol, and free androgen index (FAI). An interquartile range increase in MEHP was associated with 3.7% (95% confidence interval [CI], -6.8% to -0.5%) and 6.8% (95% CI, -11.2% to -2.4%) declines in testosterone and estradiol, respectively, relative to the population median hormone levels. There was limited evidence for effect modification of the inverse association between MEHP and FAI by the proportion of DEHP metabolites in the urine measured as MEHP (MEHP%), which is considered a phenotypic marker of less efficient metabolism of DEHP to its oxidized metabolites. Finally, the ratio of testosterone to estradiol was positively associated with MEHP (P = .07) and MEHP% (P = .007), suggesting potential relationships with aromatase suppression. In conclusion, these results suggest that urinary metabolites of DEHP are inversely associated with circulating steroid hormone levels in adult men. However, additional research is needed to confirm these findings.

Testosterone and dehydrotestosterone in maternal and cord blood in amniotic fluid

Article

Oct 1977
AM J OBSTET GYNECOL

Maternal and umbillical arterial and venous plasma and amniotic fluid testosterone (T) and dihydrotestosterone (DHT) were measured by radioimmunoassay. Maternal plasma T was 690 +/- 80 pg. per milliliter (mean +/- S.E.) in early pregnancy (less than 20 weeks) and increased significantly (p = 0.0002) to 1,095 +/- 177 pg. per milliliter in late pregnancy (greater than 20 weeks). DHT was 113.0 +/- 18.8 pg. per milliliter in early pregnancy and 179.8 +/- 30.5 pg. per milliliter in late pregnancy. Both umbilical arterial (UA) and umbilical venous (UV) plasma T were significantly higher in 11 male infants (UA T = 135.6 +/- 16.5 pg. per milliliter; UV T = 227.5 +/- 40.8 pg. per milliliter) than in 12 female infants (UA T = 92.1 +/- 9.7 pg. per milliliter; UV T = 89.6 +/- 12.6 pg. per milliliter) (p = less than 0.05 and less than 0.005, respectively). UV DHT and UA DHT showed no significant difference between male and female neonates. In midtrimester pregnancy, amniotic fluid T (AFT) was 165.2 +/- 15.4 pg. per millitier in pregnancies with a male fetus and was significantly higher (p = less than 0.001) than in pregnancies with a female fetus (mean +/- S.E. = 27.6 +/- 2.6 pg. per millitier). In late pregnancy, AFT levels were similar to those of early pregnancy, but a considerable overlap in AFT between fetuses of both sexes was observed. DHT was not detectable in amniotic fluid. The results suggest the potential value of AFT for determining fetal sex in midtrimester pregnancy and confirm that maternal T and DHT increase during pregnancy and that cord T levels reflect fetal gonadal androgen synthesis.

Normoprolactinemia in boys with marked gynecomastia

Article

Oct 1981

W Beck

Pubertal gynecomastia normally occurs as a transient phenomenon of several months duration, whereas marked pubertal gynecomastia (more than 6 cm in diameter) may persist into aduldhood. In the present study the possible involvement of prolactin (PRL) secretion in the development of marked pubertal gynecomastia was investigated. The diurnal variations of PRL, luteinizing hormone (LH), follicle-stimulating hormone (FSH), as well as the basal values of testosterone (T) and estradiol (E2) were determined in 5 pubertal boys with marked gynecomastia and in 5 age-matched controls. Mean age of all patients was 14.4 years. The pubertal development was classified as P 3–4. In comparison to controls, boys with marked gynecomastia revealed no differences in basal values of PRL, LH and FSH, as well as in peak values of all hormones during sleep. The response of PRL, LH and FSH to LHRH/TRH stimulation was normal for pubertal age in both groups. In comparison to controls, decreased mean plasma T levels (P<0.05) and slightly increased E2 levels (P<0.05) were found in boys with marked gynecomastia. The E2/T ratio was also higher in boys with gynecomastia (P<0.005). These data suggest that prolactin, a hormone which may be increased in galactorrhea, is not involved in the development of marked pubertal gynecomastia in boys. The above findings suggest that slightly elevated day-time E2 levels may be involved in the development of female-appearing breasts in pubertal boys.

Critical period for adverse effects on development of reproductive system in male offspring of rats given di-n-butyl phthalate during late pregnancy

Article

Feb 2000
TOXICOL LETT

The objective of this study was to determine the susceptible days for the adverse effects of di-n-butyl phthalate (DBP) on development of reproductive system in male offspring following maternal administration on successive 3-day period during late pregnancy. Pregnant rats were given DBP by gastric intubation at 1000 or 1500 mg/kg on days 12-14 or 18-20 of pregnancy or at 500, 1000 or 1500 mg/kg on days 15-17 of pregnancy. A significant decrease in the maternal body weight gain and/or food consumption was found in the DBP-treated groups regardless of the days on which DBP at 1000 and 1500 mg/kg was given. A significant increase in the number of resorptions per litter was found in the groups given DBP at 1500 mg/kg on days 12-14 and 15-17 of pregnancy. The weights of male and female fetuses were significantly decreased in the groups given DBP at 1000 and 1500 mg/kg on days 12-14 and 18-20 and at 1500 mg/kg on days 15-17. A significant increase in the incidence of fetuses with undescended testes was found at 1500 mg/kg on days 12-14 and at all doses on days 15-17. A significant decrease in the anogenital distance (AGD) of male fetuses was observed in the groups treated with DBP regardless of the days of treatment. The AGD/body weight ratio in male fetuses was significantly reduced in the groups given DBP on days 15-17, but neither on days 12-14 nor 18-20. The AGD of female fetuses in the DBP-treated groups was comparable to that in the control group. It was concluded that period of days 15-17 of pregnancy was the most susceptible for DBP-induced undescended testes and decreased AGD in male offspring.

Serum testosterone: Estradiol ratio and the development of hepatocellular carcinoma among male cirrhotic patients

Article

Oct 2000

The reason for the large male predominance in the occurrence of hepatocellular carcinoma (HCC) remains unknown, and sex hormones may contribute to this phenomenon. We examined possible associations of serum levels of testosterone, free testosterone, estradiol, sex hormone binding globulin, and testosterone:estradiol ratio (T:E2 ratio) with HCC development in a follow-up study of 46 Japanese male patients with liver cirrhosis predominantly of hepatitis C virus origin (76%). Serum samples were collected between December 1985 and December 1987, and the patients were completely followed until the end of 1995 for an average of 5.1 years. During the follow-up period, 20 patients (43%) developed HCC. Univariate analysis demonstrated that serum T:E2 ratio and testosterone were significant predictors of HCC; the hazard ratios (and 95% confidence intervals) in the middle and upper tertiles relative to the lower tertile were 2.0 (0.5-7.6) and 4.0 (1.1-14.6; P trend = 0.03) for T:E2 ratio and 0.8 (0.2-3.1) and 2.9 (1.0-8.5; P trend = 0.05) for testosterone. Adjustment for age, serum albumin, hepatitis virus markers, and other clinicobiological variables substantially increased the corresponding hazard ratios. In multivariate analysis, serum free testosterone appeared to be associated with increased risk, yet independent associations with estradiol and sex hormone binding globulin were not evident. These results indicate that elevated serum testosterone, together with decreased serum estrogens, may promote the development of HCC in cirrhosis.

Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: A two-generation reproductive study

Article

Nov 2000
REPROD TOXICOL

Butyl benzyl phthalate (BBP), a plasticizer, has been shown in in vitro studies to be weakly estrogenic, and in in vivo studies to possess testicular toxicity and teratogenicity, but few experimental data on BBP multigeneration effects on reproduction in mammals are available. The present two-generation reproductive study was conducted in male and female Sprague-Dawley rats using oral doses of 0, 20, 100, and 500 mg/kg/day BBP. Endpoints were chosen in order to evaluate both subchronic and reproductive toxicity. In the parent animals (F(0)), a decrease in body weight gain was observed in males in the 500 mg/kg/day group, although no significant decrease in food consumption was found. No dose-related changes were observed in estrous cyclicity, fertility, or lactation. A dose-dependent increase in kidney weight in rats of both sexes, an increase in liver weight in males, and a decrease in the weight of the ovaries in females were observed. No macroscopic or microscopic changes were found in the reproductive system of males or females. Oral administration of BBP caused a decrease in the serum concentration of testosterone, and an increase in FSH. In the next generation (F(1)), the body weight of male and female offspring at birth in the 100 and 500 mg/kg groups was significantly decreased, and the body weight in the 500 mg/kg group was lower throughout the study, while viability was not affected. Anogenital distance (AGD) at birth was decreased in male pups and was increased in female pups of the 500 mg/kg/day group. Preputial separation for male offspring in the 500 mg/kg/day group was delayed, while vaginal opening for female offspring in this group was not affected. BBP did not affect reproductive ability, including delivery and lactation, at any dose whereas macroscopic and microscopic changes of the testis, and decreased serum concentrations of testosterone were observed in male offspring of the 500 mg/kg/day group after puberty. From these data, it would appear that 20 mg/kg BBP is a no observed adverse effect level (NOAEL) for reproductive effects on parent animals and the next generation.

Effects on development of the reproductive system in male offspring of rats given butyl benzyl phthalate during pregnancy

Article

Feb 2002
REPROD TOXICOL

The objective of this study was to determine the effects of maternal exposure to butyl benzyl phthalate (BBP) on the development of the reproductive system in male offspring. Pregnant rats were given BBP by gastric intubation at 250, 500, or 1000 mg/kg on days 15 to 17 of pregnancy. A significant decrease in maternal body weight gain and food consumption was found in rats given BBP at 500 and 1000 mg/kg. A significant decrease in the number of live fetuses per litter was found at 1000 mg/kg. The weights of male and female fetuses were significantly decreased in the groups given BBP at 1000 mg/kg. A significant increase in the incidence of fetuses with undescended testes was found at 500 and 1000 mg/kg. A significant decrease in the anogenital distance (AGD) of male fetuses was observed at 500 and 1000 mg/kg. The AGD/cube root of body weight ratio in male fetuses was also significantly reduced at 500 mg/kg and higher. The AGD and AGD/cube root of body weight ratio of female fetuses in the BBP-treated groups were comparable to those in the control group. It was concluded that BBP on days 15 to 17 of pregnancy produced adverse effects on the development of the reproductive system in male offspring.

Reproducibility of Urinary Phthalate Metabolites in First Morning Urine Samples

Article

Jun 2002

Phthalates are ubiquitous in our modern environment because of their use in plastics and cosmetic products. Phthalate monoesters--primarily monoethylhexyl phthalate and monobutyl phthalate--are reproductive and developmental toxicants in animals. Accurate measures of phthalate exposure are needed to assess their human health effects. Phthalate monoesters have a biologic half-life of approximately 12 hr, and little is known about the temporal variability and daily reproducibility of urinary measures in humans. To explore these aspects, we measured seven phthalate monoesters and creatinine concentration in two consecutive first-morning urine specimens from 46 African-American women, ages 35-49 years, residing in the Washington, DC, area in 1996-1997. We measured phthalate monoesters using high-pressure liquid chromatography followed by tandem mass spectrometry on a triple quadrupole instrument using atmospheric pressure chemical ionization. We detected four phthalate monoesters in all subjects, with median levels of 31 ng/mL for monobenzyl phthalate (mBzP), 53 ng/mL for monobutyl phthalate (mBP), 211 ng/mL for monoethyl phthalate (mEP), and 7.3 ng/mL for monoethylhexyl phthalate (mEHP). These were similar to concentrations reported for other populations using spot urine specimens. Phthalate levels did not differ between the two sampling days. The Pearson correlation coefficient between the concentrations on the 2 days was 0.8 for mBP, 0.7 for mEHP, 0.6 for mEP, and 0.5 for mBzP. These results suggest that even with the short half-lives of phthalates, women's patterns of exposure may be sufficiently stable to assign an exposure level based on a single first morning void urine measurement.

Mechanisms of Phthalate Ester Toxicity in the Female Reproductive System

Article

Mar 2003

Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.

Infant exposure to polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls (PCDD/Fs, PCBs) - Correlation between prenatal and postnatal exposure

Article

Apr 2004
CHEMOSPHERE

Polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are recognized environmental endocrine disruptors, which are environmentally persistent and may bio-accumulate in human bodies. Pregnant and nursing women may pass these pollutants to their babies both trans-placentally and lactationally. We measured and examined correlations of the levels of PCDD/Fs and PCBs in perinatal venous serum, placenta, umbilical-cord serum (representing prenatal exposure), and breast milk (postnatal exposure). Subjects included pregnant women without clinical complication between the ages of 25 and 35, who delivered their babies during 2000.12.01 and 2001.11.30 in central Taiwan. A total of 20 participants were randomly selected from those provided the four biological specimens for analysis of 17 PCDD/Fs, and 12 dioxin-like PCBs and six indicator PCBs using high-resolution gas chromatography/high-resolution mass spectrometry. Higher PCDD/F levels were found in placenta (10.3 TEq-pg/g lipid) and venous serum (9.1 TEq-pg/g lipid) compared to those in breast milk (7.6 TEq-pg/g lipid). Pearson and Spearman correlation analyses showed well association of PCDD/F and PCB levels between different specimens. The total dioxin/PCB level in milk, venous and cord serum can be well predicted by that in placenta through regression functions. This first study of multi-specimen correlation further established rather consistent ratios of these chemical concentrations in various specimens relative to those in venous serum.

Male Reproductive Tract Lesions at 6, 12, and 18 Months of Age Following in Utero Exposure to Di(n-butyl) Phthalate

Article

Jan 2004

In utero exposure of male rats to the antiandrogen di(n-butyl) phthalate (DBP) leads to decreased anogenital distance (AGD) on postnatal day (PND) 1, increased areolae retention on PND 13, malformations in the male reproductive tract, and histologic testicular lesions including marked seminiferous epithelial degeneration and a low incidence of Leydig cell (LC) adenomas on PND 90. One objective of this study was to determine the incidence and persistence of decreased AGD, increased areolae retention, and LC adenomas in adult rats following in utero DBP exposure. A second objective was to determine whether AGD and areolae retention during the early postnatal period are associated with lesions in the male reproductive tract. Pregnant Crl:CD(SD)BR rats were gavaged with corn oil or DBP at 100 or 500 mg/kg/day, 10 dams per group. Three replicates of rats (n = 30 rats per replicate) were exposed from gestation day 12 to 21 and the male offspring allowed to mature to 6, 12, or 18 months of age. Gross malformations in the male reproductive tract and histologic lesions in the testes were similar to those previously described. However, testicular dysgenesis, a lesion of proliferating LCs and aberrant tubules that has not been previously described in DBP-exposed testes, was diagnosed. The incidence of this lesion was approximately 20% unilateral and 7-18% bilateral in the high-dose group and was similar among all ages examined, implicating a developmental alteration rather than an age-related change. AGD and areolae retention were found to be permanent changes following in utero exposure to 500 mg/kg/day of DBP. Decreased AGD was a sensitive predictor of lesions in the male reproductive tract, relatively small changes in AGD were associated with a significant incidence of male reproductive malformations. In utero DBP exposure induced proliferative developmental lesions, some of which would have been diagnosed as LC adenomas by the morphological criteria set forth by the Society of Toxicologic Pathology. However, these lesions were dissimilar to traditional LC adenomas as the LCs were poorly differentiated and the lesions contained aberrant seminiferous tubules. While the morphology and incidence of this DBP-induced testicular developmental lesion has been fully characterized by this study, the detailed pathogenesis warrants further investigation.

Medications as a Source of Human Exposure to Phthalates

Article

Jun 2004

Phthalates are a group of multifunctional chemicals used in consumer and personal care products, plastics, and medical devices. Laboratory studies show that some phthalates are reproductive and developmental toxicants. Recently, human studies have shown measurable levels of several phthalates in most of the U.S. general population. Despite their widespread use and the consistent toxicologic data on phthalates, information is limited on sources and pathways of human exposure to phthalates. One potential source of exposure is medications. The need for site-specific dosage medications has led to the use of enteric coatings that allow the release of the active ingredients into the small intestine or in the colon. The enteric coatings generally consist of various polymers that contain plasticizers, including triethyl citrate, dibutyl sebacate, and phthalates such as diethyl phthalate (DEP) and dibutyl phthalate (DBP). In this article we report on medications as a potential source of exposure to DBP in a man who took Asacol [active ingredient mesalamine (mesalazine)] for the treatment of ulcerative colitis. In a spot urine sample from this man collected 3 months after he started taking Asacol, the concentration of monobutyl phthalate, a DBP metabolite, was 16,868 ng/mL (6,180 micro g/g creatinine). This concentration was more than two orders of magnitude higher than the 95th percentile for males reported in the 1999-2000 National Health and Nutrition Examination Survey (NHANES). The patient's urinary concentrations of monoethyl phthalate (443.7 ng/mL, 162.6 micro g/g creatinine), mono-2-ethylhexyl phthalate (3.0 ng/mL, 1.1 micro g/g creatinine), and monobenzyl phthalate (9.3 ng/mL, 3.4 micro g/g creatinine) were unremarkable compared with the NHANES 1999-2000 values. Before this report, the highest estimated human exposure to DBP was more than two orders of magnitude lower than the no observable adverse effect level from animal studies. Further research is necessary to determine the proportional contribution of medications, as well as personal care and consumer products, to a person's total phthalate burden.

Development and validation of an isotope-dilution electrospray ionization tandem mass spectrometry method with an on-line sample clean-up device for the quantitative analysis of the benzene exposure biomarker S-phenylmercapturic acid in human urine

Article

Jun 2004

An isotope-dilution electrospray ionization tandem mass spectrometry (ESI-MS/MS) method with an on-line sample clean-up device, for the quantitative analysis of human urine for the benzene exposure biomarker S-phenylmercapturic acid (SPMA), was developed and validated. The sample clean-up system was constructed from an autosampler, a reversed-phase C18 trap cartridge, a two-position switching valve, and controlling computer software and hardware. The sample clean-up system was interfaced via 1/20 splitting to the ESI source of a triple-quadrupole mass spectrometer using negative ion mode and multiple reaction monitoring for SPMA and the isotope-labeled internal standard. A strategy was adopted to acquire pooled blank urine matrix and quality control samples spiked with standards. Validated procedures and data on method specificity, detection limits, standard curves, precision and recovery, sample storage stability, and inter-laboratory comparison are presented. The analytical system was fully automated. No tedious manual sample clean-up procedures are required. With the selectivity and the sensitivity provided by ESI-MS/MS detection, the analytical system can be used for high-throughput and accurate determination of SPMA levels in human urine samples, as a biomarker for environmental as well as occupational benzene exposure.

Imbalance of sex hormone levels in men with coronary artery disease

Article

Jul 2004
Coron Artery Dis

Sex hormones are thought to play a key role in atherogenesis, but the available evidence is inconclusive, partly because of a lack of accuracy in measurement. The aim of the study was to investigate the potential role of sex hormones in coronary atherosclerosis. We prospectively applied a simple highly-sensitive method using solid-phase extraction followed by radioimmunoassay. Both phases were carried out using commercially available kits to determine levels of estradiol (E2). We also measured the levels of free testosterone (FT), dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and progesterone in 236 consecutive male patients with angiographically-defined stable coronary artery disease and in 143 disease-free and age-matched controls. The levels of highly-sensitive E2 and FT in patients and controls differed slightly in opposing directions, but neither difference reached statistical significance. However, the ratio of FT to highly-sensitive E2 in patients was significantly higher than in the controls (mean +/- SD; 2.50 +/- 1.89 versus 2.06 +/- 1.14, P = 0.018), and this difference remained significant after adjustments for age and body mass index had been made. Multiple regression analysis revealed that age, the association of diabetes, and the presence of coronary atherosclerosis were significantly and independently associated with the values of the FT/highly-sensitive E2 ratio. Other hormones examined did not differ significantly between the patients and the controls. Highly-sensitive E2 measurement demonstrated a significant imbalance of FT to E2 in male patients with coronary artery disease, but individual sex hormone levels did not differ between the patients and the controls.

Phthalate exposure and reproductive hormones in adult men

Article

Apr 2005

Phthalates are used in personal and consumer products, food packaging materials, and polyvinyl chloride plastics and have been measured in the majority of the general population of the USA. Consistent experimental evidence shows that some phthalates are developmental and reproductive toxicants in animals. This study explored the association between environmental levels of phthalates and altered reproductive hormone levels in adult men. Between 1999 and 2003, 295 men were recruited from Massachusetts General Hospital. Selected phthalate metabolites were measured in urine. Linear regression models explored the relationship between specific gravity-adjusted urinary phthalate monoester concentrations and serum levels of reproductive hormones, including FSH, LH, sex hormone-binding globulin, testosterone, and inhibin B. An interquartile range (IQR) change in monobenzyl phthalate (MBzP) exposure was significantly associated with a 10% [95% confidence interval (CI): -16, -4.0] decrease in FSH concentration. Additionally, an IQR change in monobutyl phthalate (MBP) exposure was associated with a 4.8% (95% CI: 0, 10) increase in inhibin B but this was of borderline significance. Although we found associations between MBP and MBzP urinary concentrations and altered levels of inhibin B and FSH, the hormone concentrations did not change in the expected patterns. Therefore, it is unclear whether these associations represent physiologically relevant alterations in these hormones, or whether they represent associations found as a result of conducting multiple comparisons.

Long-term effects of intrauterine exposure to mono-n-butyl phthalate on the reproductive function of postnatal rats

Article

Mar 2005
J PEDIATR SURG

Although it is well known that phthalate esters induce testicular dysfunction in both adult and immature rats, there have been few reports on the long-term effect of phthalate esters on the testicular function of male rats exposed to phthalate esters in utero. This study was designed to assess the long-term effects of the mono-n-butyl phthalate (MBP) ester on the testicular function of neonatal and adult rat offspring from pregnant dams exposed to phthalate esters during gestation. Pregnant rats were administered MBP [0.5 g/(kg body weight/.d); 4 days] by gavage from the 15th to the 18th gestational day. Rats administered solvent only were used as control subjects. After the rats' puberty, using male pups whose testes descended normally, the authors examined their fertility while also measuring their testicular weights, mean seminiferous tubular diameter, and the developmental grade of the germ cells (Johnsen score) in their testes. Next, in neonatal rats, the authors measured the testicular concentration of the Mullerian inhibiting substance (MIS) protein using enzyme-linked immunoassay and the expression level of the MIS messenger RNA using the quantitative polymerase chain reaction method as a marker of the Sertoli cells' function. Next the concentration of testosterone protein using a radioimmunoassay as a marker of the Leydig cells' function was measured. The pregnancy rate of the female rats coupled with MBP-treated male rats decreased significantly in comparison with that of the female rats coupled with control male rats (P < .01). Both the testicular weight and the Johnsen score in the MBP-treated group were decreased significantly more than those of the control group (P < .05). Neither the concentration of the MIS protein nor the expression level of the MIS messenger RNA in the MBP-treated neonatal testes differed from those of the control testes, whereas the concentration of testosterone protein in the neonate testes decreased significantly in the MBP-treated group in comparison with that of the control group (P < .01). A prenatal short-time exposure to MBP induces a long-term effect on postnatal rats and impairs reproductive function in male offspring probably by inhibiting the Leydig cells' rather than Sertoli cells' function in the fetal period.

Determination of 16 Phthalate Metabolites in Urine Using Automated Sample Preparation and On-line Preconcentration/High-Performance Liquid Chromatography/Tandem Mass Spectrometry

Article

Jun 2005

We developed an on-line solid-phase extraction (SPE) method, coupled with isotope dilution high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) and with automated sample preparation, to simultaneously quantify 16 phthalate metabolites in human urine. The method requires a silica-based monolithic column for the initial preconcentration of the phthalate metabolites from the urine and a silica-based conventional analytical column for the chromatographic separation of the analytes of interest. It uses small amounts of urine (100 microL), is sensitive (limits of detection range from 0.11 to 0.90 ng/mL), accurate (spiked recoveries are approximately 100%), and precise (the inter- and intraday coefficients of variation are <10%). The method is not labor intensive, and, because pretreatment of the urine samples was performed automatically using an HPLC autosampler, involves minimal sample handling, thus minimizing exposure to hazardous chemicals. The method was validated on spiked, pooled urine samples and on urine samples from 43 adults with no known exposure to phthalates. The high sensitivity and high throughput (HPLC run time, including the preconcentration step, is 27 min) of this analytical method combined with the ease of use and effective automated sample preparation procedure make it suitable for large epidemiological studies to evaluate the prevalence of human exposure to phthalates.

Disruption of reproductive development in male rat offspring following in utero exposure to phthalates

Article

Mar 2006

Paul M D Foster

Certain Phthalate esters have been shown to produce reproductive toxicity in male rodents with an age dependent sensitivity in effects with foetal animals being more sensitive than neonates which are in turn more sensitive than pubertal and adult animals. While the testicular effects of phthalates in rats have been known for more than 30 years, recent attention has been focused on the ability of these agents to produce effects on reproductive development in male offspring after in utero exposure. These esters and in particular di-butyl, di-(2-ethylhexyl) and butyl benzyl phthalates have been shown to produce a syndrome of reproductive abnormalities characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate, external genitalia (hypospadias), cryptorchidism and testicular injury together with permanent changes (feminization) in the retention of nipples/areolae (sexually dimorphic structures in rodents) and demasculinization of the growth of the perineum resulting in a reduced anogenital distance (AGD). Critical to the induction of these effects is a marked reduction in foetal testicular testosterone production at the critical window for the development of the reproductive tract normally under androgen control. A second Leydig cell product, insl3, is also significantly down regulated and is likely responsible for the cryptorchidism commonly seen in these phthalate-treated animals. The testosterone decrease is mediated by changes in gene expression of a number of enzymes and transport proteins involved in normal testosterone biosynthesis and transport in the foetal Leydig cell. Alterations in the foetal seminiferous cords are also noted after in utero phthalate treatment with the induction of multinucleate gonocytes that contribute to lowered spermatocyte numbers in postnatal animals. The phthalate syndrome of effects on reproductive development has parallels with the reported human testicular dysgenesis syndrome, although no cause and effect relationship exists after exposure of humans to phthalate esters. However humans are exposed to and produce the critical phthalate metabolites that have been detected in blood of the general population, in children and also human amniotic fluid.

Diisobutyl phthalate has comparable anti-androgenic effects to di-n-butyl phthalate in fetal rat testis

Article

Jul 2006
TOXICOL LETT

Unlabelled: Phthalates are widely used as plasticizers in various consumer products and building materials. Some of the phthalates are known to interfere with male reproductive development in rats, and di-n-butyl phthalate (DBP), diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP) were recently banned for use in toys in the EU mainly due to their reproductive toxicity. Diisobutyl phthalate (DiBP) has similar structural and application properties as DBP, and is being used as a substitute for DBP. However, knowledge on male reproductive effects of DiBP in experimental animals is lacking. Methods: In the current study, four groups of pregnant Wistar rats were exposed to either 0mg/kg bw/day or 600 mg/kg bw/day of DiBP from gestation day (GD) 7 to either GD 19 or GD 20/21. Male offspring was examined at GD 19 or GD 20/21 for effects on testicular testosterone production and testicular histopathology. Changes in anogenital distance (AGD) were evaluated as an indication of feminisation of males. Results: Anogenital distance was statistically significantly reduced at GD 20/21 together with reductions in testicular testosterone production and testicular testosterone content. Histopathological effects (Leydig cell hyperplasia, Sertoli cell vacuolisation, central location of gonocytes and presence of multinuclear gonocytes) known for DBP and DEHP were observed in testes of DiBP-exposed animals at GD 20/21. Additionally, immunohistochemical expression of P450scc and StAR proteins in Leydig cells was reduced by DiBP. At GD 19, these effects on anogenital distance, testosterone levels and histopathology were less prominent. Conclusion: In this study, GD 20/21 rather than GD 19 appears to be the optimal time for investigating changes in anogenital distance, testosterone levels, and testicular histopathology. DiBP has similar testicular and developmental effects as DBP and DEHP, and although more developmental and especially postnatal studies are needed to clearly identify the reproductive effects of DiBP, this study indicates a reason for concern about the use of DiBP as a substitute for DBP.

Possible impact of phthalates on infant reproductive health

Article

Mar 2006

Phthalates adversely affect the male reproductive system in animals, inducing hypospadias, cryptorchidism, reduced testosterone production and decreased sperm counts. Phthalate effects are much more severe after in utero than adult exposure. Little is known about human health effects. This study discusses two recent studies on perinatal phthalate exposure, which indicated that human testicular development might be susceptible to phthalates. One study analysed phthalate monoesters in breast milk and reproductive hormone levels in infants. Five of six phthalates [monoethyl-(MEP), monobutyl- (MBP), monomethyl- (MMP), mono-2-ethylhexyl- (MEHP) and mono-isononyl phthalate (MiNP)] showed correlation with hormone levels in healthy boys, which were indicative of lower androgen activity and reduced Leydig cell function. MEP and MBP were positively correlated with serum sex hormone-binding globulin (SHBG) levels. MMP, MEP, MBP, MEHP and MiNP were positively correlated with the LH/testosterone ratio. Another study found a reduction of the anogenital index (AGI) in infant boys with increasing levels of MBP, MEP, monobenzyl- and mono-isobutyl phthalate in maternal urine samples during late-pregnancy. Boys with small AGI showed a high prevalence of cryptorchidism and small genital size. Taken together these studies suggest an antivirilizing effect of phthalates in infants. Most of these findings are in line with animal observations. However, the possible effects of MEP appear to be limited to humans. This may be due to differences in exposure routes (inhalation and dermal absorption which circumvents liver detoxification in addition to oral) and metabolism, or this association could be spurious. As phthalates are produced as bulk chemicals worldwide, these new findings raise concern about the safety of phthalate exposure for pregnant women and infants.

Phthalate exposure and male infertility

Article

Oct 2006
TOXICOLOGY

Phthalates have been used as additives in industrial products since the 1930s, and are universally considered to be ubiquitous environmental contaminants. The general population is exposed to phthalates through consumer products, as well as diet and medical treatments. Animal studies showing the existence of an association between some phthalates and testicular toxicity have generated public and scientific concern about the potential adverse effects of environmental changes on male reproductive health. In particular, prenatal exposure to phthalates seems to play a relevant role in determining these adverse effects given that human exposure has been demonstrated to begin during the intrauterine life. Unprecedented declines in fertility rates and semen quality of antenatal origin have been reported during the last half of the 20th century in developed countries and increasing interest exists on the potential relationship between exposure to environmental contaminants, including phthalates, and human male reproductive health. Here we review the data that support or discounts the evidence existing to date linking phthalate exposure and the decline of human male fertility, especially in developed countries.

A dose–response study following in utero and lactational exposure to di-(2-Ethylhexyl)-Phthalate (DEHP): non-monotonic dose–response and low dose effects on rat brain aromatase activity

Article

Nov 2006
TOXICOLOGY

Di-(2-ethylhexyl)-phthalate (DEHP) is a commonly used plasticizer which can act as an endocrine disruptor. It has been suggested that in addition to its antiandrogenic effects, DEHP may interfere with estrogen metabolism through suppression of aromatase enzyme activity. This enzyme catalyzes the conversion of testosterone to estradiol and plays a critical role in brain sexual differentiation. We investigated the effects of two wide ranges of DEHP doses on brain aromatase activity of male and female rat offspring. Wistar rat dams were treated daily with DEHP and peanut oil (control) by gavage from gestation day 6 to lactation day 21 at doses of 0.015, 0.045, 0.135, 0.405 and 1.215mgDEHP/kgbodyweight(bw)/day (low doses) and at 5, 15, 45, 135 and 405mgDEHP/kgbw/day (high doses). Aromatase activity was determined in hypothalamic/preoptic area (HPOA) brain sections from male and female pups on postnatal days (PNDs) 1 and 22. In males on PND 1, aromatase activity was inhibited at low doses and increased at high doses resulting in a non-monotonic dose-response profile which resembled a J-shaped curve. Inhibition was statistically significant at 0.135 and 0.405mgDEHP/kg/day, while increased activity was observed at 15, 45 and 405mg/kg/day. In contrast to findings on PND 1, aromatase activity at weaning (PND 22) was more affected in females than in males. An increase in aromatase activity was observed at only one dose in males (0.405mg/kg/day) while an increase in activity was observed at all doses in the females except for 0.045 and 5mgDEHP/kg/day. Overall, these results indicate that males and females respond differently to DEHP not only in regard to the age at which effects are manifested, but also in the shape of the dose-response curve. To our knowledge, this is the first study to report biological effects of DEHP at doses that overlap with the estimated exposure of the general human population.

A dose–response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): Reproductive effects on adult female offspring rats

Article

Feb 2007
TOXICOLOGY

Di(2-ethylhexyl) phthalate (DEHP) is used in numerous consumer products, mainly imparting flexibility and durability to polyvinyl chloride (PVC) based plastics. It is a known reproductive and developmental toxicant in male rodents. However, data regarding effects of DEHP on female reproductive health are particularly sparse. We performed an extensive dose-response study following developmental exposure to DEHP and evaluated the effects on adult female reproductive function. Two wide ranges of doses, low and high, were tested. Female Wistar rats were treated daily with DEHP and peanut oil (vehicle control) by gavage from gestation day 6 to lactation day 21. The low doses were: 0.015, 0.045, 0.135, 0.405 and 1.215mgDEHP/kg/bw/day and the high doses were: 5, 15, 45, 135 and 405mg DEHP/kg/bw/day. At the doses tested, no effects on organ (liver, kidney, spleen, thymus, thyroid, ovary and uterus) or body weights were detected. Female offspring presented a normal pattern of estrous cyclicity with no hormonal alterations (serum estradiol and progesterone). A statistically significant increase in tertiary atretic follicles was observed at the highest dose (405mgDEHP/kg/day). Morphometric analysis indicated that uterus and vagina luminal epithelial cell height were unaffected by treatment. An increase in the number of ovarian atretic tertiary follicles was the only effect observed in adult female offspring exposed in utero and during lactation to DEHP.

Sex hormone ratio changes in men and postmenopausal women with coronary artery disease

Article

May 2007
MENOPAUSE

The goal of this study was to investigate the potential role of sex hormones in coronary atherosclerosis in both men and postmenopausal women. A total of 258 male and 236 female postmenopausal participants with angiographically defined stable coronary artery disease (CAD) were enrolled. We measured the levels of estradiol (E2), progesterone (P), testosterone (T), follicle-stimulating hormone, and luteinizing hormone in the participants and in 156 male and 132 female disease-free and age-matched controls using commercially available radioimmunoassay kits. In the male study participants and control subjects, the levels of E2 and P differed slightly in opposing directions; however, these differences were not significantly different, nor were there significant differences in T. However, the ratio of E2 to P in participants was significantly (P < 0.01) lower (even after adjustments for age and body mass index) than in the control subjects (mean +/- SEM: 70.2 +/- 56.4 vs 90.7 +/- 59.5, respectively). In the postmenopausal women, a slight decrease in E2 and increases in P and T in participants were not significantly different from levels in the control group. However, the E2 to P and E2 to T ratios were significantly (P < 0.01) lower (before and after adjustments for age and body mass index adjustments) in the participants relative to the control subjects (38.7 +/- 28.4 vs 49.6 +/- 36.3 and 46.5 +/- 37.6 vs 60.6 +/- 40.8, respectively). Correlation analyses demonstrated that the sex hormone ratio changes in both men and postmenopausal women were related with atherogenic blood lipoprotein changes. In both the male and female groups, levels of follicle-stimulating hormone and luteinizing hormone did not differ significantly between the participants and controls, and correlation analyses revealed no association between these hormones and the ratio of E2 to P in males and the ratios of E2 to P and E2 to T in females (r < 0.2, P > 0.05). Multiple regression analyses demonstrated that age and the presence of CAD were significantly and independently associated with the E2-to-P ratio in men and the E2-to-P and E2-to-T ratios in women and that E2-to-P ratio and low-density lipoprotein cholesterol level were significant independent predictors of CAD in males; E2-to-P and E2-to-T ratios and low-density lipoprotein cholesterol level were significant predictors of CAD in women. In both men and postmenopausal women with angiographic CAD, there were significant differences (relative to age-matched control subjects) in sex hormone ratios, suggesting an abnormality that could influence coronary health. A lower E2-to-P ratio may be associated with the male disposition to coronary atherosclerosis, whereas lower E2-to-P and E2-to-T ratios may be associated with the same condition in females.

Role of Androgens in Fetal Testis Development and Dysgenesis

Article

Jun 2007

This study sought to establish whether reduced androgen levels/action in the fetal rat testis induced by di(n-butyl) phthalate (DBP) contributes to dysgenetic features, namely reduced Sertoli cell number, occurrence of multinucleated gonocytes (MNG), and Leydig cell aggregation. Pregnant rats were administered treatments or cotreatments designed to manipulate testosterone levels [DBP, testosterone propionate (TP)] or action [flutamide, 7,12-dimethyl-benz[a]anthracene (DMBA)]. The aforementioned end points were analyzed and related to intratesticular testosterone (ITT) levels and peripheral androgen action (anogenital distance). Dysgenetic features were also evaluated in mice with inactivation of the androgen receptor (testicular feminized or ARKO mice). Exposure to DBP alone, or combined with flutamide, DMBA, or TP, resulted in reduced Sertoli cell number and ITT levels, as did exposure to TP alone; coadministration of DBP + TP caused the most severe reduction in both parameters. A positive correlation between ITT levels and Sertoli cell number was found (r = 0.791; P = 0.019). Similarly, exposure to DBP alone, or as a cotreatment, significantly increased occurrence of MNG and Leydig cell aggregation, and these were negatively correlated with ITT levels. Exposure to flutamide or DMBA alone had no significant effect on these dysgenetic end points. These findings suggest that reduced ITT decreases fetal Sertoli cell numbers and might be involved in Leydig cell aggregation and MNG. However, of these three end points, only Sertoli cell number was affected significantly in ARKO/testicular feminized mice with absent androgen action. Therefore, induction of MNG and Leydig cell aggregation might result from DBP-induced effects other than suppression of ITT levels.

Differential expression of the phthalate syndrome in male Sprague-Dawley and Wistar rats after in utero DEHP exposure

Article

Jun 2007
TOXICOL LETT

Exposure to phthalate esters during sexual differentiation disrupts testosterone and insulin-like three hormones resulting in malformations of androgen- and insulin-like three-dependent tissues. The current study was designed to test the hypothesis that gubernacular lesions would be more prevalent in the DEHP-treated (750 mg/kg/day, gestational days 14-18) Wistar male than in the SD rat offspring, whereas the SD rat would display a higher incidence of epididymal agenesis. As hypothesized, striking differences were seen in the incidences of epididymal (67% in SD versus 8% in Wistar) and gubernacular lesions (0% in SD versus 64% in Wistar) among the two strains. In addition, fetal androgen and insl3 mRNA levels differed among the strains. SD fetal males had higher insl3 mRNA and lower T levels than Wistar males. The ratio of insl3 mRNA to T differed among DEHP-treated SD and Wistar fetal males, indicating that the steroidogenic pathway was more affected in the SD strain than in the Wistar strain. Taken together, these results suggest that the different malformation profiles produced by in utero phthalate treatment arise, at least in part, from strain differences in fetal Leydig cell function and the manner in which these cells respond to DEHP treatment.

The internal exposure of Taiwanese to phthalate—An evidence of intensive use of plastic materials

Article

Feb 2008
ENVIRON INT

Phthalates are widely used in industry and consumer products. Di-(2-ethylhexyl) phthalate (DEHP) and di-n-butylphthalate (DBP) show the greatest potency of reproductive toxicants among phthalates. The purposes of this study are to examine the migration level of phthalate from PVC films by simulating food handling and to reveal the body burden of phthalate for Taiwanese. In order to estimate a worst-case of phthalate migration, food was covered with polyvinyl chloride (PVC) films and then microwave heated. Results show that DEHP level in food increased significantly after heating for 3 min. Under the heating condition, the calculated intake of phthalate and the percentage of the tolerable daily intake (TDI, based on body weight of 60 kg) from eating one 400-g meal were 1705.6 microg and 92.2% for DEHP. Determination of urinary metabolites from 60 subjects reveals more than 90% of samples were detectable for mono-methyl phthalate (MMP), mono-butyl phthalate (MBP) and mono-ethylhexyl phthalate (MEHP). Notably, the median value of estimated daily intake of DEHP had reached 91.6% of TDI established by the European Union Scientific Committee for Toxicity, Ecotoxicity and the Environment (CSTEE) (1998). Thirty-seven percent of the study population exceeded the TDI and 85% exceeded the reference dose (RfD) of the US EPA. We conclude that the body burden of DEHP for Taiwanese reflects the intensives use of plastic materials in the region. The regulation of PVC for food preparation is necessary.

Associations between maternal phthalate exposure and cord sex hormones in human infants

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