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Possible impact of phthalates on infant reproductive health
Abstract
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.
... The in silico study by Sheikh et al. [214] showed that phthalates' substituent DEHT had a higher affinity to SHBG as well. MEP, monobutyl phthalate (MBP), and MEHP were inversely associated with the levels of SHBG in boys [196,215]. MEHP was inversely associated with SHBG in boys. DEHP was positively associated with the levels of SHBG in girls [196]. ...
... DEHP was positively associated with the levels of SHBG in girls [196]. These studies support the anti-androgenic and pro-estrogenic effects of DEHP, MEP, and mono-n-butyl phthalate (MnBP) [196,215]. ...
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.
... Because DEHP constitutes up to 40% of PVC plastic by weight and is not covalently bonded to plastic polymers, it can readily leach into the environment, becoming pervasive [1]. Consequently, DEHP is easily absorbed into the body through skin contact, ingestion, or inhalation, leading to various adverse effects, such as reproductive issues, hindering fetal growth [3], endocrine imbalances, miscarriages [4], and sexual differentiation disorders [5]. The current epidemiological study estimates that the total average daily dose of DEHP ranges from 17.03 to 24.54 µg/kg/day for children and adolescents in Eastern China [6]. ...
Di-(2-Ethylhexyl) phthalate (DEHP) is a prevalent environmental endocrine disruptor that affects homeostasis, reproduction, and developmental processes. The effects of DEHP have been shown to differ based on sex and sexual maturity. This study examines the metabolic profiles of mature adult rats from both sexes, aged 10 weeks, and adolescent female rats, aged 6 weeks, following a single 5 mg/kg of body weight DEHP oral administration. An untargeted metabolomic analysis was conducted on urine samples collected at multiple times to discern potential sex- and maturity-specific DEHP toxicities. Various multivariate statistical analyses were employed to identify the relevant metabolites. The findings revealed disruptions to the steroid hormone and primary bile acid biosynthesis. Notably, DEHP exposure increased hyocholic, muricholic, and ketodeoxycholic acids in male rats. Moreover, DEHP exposure was linked to heart, liver, and kidney damage, as indicated by increased plasma GOT1 levels when compared to the levels before DEHP exposure. This study provides detailed insights into the unique mechanisms triggered by DEHP exposure concerning sex and sexual maturity, emphasizing significant distinctions in lipid metabolic profiles across the different groups. This study results deepens our understanding of the health risks linked to DEHP, informing future risk assessments and policy decisions.
... Recent epidemiologic studies have found associations between environmental exposure to phthalates and adverse reproductive health outcomes, such as reduced fertility and disruptions in testicular development, mainly derived from their alteration of the hypothalamicpituitary-gonadal axis. Phthalates' effect on peroxisome proliferator activated receptors (PPARs) and oxidative stress may also influence health outcomes (Hlisníková et al., 2020;Lottrup et al., 2006;Lyche et al., 2009;Heudorf et al., 2007;Hauser and Calafat, 2005;Baken et al., 2019;Benjamin et al., 2017). Phthalates are added to manufactured plastic products, such as vinyl flooring or food packaging, to improve flexibility and durability (Heudorf et al., 2007;Cadogan and Howick, 2012;Schettler, 2006). ...
Non-persistent endocrine-disrupting chemicals (EDCs), including phthalates and phenols, are ubiquitous in both the environment and human body. A growing body of epidemiologic studies have identified concerning links between EDCs and adverse reproductive and developmental health effects. Despite consistent evidence, risk assessments and policy interventions often arrive late. This presents an urgent need to identify evidence-based interventions for implementation at both clinical and community levels to reduce EDC exposure, especially in susceptible populations. The reproductive life cycle (menarche to menopause for females and after pubertal onset for males) includes some of the most vulnerable periods to environmental exposures, such as the preconception and perinatal stages, representing a key window of opportunity to intervene and prevent unfavorable health outcomes. This review aims to synthesize and assess behavioral, dietary, and residential EDC-driven interventions to develop recommendations for subsequent, larger-scale studies that address knowledge-gaps in current interventions during the reproductive life cycle. We selected 21 primary interventions for evaluation, in addition to four supplemental interventions. Among these, accessible (web-based) educational resources, targeted replacement of (known) toxic products, and personalization of the intervention through meetings and support groups, were the most promising strategies for reducing EDC concentrations. However, we document a paucity of interventions to prevent phthalate and phenol exposures during the reproductive years, especially among men. Accordingly, we recommend additional, larger clinical and community-based intervention studies to reduce EDC exposure. Specifically, future intervention studies should focus on short-term, mid-, and long-term exposure reduction to phthalates and phenols. The latter, especially, is required for the development of clinical and public health guidelines to promote reproductive and developmental health globally.
... As a typical plasticizer, DBP was widely used in cosmetics, children's toys, food packaging and medical devices to increase the exibility of plastics (Kavlock et al. 2002;Pan et al. 2006). Due to the relatively weak interactions between DBP and plastics through hydrogen bonding or van der Waals's forces, DBP has been widely detected in the environment (Heudorf et al. 2007; Lottrup et al. 2006;Swan 2008). In some areas, the concentration of DBP in the environment has reached a hazardous level. ...
Since Sertoli cells (SCs) play an important role in providing energy for spermatogenesis, the present study was aimed to investigate the effects of maternal exposure to plasticizer Dibutyl phthalate (DBP) on onset of spermatogenesis in male offspring through metabolism pathway as well as the underlying molecular mechanism. By detecting the level of the glucose metabolism in SCs, we found that monobutyl phthalate (MBP, the active metabolite of DBP) promoted cellular glycolysis accompanied by GLUT1, GLUT3, LDHA and MCT4 upregulated, leading to increased lactate which was provided spermatogenesis as energy substrate. Further mechanism research revealed that DBP/MBP increased fatty acid uptake and ATP production by promoting the expression of CD36, so as to accelerate their own maturity. Therefore, our findings provided new perspective at glycolipid metabolism to explain prenatal DBP exposure leading to earlier onset of spermatogenesis in male offspring mice.
... Since these emerging contaminants (PAEs) are not chemically bound to plastic polymers, therefore they leach, or migrate and enter into aquatic ecosystems through various pathways (industrial and domestic wastes, sewage sludge, surface runoff etc.) (Kastner et al., 2012;Liu et al., 2013;Net et al., 2014). These organic contaminants also cause serious health effects in humans such as fertility, organ damage, postnatal development alterations and birth defects (Lottrup et al., 2006;Guerrero-Bosagna and Skinner, 2014). At the experimental level, some phthalates such as di-isobutyl phthalate (DIBP) has been observed as a male reproductive toxicant (Yost et al., 2019), while di(2-ethylhexyl) phthalate (DEHP), a phthalate compound used in PVC medical devices, migrates to surrounding media such as blood, plasma and results in reproductive and developmental toxicity (Ito et al., 2005). ...
The present study provides baseline information on the concentration levels, distribution characteristics and pollution sources of environmental contaminants, such as phthalic acid esters (PAEs or phthalates) and petroleum hydrocarbons in surface sediments of the tropical estuaries (Mandovi and Ashtamudi) from western Peninsular India. Total PAEs (∑5PAEs), hopanes, steranes and diasteranes concentrations from Ashtamudi estuary ranged from 7.77 to 1478.2 ng/g, n. d.-363.2 ng/g, n. d.-121.5 ng/g and n. d.-116.6 ng/g, respectively. Likewise, PAEs (∑6PAEs), steranes and diasteranes concentrations from Mandovi estuary ranged from 60.1 to 271.9 ng/g, 2.33–40.1 ng/g and 2.28–23.0 ng/g, respectively. The PAEs comprising di-isobutyl phthalate (DIBP), dibutyl phthalate (DBP), an isomer peak for DBP, di (2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate were dominant in Ashtamudi estuary sediments, while PAEs including diethyl phthalate, DIBP, DBP and its isomer, DEHP, di (2-ethylhexyl) terephthalate were detected in the Mandovi sediment samples. The results of this study show an insignificant correlation of TOC with PAEs, and indicates that the varying spatial distributions of the PAEs in both the estuaries can be the result of discharge sources. The higher concentration of PAE congeners was noticed in Ashtamudi, a Ramsar wetland site, that can be attributed to land-based plastic waste. The petroleum biomarkers were abundantly present in Mandovi estuary due to anthropogenic activities such as boating and spillage from oil tankers. The findings of the present study will serve as a reference point for future investigation of organic contaminants in Indian estuaries, and calls for attention towards implementing effective measures in controlling the pervasion of the PAEs and petroleum biomarkers.
... Endocrine disruptors interfere with the action of hormones in biological systems, with ramifications for reproduction, metabolism, neurodevelopment and growth, among other functions (Gore et al., 2015). Among the hallmarks of phthalate exposure are the antiandrogenic effects they elicit in human and animal models (Barakat et al., 2019;Lottrup et al., 2006). They have additionally been associated with altered thyroid, progesterone, and estrogen activity in pregnant women as well as nonpregnant adults and children (Du et al., 2019;Ferguson et al., 2014b;Huang et al., 2016;Long et al., 2021). ...
Phthalates are ubiquitous compounds known to leach from the plastic products that contain them. Due to their endocrine disrupting properties, a wide range of studies have elucidated their effects on reproduction, metabolism, neurodevelopment, and growth. Additionally, their impacts during pregnancy and on the developing fetus have been extensively studied. Most recently, there has been interest in the impacts of phthalates on the placenta, a transient major endocrine organ critical to maintenance of the uterine environment and fetal development. Phthalate-induced changes in placental structure and function may have significant impacts on the course of pregnancy and ultimately, child health. Prior reviews have described the literature on phthalates and placental health, however to date, there has been no comprehensive, systematic review on this topic. Here we review 35 papers (24 human and 11 animal studies) and summarize phthalate exposures in relation to an extensive set of placental measures. Phthalate-related alterations were reported for placental morphology, hormone production, vascularization, histopathology, and gene/protein expression. The most consistent changes were observed in vascular and morphologic endpoints, including cell composition. These changes have implications for pregnancy complications such as preterm birth and intrauterine growth restriction as well as potential ramifications for children’s health. This comprehensive review of the literature, including common sources of bias, will inform the future work in this rapidly expanding field.
... Exposure to phthalates may occur through multiple routes, including ingestion (e.g., from food packaging and children's toys), inhalation (e.g., from building materials and furniture), and dermal contact (e.g., cosmetics and other personal care products) [80,81]. Dietary intake has been considered as the major route of exposure to phthalates [82]. ...
Plastic-associated endocrine disrupting chemicals (EDCs) have been implicated in the etiology of cardiovascular disease (CVD) in humans, but the underlying mechanisms remain elusive. Dicyclohexyl phthalate (DCHP) is a widely used phthalate plasticizer; whether and how exposure to DCHP elicits adverse effects in vivo is mostly unknown. We previously reported that DCHP is a potent ligand of the pregnane X receptor (PXR) which acts as a xenobiotic sensor to regulate xenobiotic metabolism. PXR also functions in macrophages to regulate atherosclerosis development in animal models. In the current study, LDL receptor-deficient mice with myeloid-specific PXR deficiency (PXRΔMyeLDLR−/−) mice and their control littermates (PXRF/FLDLR−/−) were used to determine the impact of DCHP exposure on macrophage function and atherosclerosis. Chronic exposure to DCHP significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of PXRF/FLDLR−/− mice by 65% and 77%, respectively. By contrast, DCHP did not affect atherosclerosis development in PXRΔMyeLDLR−/− mice. Exposure to DCHP led to elevated expression of the scavenger receptor CD36 in macrophages and increased macrophage form cell formation in PXRF/FLDLR−/− mice. Our findings provide potential mechanisms underlying phthalate-associated CVD risk and will ultimately stimulate further investigations and mitigation of the adverse effects of plastic-associated EDCs on CVD risk in humans.
... The amount of arachidonic acid and docosahexaenoic acid exerts a significant influence on neurodevelopment, regulation of sex hormones, and the normal growth of the fetal brain. Diethylhexyl phthalate, as an anti-androgenic compound, can affect fetal brain development [35,36]. Additionally, infant exposure to phthalates causes a severe decline in the number of neurons, movement impairment, and hyperactivity via increasing oxidative stress in the brain tissue [33,37]. ...
Background
Di-2-Ethylhexyl phthalate (DEHP) is one of the essential phthalate metabolites that disrupt the function of endocrine glands and causes numerous effects on animals, humans, and the environment. Phthalates are widely used in the plastics industry. Low doses of DEHP increase neurotoxicity in the nervous system that has arisen deep concerns due to the widespread nature of DEHP exposure and its high absorption during brain development.
Objective
This review article evaluated the impacts of DEHP exposure from birth to adulthood on neurobehavioral damages. Then, the possible mechanisms of DEHP-induced neurobehavioral impairment were discussed.
Methodology
Peer-reviewed articles were extracted through Embase, PubMed, and Google Scholar till the year 2021.
Results
The results showed that exposure to DEHP during pregnancy and infancy leads to memory loss and irreversible nervous system damage.
Conclusion
Overall, it seems that increased levels of oxidative stress and inflammatory mediators possess a pivotal role in DEHP-induced neurobehavioral impairment.
... Mustapha A Olajide 1 , Michael Coffey 2 and Jason W. Birkett 3 analytes found. In foetus studies, high bioaccumulation of phthalates due to easy placental transfer [8] has been observed and the effects of high doses of phthalates on male's reproductive organs have been shown but in most organ systems, they are relatively non-toxic. A reduction in testosterone production in rats exposed to phthalates confirmed extensive studies of phthalates with the increased high levels of human exposure in human spermatozoa increased damage to DNA [9][10][11][12][13][14]. ...
... Phthalates can bind to the transport protein for gonadal hormones-sex hormone-binding globulin (SHBG) and inhibit the transport mechanism for endogenous hormones in the blood circulation. An epidemiological study reported a positive association between phthalate metabolites and levels of SHBG in children [127]. Contrary, the next human study showed opposite results based on the sex of children. ...
During the period of mass industrial production of plastic products, the quality of human health has decreased significantly, especially in children’s neurodevelopmental disorders. Phthalates are endocrine-disrupting chemicals that can induce neurological disorders. This review aims to compile evidence concerning the associations between neurological disorders, such as attention-deficit/hyperactivity disorder, autism spectrum disorder, decreased masculine behavior, and phthalate exposure. Phthalates dysregulate the hypothalamic–pituitary–gonadal, adrenal, and thyroid axis, which is crucial for the neurodevelopmental process. Phthalates interfere with nuclear receptors in various neural structures involved in controlling brain functions and the onset of neurological disorders at the intracellular level. It is critical to increase the current knowledge concerning phthalates’ toxicity mechanism to comprehend their harmful effect on human health.
... Although DEHP is somewhat degradable, phthalates can cross the placenta lining and build up in the bodies of children, creating health problems. 6 Previous studies have suggested that exposure to DEHP leads to adverse pregnancy outcomes due to the suppressed placenta growth and development. 7 Fiandanese et al. demonstrated that maternal exposure to DEHP and polychlorinated biphenyls results in reproductive dysfunction of adult male mouse offspring. ...
The organic compound di(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in many products. Exposure to DEHP has been reported to lead to adverse pregnancy outcomes by suppressing placenta growth and development. The aim of this study was to determine the gene expression profiles of rat placenta exposed to (DEHP) and identify genes crucial for the DEHP response. Three groups of Wistar rats were administered an intragastric dose of 1,000 mg/kg DEHP, 500 mg/kg DEHP, or corn oil, RNA was isolated from placenta tissue, and hybridization was performed. Gene expression profiles were analyzed by identifying functional enrichment, differentially expressed genes (DEGs), protein-protein interaction (PPI) networks and modules, and transcription factor (TF)-miRNA-target regulatory networks. We obtained 2,032 DEGs, including cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1), sterol O-acyltransferase 2 (SOAT2), and 24-dehydrocholesterol reductase (DHCR24) from the steroid biosynthesis pathway and somatostatin receptor 4 (SSTR4) and somatostatin receptor 2 (SSTR2) in the neuroactive ligand-receptor interaction pathway. The PPI network included 476 nodes, 2,682 interaction pairs, and three sub-network modules. Moreover, eight miRNAs, three TFs, and 176 regulatory pairs were obtained from the TF-miRNA-target regulatory network. CYP2R1, SOAT2, DHCR24, SSTR4, and SSTR2 may affect DEHP influence on rat placenta development.
... Важный фактор биологического рискакомплексный характер воздействия спор грибов и их метаболитов, способствующий возникновению и усугублению, прежде всего, респира-торных симптомов и микоаллергозов [1,5]. В то же время длительное воздействие даже низких концентраций микотоксинов и других метаболитов грибов может приводить к появлению системных нарушений, в том числе со стороны репродуктивной системы [6], а также, возможно, оказывать цитотоксическое и нейротоксическое действие [7,8]. ...
Aim. To assess the degree of fungal contamination and the species composition of the fungal microbiota of residential apartments in Kazan Methods. A mycological study of 90 air samples and 60 samples from sites of fungal biodeterioration from the residential buildings of Kazan was carried out using cultural and microscopic methods. Results. The presence of micromycetes fungi were detected in 90% of air samples and 100% of samples from sites of biodeterioration. Higher fungal species diversity was noted in the sites, compared with air samples. Fungal concentrations in indoor air varied between 8 and 360 CFU/m3. Fungal community composition analysis of the sites of biodeterioration showed that the surfaces were more frequently contaminated by undemanding and capable of growth at different moisture levels fungal species (Penicillium spp., Aspergillus spp., Rhizopus stolonifer). The resulting fungal plaque can create conditions favorable for aggressive fungal species that actively damage materials (Chaetomium spp., Acremonium spp., Aureubasidium spp). Allergenic fungi, as well as potentially pathogenic and toxin-forming species, were widespread in the air that can be a health risk factor. A quantitative assessment of air mycobiota indicated the moderate level of fungal contamination. Conclusion. The presence of potentially pathogenic, allergenic and biodegradable fungal species in the sites of biodeterioration has been confirmed, as well as the relationship between airborne fungal contamination and the spread of fungi in indoors, confirming the need to prevent fungal biodeterioration and control indoor air quality.
... EDCs may perform anti-androgenic and xenoestrogenic actions; androgens and estrogens are involved in the regulation of lipid and glucose metabolism and in the regulation of adipose tissue [71,72]. As a result, EDCs can exert their obesogenic action by altering sex hormones receptor pathways, inhibiting the androgen receptor pathway, enhancing the estrogen pathway, or reducing androgen conversion through the upregulation of the aromatase enzyme [73][74][75]. ...
The purpose of this article is to review the evidence linking background exposure to endocrine-disrupting chemicals (EDCs) with insulin resistance in children. Although evidence in children is scarce since very few prospective studies exist even in adults, evidence that EDCs might be involved in the development of insulin resistance and related diseases such as obesity and diabetes is accumulating. We reviewed the literature on both cross-sectional and prospective studies in humans and experimental studies. Epidemiological studies show a statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, aromatic polycyclic hydrocarbides, or dioxins and insulin resistance.
... In addition to lipophilic matters, PAEs (phthalic acid esters) were found in the leachate, which were widely used as plasticizers in plastic manufacturing industries and the using rate was rapidly increased, both in domestic and international areas [36,37]. However, PAEs including dimethyl phthalate (DMP), di-n-butyl phthalate (DBP) and di (2-ethylhexyl) phthalate (DEHP) were considered to be carcinogenic [38,39]. Several countries, including the United States and China, have treated PAEs as top priority pollutants [40]. ...
Water washing on biomass can effectively remove K, Na and Cl, which will cause serious problems such as fouling, slagging and corrosion during thermal conversion processes of biomass. But amounts of leachates remain to be disposed. Investigating the organics release will be helpful to the leachate disposal. In this study, four types of biomass are water washed at different temperatures. The organic species and DBP (di-n-butyl phthalate) concentrations in leachates are determined by GC-MS. The results show that organics tend to release in the high-temperature region (60–90 °C). At 90 °C, 80% of organic matters in the wheat straw leachate are AR (aromatic hydrocarbons) and AL (alkanes, cycloalkanes and heterocyclic hydrocarbons). The organics distributions in the rice hull leachate are relatively uniform, compared with other leachates. The DBP concentrations in four leachates at 90 °C are lower than that at 30 °C because of its volatility. DBP concentrations in rice hull and corn stalk leachates show a trend of “reduction−increase”, with minimum values of 0.0001 and 0.001 mg L⁻¹ at 60 °C, respectively. Whereas in the sorghum stalk leachate, a tendency of “increase−reduction” is observed. The corresponding content achieves the maximum value of 0.024 mg L⁻¹.
... 4 PAEs have estrogenic effects and can destroy the hormonal balance of human beings, animals and their offspring. 5,6 Among PAEs, di-n-butyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) are the most widely used and are considered to be the main substance that produces estrogen in leachate. 7,8 Dissolved organic matter (DOM) in landll leachate is mainly distributed in humic acid (HA), fulvic acid (FA) and hydrophilic organic components (HyI). ...
The removal of di-n-butyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) with dissolved organic matter (DOM) was studied in a laboratory scale anaerobic/anoxic/oxic reactor for landfill leachate treatment. The removal rate was up to 98.0% for DBP and 78.2% for DEHP, which was related to humification of DOM (i.e., the aromaticity and molecular weight (MW) of humic substances in landfill leachate). The dissolved organic carbon (DOC) was mostly humic acid and fulvic acid in the fraction of 1–100 kDa MW, indicating strong aromaticity and a high DBP/DEHP concentration. With complete removal of the fraction, the removal rate of DBP/DEHP was also high. The positive correlation of the DOC and DBP/DEHP concentration in raw leachate and the effluent from each reactor showed that the interaction between DOM and DBP/DEHP facilitated the removal of organic pollutants.
... The action of exogenous factors on the male reproductive function seems, however, also supported by a genetic predisposition substrate, which is the basis of what is termed Testicular Dysgenesis Syndrome (TDS); the etiological hypotheses related to this condition relate to the possible estrogenic and anti-androgenic actions of exogenous substances, which not only can act by antagonizing hormone ligands, but can also operate at the molecular level by influencing the expression of genes involved in the regulation of reproductive function 186 . The time of exposure to EDCs, as well as the gender of the exposed individual, can have a significant importance in the occurrence of alterations in the pre and postnatal development; studies in animal models have shown that prenatal administration of phthalates can cause cryptorchidism in male rats, and is also responsible for early puberty in females 187 . Studies on the effects of EDCs on humans are still limited and poorly substantiated; some of the current knowledge is based on clinical experience of the past, as in the case of prenatal exposure to DES, once administered to pregnant women, which later turned out to be responsible for an increased incidence of urinary genital malformations such as hypospadias and cryptorchidism 188 . ...
The people of the world are facing a health crisis that arises from multiple degradations in the manner of producing and marketing food. These degradations affect every dimension of the food systems upon which we all depend, from soil, water and seeds to production and processing and distribution, and involve, above all, the abandonment of natural and organic food systems, and accompanying diets that were the foundation of human health throughout the world, throughout most of known human history. The root of the problem is the growing dependence on a dysfunctional productive paradigm that relies on chemicals such as pesticides and economies of scale to accelerate the quantities of food produced, not taking into account their nutritional quality and the harmful effects of these modes of production on people’s health and the ecosystem. These health effects adversely affect every stage of human life and range from still widely prevalent and growing undernutrition and malnutrition to a wide variety of chronic diet related diseases that are now the leading contributors to premature death and disability across the world. Alarmingly, the harmful health effects of the globalised industrial food system extend across generations through transmissible epigenetic effects, commercial conditioning of family diets and health impact of climate change. We are creating a dark, uncertain future for our children, as evidenced by the growing epidemics of childhood obesity and early onset of diabetes. We cannot continue to create a society where our children and their children will be deprived of nutritional security because of the actions of commercial interests and inaction on part of governments and other stakeholders in society. The justification for this emphasis on industrial agriculture, with its fossil fuel based chemical intensive agriculture and chemical intensive systems, centered around maximising production, is the need for sufficient food to feed a growing global population. However, nutrition empty commodities loaded with pesticides and toxics are not providing nourishment and health. They are, on the contrary, degrading the environment and our health by diminishing nutritional quality and diversity of food. Furthermore, the
Preamble
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industrial agri-food system consumes an immense amount of fossil energy (producing almost a third of all global greenhouse gas emissions), thus contributing to altering the ecosystem in the short term (climate variability) and in the long term (climate change). It is evident that, despite its exploitation of resources, industrial agriculture is not able to guarantee food security. Most of the food we eat is still produced by small and medium-sized farmers, while the vast majority of industrialised crops, such as corn and soya, are primarily used as animal feed or converted into biofuel. This shift away from traditional farming based on time tested principles of agroecology - working in harmony with, not against, nature - along with the lack of significant investment in independent research and innovation by scientific institutions and governments, is due to the influence of a series of mega-corporations take-overs, driven by the quest for maximum profits and minimum regulation. These multinationals, which are steadily taking over land throughout the world, rely on huge quantities of chemical fertilisers, pesticides, herbicides, and modified seeds responsible for the loss of micro-nutrient content that is the foundation of healthy food, while poisoning citizens indiscriminately, from producer to user. This push-for-profits is packaged as ‘smart agriculture’ as remedy to adverse impacts of agriculture on climate change. It is crucial to recognise that the agriculture sector is a major component of what can be best described as ‘predatory globalisation,’ the control and management of the world economy to ensure the efficiency of capital rather than the wellbeing of people and the planet. There is now a growing refusal of this way of satisfying the growing demand for food to implement the right to food for all while protecting the right to health as integral elements of human rights. The logic of the market is unfriendly to social and economic rights, and seeks to avoid recognizing the right to adequate, healthy, accessible and affordable food for all. To achieve food security for everyone on the planet depends on discarding policies and practices that lead to the physical and moral degradation of the food system while destroying our health and endangering the planet’s ecological stability, and endangering the biogenetic survival of life on the planet. Not only is the nutritional quality of food sacrificed to reach quantitative goals but the great benefits of biodiversity are seriously reduced with the growing dependence on a handful of globally traded commodities coming from chemical monocultures, with harmful effects on the quality and range of seeds as well as the biodiversity of all species, including the contamination of soil and ground water, leading to a significant contribution to climate change. These high environmental and health costs are largely excluded from the pricing of food, creating the illusion that food produced with high financial, ecological and health costs is “cheap”. Yet there exists a vibrant and growing alternative approach to food security and food production – Agroecology - based on biodiversity, which combines quantity and quality and maximizes the benefits to the health and wellbeing of the planet and its people. A new generation of farmers across the globe is increasingly conscious of their role in farming, in the defense of biodiversity, the defense and care of the land and
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the environment and in producing good and nutritious food. Across the world, farmers’ agroecology networks are springing up, becoming custodians of the emerging sustainable food production and agriculture practices while promoting the essential shift from the present extractive, linear approach to agriculture and food production, to one based on circularity, reciprocity and sharing, that lead lead to a brighter future for humankind. This emerging paradigm of agriculture, food, nutrition and health is an alternative to the chemical based monoculture paradigm that degrades our land, our food, our health, and instead regenerates the health of the planet’s ecosystems and communities. This new, and at the same time time-honoured approach is displacing the current damaging trends with policies, practices, and knowledge that ensure renewal. We interpret renewal to mean above all a revived reliance on the health potentialities of the natural food systems that work in harmony with nature, are based on food sovereignty and the return of seed into farmers’ hands, that are mindful of environmental impacts and contribute to preventing global warming caused by greenhouse gas emissions produced by industrial agriculture and long distance trade. The right to health can be realised only if the right to good nutrition is recognised, respected and realised. It is possible to create good health through good nutrition. For this we have to transform our food systems. This task is pivotal, not only for reaching the Sustainable Development Goals of 2030 but also for ensuring human and planetary health for generations to come. The transition to a new paradigm, based on the realisation of rights to health and food security, will depend on the commitment of civil society, the private sector, governments and global institutions. We believe that the renewal and adaptation of the best scientific and medical knowledge is necessary and possible, leading to a historic collaboration between popular movements and those experts attuned to the renewal of natural systems of food production and congenial social movements and initiatives, and a moral commitment to food justice as well as to human health. This manifesto is, above all, a call for responsible citizenship, which at once acknowledges the planetary dimensions of the challenge, calling for the supplementing of conventional ideas of citizenship of sovereign states with a boundary-less vision of planetary citizenship. It also recognises that the new paradigm can only come into being through a felt reality of global community; a future-oriented project, through the rise of citizen pilgrims, those recognising that a journey to a more humane future is essential for safeguarding the health and life prospects of unborn generations. In effect, we recognise that the renewal we call for is based on new, yet available, knowledge, and a moral commitment to food justice as well as to human health. We believe that the renewal and adaptation of the best scientific and medical knowledge are necessary and possible, and highly desirable, generating a historic collaboration between popular movements and those experts attuned to the renewal of natural systems of food production and congenial social movements and initiatives.
... PAEs, which are widely used in the plastics, coatings, and cosmetics industries, have received extensive attention in recent years [7,8]. They are suspected mutagens and carcinogens, and the United States Environmental Protection Agency, European Union, and China National Environmental Monitoring Center classify PAEs as priority environmental pollutants and endocrine-disrupting compounds [9,10]. ...
Transformations of di-n-butyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) have been investigated in anaerobic/anoxic/oxic (A/A/O) leachate treatment processes. Although the DBP removal processes are different when the DBP initial concentration is different, the overall system DBP removal efficiencies are high (> 94%). DEHP is much more difficult to remove than DBP. The removal efficiency of DEHP is approximately 75%–78%. The results of mass balance calculations indicate that approximately 33.7%–50.7% of the DBP is degraded by the activated sludge, 48.9%–64.9% accumulates in the system, and 0.4%–1.4% is contained in the final effluent. Approximately 15.0%–19.0% of the DEHP is degraded by activated microcosms, 75.8%–79.0% accumulates in the system, and 5.2%–6.0% is contained in the final effluent. Biodegradation and adsorption to the activated sludge are the main mechanisms for DBP removal and adsorption to the activated sludge is the main mechanism for DEHP removal. The different removal mechanisms of the two PAEs may be related to their different molecular structures. However, PAEs are not really removed when they adsorb onto the sludge. Therefore, methods for decreasing PAEs adsorption and increasing the biodegradation efficiencies of the leachate treatment processes should be further investigated.
... DEHP (when utilized in products such as medical devices/supplies) is detected at higher concentration in pregnant women and infants (Lottrup et al., 2006). Many scientists suggest that phthalates including DEHP are EDCs with antiandrogenic, estrogenic, or thyroid-disrupting effects (Ema and Miyawaki, 2001;Dong et al., 2017;Ghisari and Bonefeld-Jorgensen, 2009;Cha et al., 2018). ...
Phenobarbital (PB) and Di (2-ethylhexyl) phthalate (DEHP), an anti-epileptic drug and a plasticizer used in flexible polyvinylchloride formulations, respectively, are well-known typical hepatotoxicants. This study investigated the effects of PB (100 mg/kg/day) or DEHP (500 mg/kg/day) on the endocrine system in intact juvenile/peripubertal male rats exposed for 31 days beginning on postnatal day 23. Slight hormone level changes, histopathological changes in thyroid gland or induction of UDP-glucuronosyltransferase in liver were observed in both the PB and DEHP groups. One of the assumed mechanisms inducing thyroid effects is predictable to be secondary changes based on the enhancement in thyroid hormone metabolism via the induction of hepatic microsomal enzymes. No reproductive system-related changes in organ weights, histopathology, and sexual maturation were observed in both groups. Lower testosterone level was observed in the PB group. CYP2B and CYP3A, which are involved in testosterone metabolism, were induced in liver of the PB group. There was no change of 17β-hydroxysteroid dehydrogenase activity in testis of both groups. Lower testosterone level in the PB-treated male rats was attributed to an indirect, hepatotoxicity-associated effect on the reproductive system and not to direct effects on testis such as the antiandrogenic activity and the inhibition of steroidogenesis. These results did not indicate that PB or DEHP exposure affects the endocrine system directly.
... In plastics, PAEs act as "lubricants" between molecules, which are connected with polyolefin-based plastic molecules by hydrogen bonds or van der Waals forces, retaining their independent chemical properties. Therefore, PAEs can easily migrate from plastic to the external environment (Keizer-Schrama et al. 2006). However, only 18% of PAEs with typical settings could be removed by wastewater treatment plans (Simoneit et al. 2005). ...
Phthalates (PAEs) in drinking water sources such as the Yangtze River in developing countries had aroused widespread concern. Here, the water, suspended particulate matter (SPM), and sediment samples were collected from 15 sites in wet and dry seasons in Zhenjiang, for the determination of six PAEs (DMP, DEP, DIBP, DBP, DEHP, and DOP) using the solid-phase extraction (SPE) or ultrasonic extraction coupled with gas chromatography-mass spectrometry (GC-MS). The total concentrations of six PAEs (Σ6PAEs) spanned a range of 2.65–39.31 μg L⁻¹ in water, 1.97–34.10 μg g⁻¹ in SPM, and 0.93–34.70 μg g⁻¹ in sediment. The partition coefficients (Kd1) of PAEs in water and SPM phase ranged from 0.004 to 3.36 L g⁻¹ in the wet season and from 0.12 to 2.84 L g⁻¹ in the dry season. Kd2 of PAEs in water and sediment phase was 0.001–9.75 L g⁻¹ in the wet season and 0.006–8.05 L g⁻¹ in the dry season. The dominant PAEs were DIBP, DBP, and DEHP in water and SPM, DIBP, DEHP, and DOP in sediment. The concentration of DBP in water exceeded the China Surface Water Standard. The discharge of domestic sewage and industrial wastewater might be the main potential sources of PAEs. The risk quotient (RQ) method used for the risk assessment revealed that DBP (0.01 < RQ < 1) posed a medium risk, while DIBP and DEHP (RQ > 1) posed a high environmental risk in water, DIBP (RQ > 1) also showed a high risk in sediment.
... While high molecular weight phthalates, such as di-(2ethylhexyl) phthalate (DEHP), are mainly used as PVC plasticizers, low molecular weight compounds, including di-n-butyl phthalate (DBP), are used as additives in many industrial products, as for instance, stickers, paints, personal hygiene products, air purifiers and pharmaceuticals. Epidemiologic studies suggest positive associations between maternal phthalate exposure and human reproductive abnormalities, including reductions in the anogenital distance in male infants, an external marker of prenatal androgenization (Lottrup et al., 2006;Meeker et al., 2009;Swan et al., 2015). Consequences of fetal exposure to phthalates on the reproductive system have already been demonstrated and are well established in rodent models. ...
Prenatal exposure to phthalates is associated with reproductive and metabolic systems alterations. We investigated the effects of in utero and lactational exposure to Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-n-butyl phthalate (DBP) on the reproductive system and glycemic homeostasis in male and female offspring of rats. Pregnant rats were exposed to equimolar doses (0.018, 0.18 and 1.8 mmol/kg/day) of DEHP or DBP corresponding to 7, 70, and 700 mg/kg/day for DEHP and 5, 50, and 500 mg/kg/day for DBP, respectively, by oral gavage from gestation day 13 to postnatal day 21, and using canola oil as vehicle control. Male and female offspring were examined for body weight development, external markers of prenatal androgenization and puberty onset, plasma concentrations of glucose and insulin, insulin tolerance (ITT), glucose-stimulated insulin secretion (GSIS), and the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and pancreatic and duodenal homeobox 1 protein (PDX-1). Male and female rats exposed to the highest doses of DEHP and DBP exhibited increased fasting glucose levels. In rats exposed to DEHP 700 mg/kg/day we also observed a reduced glucose decay rate (Kitt) following insulin administration and decreased insulin secretion in the GSIS assay. Male offspring exposed to DEHP 700 mg/kg/day had reduced anogenital distance (AGD) on PDN 4 and delayed preputial separation at puberty, while female offspring exposed to DEHP 70 and 700 mg/kg/day and to the highest DBP dose had delayed vaginal opening. Our results suggest that maternal treatment with DEHP and DBP can induce a wide range of metabolic and reproductive alterations in offspring rats, with more pronounced effects following DEHP exposure.
... Phthalate toxicity is associated with endocrine system disruption in different species of fish and mammals. These compounds were also observed to interfere with the reproductive system and in human and animal development (Lottrup et al., 2006;Li et al., 2010). Concurrent observation of phenols and phthalate esters has been reported in the Selangor River basin in Malaysia (Santhi and Mustafa, 2013) and induction of lactate dehydrogenase release from Sertoli cells, which is associated with infertility, coexist compared to individual chemical effects (Li et al., 2010). ...
... Phthalate toxicity is associated with endocrine system disruption in different species of fish and mammals. These compounds were also observed to interfere with the reproductive system and in human and animal development (Lottrup et al., 2006;Li et al., 2010). Concurrent observation of phenols and phthalate esters has been reported in the Selangor River basin in Malaysia (Santhi and Mustafa, 2013) and induction of lactate dehydrogenase release from Sertoli cells, which is associated with infertility, coexist compared to individual chemical effects (Li et al., 2010). ...
Production of fuels, therapeutic drugs, chemicals, and biomaterials using sustainable biological processes have received renewed attention due to increasing environmental concerns. Despite having high industrial output, most of the current chemical processes are associated with environmentally undesirable by-products which escalate the cost of downstream processing. Compared to chemical processes, whole cell biocatalysts offer several advantages including high selectivity, catalytic efficiency, milder operational conditions and low impact on the environment, making this approach the current choice for synthesis and manufacturing of different industrial products. In this review, we present the application of whole cell actinobacteria for the synthesis of biologically active compounds, biofuel production and conversion of harmful compounds to less toxic by-products. Actinobacteria alone are responsible for the production of nearly half of the documented biologically active metabolites and many enzymes; with the involvement of various species of whole cell actinobacteria such as Rhodococcus, Streptomyces, Nocardia and Corynebacterium for the production of useful industrial commodities.
Di-n-butyl phthalate (DBP) is one of the most dominant phthalate esters and is a widely distributed environmental contaminant. The endocrine disrupting properties of DBP are well established both in humans and animal models. In this study, we examined the effects of low levels gestational exposure to DBP on the expression of steroidogenic acute regulatory protein (StAR) and the mitochondrial enzyme cytochrome P450 side chain cleavage (P450scc). The biosynthesis of active neurosteroids starts with the transfer of cholesterol from the outer to the inner mitochondrial membrane by StAR protein and the subsequent cleavage of the side chain by P450scc. This results in cholesterol conversion to pregnenolone. Gestational exposure of DBP disrupts neurosteroidogenesis by affecting the expression levels of key proteins critical for the biosynthesis of neurosteroids like pregnenolone. Neuroactive steroids regulate neuronal function through their concurrent influence on neuronal excitability and gene expression. There is now considerable evidence that neuroactive steroids have modulatory effects on the release of multiple neurotransmitters and are potent positive allosteric modulators of neurotransmitter receptors through increasing the frequency and/or duration of openings of gated channels. At the molecular level, neuroactive steroids can bind to intracellular receptors that act as transcription factors and regulate gene expression. Therefore, active neurosteroids play an important role in neuronal development through their genomic and non-genomic effects. Our results showed that gestational exposure of DBP (1 mg/kg BW) at embryonic day 10 induced alterations in gene expression that persisted into adulthood. We examined the brains and testis of 2 month old mice, offspring of dams injected with DBP at gestational day 10, and found a significant decrease in mRNA levels of StAR and P450scc in the hippocampus and testis. Additionally, mRNA levels of the β3 subunit of the GABAA receptor and glutamic decarboxylase in the hippocampus were significantly downregulated. Consistent with this reduction in gene expression of StAR, P450scc, GAD67 and the GABAA receptor, protein expression was also reduced. These data suggest that gestational exposure to endocrine disruptors induces long-lasting neurochemical changes that persist into adulthood.
The petroleum sector's contribution to the global economy is significant and remarkable, with a vast spectrum of products utilised in transportation, industry, and household consumption. However, the petroleum industry generates a vast amount of emerging petroleum pollutants. As petroleum pollutants have a detrimental effect on human health and the environment, these pollutants are rising sources of concern. One highly concerning emerging petroleum contaminant is Polycyclic aromatic hydrocarbons (PAHs). PAHs have been related to cancer, and adverse effects on development and reproduction are among other health issues. Polychlorinated biphenyls (PCBs) are another emerging pollutant extensively employed in industrial and commercial applications as coolants and lubricants in electrical equipment. But cancer and immune system malfunction are some health issues connected to PCB exposure. These pollutants are joined by perfluoroalkyl and polyfluoroalkyl substances (PFAS), utilized in various applications. They may penetrate the food chain and harm wildlife. These contaminants may harm many creatures, from tiny plankton to bigger fish and mammals, and have long-term repercussions on the environment. These toxins may accumulate in these species' tissues and damage animals who consume them. Nitrogen-containing compounds, oxygenated compounds, Endocrine disrupting compounds (EDCs), nanoparticles, and flame retardants are some of the emerging petroleum pollutants that are notoriously difficult to eliminate and pose severe human and environmental health risks. Emerging petroleum pollutants constitute a significant problem that must be addressed to safeguard human health and the natural environment. The removal of these contaminants will need substantial efforts in the areas of research, regulatory reform, and environmental cleaning.
Low-density polyethylene (LDPE) is a synthetic plastic used globally in quantities ranging from 57 million tonnes per year. The increasing accumulation rate and non-biodegradability are wreaking havoc on the organism and the environment. The biodegradation method can be used in a more environmentally friendly way to eliminate plastics from the soil. The microbial population is primarily involved in biodegradation because it is capable of secreting specific enzymes that cleave higher molecular weight molecules in LDPE, increasing the rate of biodegradation and eliminating them from the environment. This chapter focuses on the steps involved in the biodegradation process, like biodeterioration, biofragmentation, bioassimilation, and mineralization. Several other factors have contributed to the process’s speeding up. The exposure circumstances (abiotic—moisture, pH, temperature, nutrients; biotic—microbe exposure) on LDPE, as well as polymer characteristics (molecular weight, hydrophobicity, size, shape, functional groups, additives) of an LDPE, have a significant impact in this regard. Nanoparticles (SPION, NBT, fullerene-60) and other pretreatments (UV treatment, prooxidants, photocatalysis) are promising techniques for combining with bacteria to increase biodegradation results.
There is little research on the relationship between phthalates exposure and sleep problems in adult females, with existing studies only assessing the association between exposure to individual phthalates with sleep problems. We aimed to analyse the relationship between phthalates and sleep problems in 1366 US females aged 20 years and older from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) by age stratification. Multivariate logistic regression showed that the fourth quartile of MECPP increased the risk of sleep problems in females aged 20-39 compared with the reference quartile (OR: 1.87, 95% CI: 1.14, 3.08). The WQS index was significantly associated with the sleep problems in females aged 20-39. In the BKMR, a positive overall trend between the mixture and sleep problems in females aged 20-39. In this study, we concluded that phthalates might increase the risk of sleep problems in females aged 20-39.
Di (2-ethyl hexyl) Phthalate (DEHP) is one of the plasticizers widely used in the manufacturing of plastics to make it flexible and durable. Present study is focussed to observe the deleterious effects of DEHP on male reproductive system of animals. For this, 1000 mg/kg body wt. of DEHP was administered to different groups of male Wistar rat for 2, 4, 6 and 8 weeks. After each interval, rats were sacrificed and histological alterations in testis of rats were observed. On hormonal assay, testosterone level decreased significantly in DEHP exposed groups. The histological structure of the testis was also observed to be disrupted significantly with increasing duration of DEHP exposure. Organisation of seminiferous tubule was found distorted and disoriented showing large gaps between them along with degenerated epithelium. Evident changes in morphology of spermatozoa were seen with gradual loss of head and tail structure. Decrease in the number of Leydig cells and sertoli cells were also found suggesting DEHP as a potent toxicant for male reproductive system.
Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse health effects. Via hydrolysis of one of the two ester bonds in the human body, DEHP and DINCH form the monoesters MEHP and MINCH, respectively. Previous studies demonstrated binding of these metabolites to PPARγ and the induction of adipogenesis via this pathway. Detailed structural understanding of how these metabolites interact with PPARγ and thereby affect human health is lacking until now. We therefore characterized the binding modes of MINCH and MEHP to the ligand binding domain of PPARγ by X-ray crystallography and molecular dynamics (MD) simulations. Both compounds bind to the activating function-2 (AF-2) binding site via an interaction of the free carboxylates with the histidines 323 and 449, tyrosine 473 and serine 289. The alkyl chains form hydrophobic interactions with the tunnel next to cysteine 285. These binding modes are generally stable as demonstrated by the MD simulations and they resemble the complexation of fatty acids and their metabolites to the AF-2 site of PPARγ. Similar to the situation for these natural PPARγ agonists, the interaction of the free carboxylate groups of MEHP and MINCH with tyrosine 473 and surrounding residues stabilizes the AF-2 helix in the upward conformation. This state promotes binding of coactivator proteins and thus formation of the active complex for transcription of the specific target genes. Moreover, a comparison of the residues involved in binding of the plasticizer metabolites in vertebrate PPARγ orthologs shows that these compounds likely have similar effects in other species.
Since Sertoli cells (SCs) play an essential role in providing energy for spermatogenesis, the present study aimed to investigate the effects of maternal exposure to plasticizer Dibutyl phthalate (DBP) on the onset of spermatogenesis in male offspring through the metabolism pathway as well as the underlying molecular mechanism. Here, pregnant mice were treated with 0 (control), 50, 250, or 500mg/kg/day DBP in 1mL/kg corn oil administered daily by oral gavage from gestation day (GD) 12.5 to parturition. The in vivo results showed that 50mg/kg/day DBP exposure could promote the expression of glucose metabolism-related proteins (GLUT3, LDHA, and MCT4) in the testis of 22 days male offspring. The in vitro results demonstrated that 0.1mM monobutyl phthalate (MBP, the active metabolite of DBP) promoted the lactate production, glucose consumption, and glycolytic flux of immature SCs, which was paralleled by the upregulated expression of glucose metabolism-related proteins (GLUT1, GLUT3, LDHA, and MCT4). On the other hand, DBP/MBP increased fatty acid (FA) uptake, FA β-oxidation, and ATP production by promoting the expression of CD36 in immature SCs, which might accelerate the maturity of SCs to support the onset of spermatogenesis. Therefore, our findings provided a new perspective on glycolipid metabolism to explain prenatal DBP exposure leading to earlier onset of spermatogenesis in male offspring mice.
Over the past few decades, several pollutants classified as environmental endocrine-disrupting chemicals (EDCs) have become a matter of significant public health concern. Companion animals play a major role in human society, and pet ownership is substantially increasing worldwide. These intimate human–pet relationships imply sharing much of the same environment, thus including exposure to similar levels of EDCs in daily routine. Here, we review the current knowledge on the sources and routes of exposure to EDCs in domestic indoor and outdoor environments and discuss whether endocrine disruption is a health concern in pets. We summarize the phenomenon of endocrine disruption, providing examples of EDCs with a known impact on dog and cat health. Then, we propose an overview of the literature on the adverse effects of EDCs in domestic pets, with a special focus on the health of reproductive and thyroid systems. Finally, we explore the potential role of companion animals as unintentional sentinels of environmental exposure to EDCs and the implications for public health risk assessment in a “shared risk” scenario. Overall, this review supports the need for an integrated approach considering humans, animals, and the environment as a whole for a comprehensive assessment of the impact of EDCs on human and animal health.
Major problem of plastic pollution has been arising due to misuse of plastic. Single-use plastics and microbeads are the main contributors to this global environmental issue. When this plastic entered in environment poses negative environmental impacts. Due to lack of effective policies on single-use plastic and microbeads, the problem is on rise. Although there is lack of studies on this escalating problem, few studies reveal the alarming situation. This chapter highlights the current scenario of environmental consequences, fate, ecofriendly alternatives and efficacy analysis with the impact of current policies to reduce the plastic pollution. It provides fruitful information and highlights the loopholes for authorities and decision-makers with a view of policy recommendation to curb pollution due to single-use plastics.
Much evidence on the adverse health effects of endocrine-disrupting chemicals (EDCs) has accumulated during recent decades. EDCs are commonly found in various foods and personal care products (PCP). Data documenting a diurnally varying EDC metabolism in humans is scarce. This study examined (i) the time-of-day effect on the diurnal magnitude and variance of urinary biomarkers of exposure to EDCs, and (ii) the association between EDC exposures and oxidative damage in a Norwegian adult subpopulation. This was a cross-sectional panel study using biobanked samples from the EuroMix project. During a typical weekday, participants were asked to collect all day’s urine voids and record dietary and PCP habitual uses in a diary. Collected time stamps of urine voids were classified into three distinct periods in the day (morning 6 a.m.–12 p.m., mid-day 12 p.m.–6 p.m., evening 6 p.m.–6 a.m.). Questionnaires regarding demographic characteristics, personal care product usage, and dietary habits were completed. Urinary levels of EDCs (phthalates, parabens, and bisphenols) were measured using mass spectrometry and adjusted for urinary volume using specific gravity. Urinary 4-hydroxynonenal (4HNE), a lipid peroxidation marker, was measured using an immunoassay kit. Linear mixed-effect models identified EDCs under the influence of a diurnal variation effect that was adjusted for dietary habits and PCP use and examined associations between EDC and 4HNE. p-values were FDR-adjusted. Most phthalates appeared to be diurnally varying with higher urinary levels towards the evening (q < 0.001) than those measured during mid-day; this strong diurnal variation effect was not present for parabens and bisphenols. Significant (q < 0.001) positive associations were observed between all phthalates, parabens, and bisphenols (except bisphenol S) and 4HNE. This study’s findings highlighted the diurnal variation of excretion for certain EDC, but not for others, in real-life conditions. The degree of EDC chronotoxicity in distinct diurnal windows of the day warrants further investigation with longitudinal human studies.
The effect of hydraulic parameters of an anaerobic/anoxic/oxic leachate treatment reactor on the removal of di(2-ethylhexyl) phthalate (DEHP) from aged landfill leachate was studied. The mean DEHP removal efficiencies were 79.5%, 87.1%, 89.7% and 87.8% at hydraulic retention times of 6, 4.5, 3 and 2 d, respectively. The removal efficiency of DEHP was significantly higher when the internal reflux ratio was 200% than others. There was no significant difference among the DEHP removal efficiencies at different external reflux ratios of the reactor. Due to the overall efficiency of the reactor, hydraulic retention time 3 d, internal reflux ratio 200% and external reflux ratio 60%, were considered the optimal hydraulic parameters for DEHP removal from aged leachate. The removal efficiency of DEHP was significantly improved (from 75.7% to 89.1%) after the optimization of hydraulic parameters of the reactor. The removal percentages of DEHP in the anaerobic, anoxic, and oxic units of the reactor were 42.8%, 17.6%, and 15.3%, respectively. The oxic microcosms in the reactor had little effect on DEHP removal. The correlation between DEHP and leachate pollutants indicated that DEHP removal was strongly correlated with leachate COD and NH4⁺–N.
Kozmetik ürünler genellikle daha güzel görünmek, kendini daha iyi hissetmek, görünmesi istenmeyen durumları örtmek, güneşten korunmak ve tedavi amaçlı kullanılmaktadır. Kozmetiklerin kullanımı tüm dünyada giderek artmaktadır. Kullanım sıklığı giderek artan kozmetiklerin içerisinde ise birçok kimyasal bulunmaktadır. Gebelik dönemi bu kimyasalların alınması bakımından daha temkinli davranılan ve hassas bir dönemdir. Gebelik döneminde kozmetiklerdeki kimyasal maruziyeti fetüsün sağlığını bozarak sağlık problemlerine yol açabilir. Bu sorunlar arasında mental retardasyon, anlama bozuklukları ve ilerleyen zamanlarda hormonal bozukluklar gibi geri dönüşümü olmayan hasarlara neden olabilir. Bu makalenin amacı sık kullanılan kozmetikleri ve içerisindeki kimyasalların etkilerini değerlendirerek hassas olan gebelik dönemine etkilerini ortaya koymak, fetüsü nasıl etkilediğini ve olumsuz sonuçlarını irdelemektir.
The feasibility of using the conversion of phthalates to fluorescein in analytical luminescence spectroscopy for the detection of phthalates is considered. Phthalates are converted to fluorescein by their prior hydrolysis to give phthalic acid followed by dehydration of this acid to give phthalic anhydride and the reaction of the latter with resorcinol. The formation of luminescent byproducts in the autocondensation of resorcinol molecules presumably with the products of their own oxidation and decomposition was detected. The luminescence spectrum of the by product mixture obtained upon the transformation of resorcinol overlaps the spectrum of fluorescein and the relative quantum yield of the mixture luminescence was 25%. This behavior hinders the use of this reaction for analytical purposes since special care is required for sample preparation and selection of the reaction conditions in order to minimize or, hopefully, eliminate the formation of such luminescent by products.
The male reproductive system is exposed to a great number of chemical substances which can interfere with the normal hormonal milieu and reproductive function; these are called endocrine disruptors (EDs). Despite a growing number of studies evaluating the negative effects of EDs, their production is continuously growing although some of which have been prohibited. The prevalence of poor semen quality, hypospadias, cryptorchidism, and testicular cancer have increased in the last decades, and recently, it has been postulated that these could all be part of a unique syndrome called testicular dysgenesis syndrome. This syndrome could be related to exposure to a number of EDs which cause imbalances in the hormonal milieu and oestrogenic over-exposure during the foetal stage. The same EDs can also impair spermatogenesis in offspring and have epigenetic effects. Although studies on animal and in vitro models have raised concerns, data are conflicting. However, these studies must be considered as the basis for future research to promote male reproductive health.
Fetal development of the mammalian testis relies on a series of interrelated cellular processes: commitment of somatic progenitor cells to Sertoli and Leydig cell fate, migration of endothelial cells and Sertoli cells, differentiation of germ cells, deposition of basement membrane, and establishment of cell-cell contacts, including Sertoli-Sertoli and Sertoli-germ cell contacts. These processes are orchestrated by intracellular, endocrine, and paracrine signaling processes. Because of this complexity, testis development can be disrupted by a variety of environmental toxicants. Toxicity of phthalic acid esters (phthalates) to the fetal testis has been the subject of extensive research for two decades, and phthalates have become an archetypal fetal testis toxicant. Phthalates disrupt the seminiferous cord formation and maturation, Sertoli cell function, biosynthesis of testosterone in Leydig cells, and impair germ cell survival and development, producing characteristic multinucleated germ cells. However, the mechanisms responsible for these effects are not fully understood. This review describes current knowledge of the adverse effects of phthalates on the fetal testis and their associated windows of sensitivity, and compares and contrasts the mechanisms by which toxicants of current interest, bisphenol A and its replacements, analgesics, and perfluorinated alkyl substances, alter testicular developmental processes. Working towards a better understanding of the molecular mechanisms responsible for phthalate toxicity will be critical for understanding the long-term impacts of environmental chemicals and pharmaceuticals on human reproductive health.
The effects of hydraulic condition of reactor and the dominant degrading bacteria on the removal of di-n-butyl phthalate (DBP) from aged landfill leachate by anaerobic/anoxic/oxic (A/A/O) leachate treatment process were investigated. The optimal DBP removal (96.0%) was obtained from aged leachate when the hydraulic retention time (HRT) of the reactor was 3 d, internal reflux ratio of the reactor was 200%, and external reflux ratio of the reactor was 60%, respectively. The removal efficiency of DBP was significantly improved after the inoculation of the dominant DBP-degrading bacteria (Pseudomonas sp. W1) in the reactor. The mean removal efficiencies of DBP before and after inoculation were 94.1% and 97.7%, respectively. Furthermore, the inoculation of dominant DBP-degrading bacteria changed the original sludge structure and characteristics, which was more conducive to the removal of DBP. These results provide theoretical basis for the effective removal of DBP from aged leachate by the biological treatment process.
Di-n-butyl phthalate (DBP) is considered as a potential modifier of puberty. However, different results indicate that DBP plays an accelerated, delayed, or neutral role in the initiation of puberty. Furthermore, whether the effect of DBP on puberty will disrupt the function of reproductive system in the adults is still ambiguous. Therefore, we aimed to investigate the effect of maternal exposure to DBP on the onset of puberty in male offspring mice and the subsequent changes in the development of reproductive system. Here, pregnant mice were treated with 0 (control), 50, 250, or 500 mg/kg/day DBP in 1 mL/kg corn oil administered daily by oral gavage from gestation day (GD) 12.5 to parturition. Compared with the control group, the 50 mg/kg/day DBP group accelerated puberty onset and testicular development were quite remarkable in male offspring mice during early puberty. Furthermore, in 22-day male offspring mice, 50 mg/kg/day DBP induced increased levels of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone in serum, and promoted the expression of steroidogenesis-related genes in the testes. Testicular Leydig cells (LCs) were isolated from the testes of 3-week-old mice and treated with 0 (control), 0.1, 1 mM monobutyl phthalate (MBP, the active metabolite of DBP) for 24 h. Consistent with the in vivo results, the expression of steroidogenesis-related genes and testosterone production were increased in LCs following exposure to 0.1 mM MBP. In adulthood, testes of the male offspring mice exposed to all doses of DBP exhibited adverse morphology compared with the control group. These results demonstrated that maternal exposure to 50 mg/kg/day DBP induced earlier puberty and precocious development of the testis, and eventually damaged the reproductive system in the later life.
Aims:
It is commonly known that stored blood and blood products are heated before transfusion to prevent hypothermia, which leads to increased di-(2-ethylhexyl) phthalate (DEHP) content leaching into the blood and blood products and thereby causes greater conversion of di-(2-ethylhexyl) phthalate to mono (2-ethylhexyl) phthalate (MEHP). However, there has been no study in the literature reporting on the amount of toxic phthalates in blood following the erythrocyte suspension transfused via warming. In this study, we aimed to investigate the DEHP and MEHP content in blood following the heated erythrocyte suspension transfusions administered by DEHP-containing and DEHP-free infusion sets.
Methods:
The study included 30 patients that were randomly divided into two groups with 15 patients each: group I underwent erythrocyte suspension transfusion via DEHP-containing infusion sets warmed with blood-fluid warmers, and group II underwent erythrocyte suspension transfusion via DEHP-free infusion sets warmed with blood-fluid warmers. DEHP and MEHP levels were measured both before and after transfusion.
Results:
DEHP-free infusion sets led to no increase in the phthalate content, whereas DEHP-containing infusion sets significantly increased the DEHP and MEHP, where the DEHP level increased almost four times (p=0.001).
Conclusion:
DEHP-containing products lead to toxicity. Therefore, using DEHP-free medical devices may prevent toxicity in patients undergoing erythrocyte suspension transfusion.
https://drum.lib.umd.edu/handle/1903/10083
One of the most potent EDCs in the environment is 17-ethynylestradiol (EE 2), the hormone in most birth control pills. EE 2 is released into the ecosystem through human wastewater, affecting the environment and its inhabitants. Fish both live and reproduce in these affected ecosystems, which may make them particularly susceptible to the effects of EE 2. This study investigates the impacts on reproductive efficacy of acute, direct exposure of male hybrid striped bass sperm cells to EE 2. In the study, reproductive efficacy is measured by two endpoints: genetic integrity of sperm DNA and sperm cell viability. Genetic integrity and cell viability were assessed by the comet assay and SYBR-14/Propidium Iodide stains, respectively. The results concerning genetic integrity were not statistically significant, but the results of the sperm viability assay suggest that acute direct exposure to EE 2 does not cause significant death within a population of sperm.
Indoor environment constitutes an important source of industrial additive chemicals to human exposure. We hypothesized that the influence of residential environment on human exposure varies among different types of additive chemicals and differs between children and mothers. This study determined a suite of additive chemicals in house dust from South China dwellings (n = 47) and urine from child-mother pairs. Concentrations of phthalates (PAEs; median 601 μg/g) were 2 - 3 orders of magnitude greater than those of parabens (0.82 μg/g), bisphenols (3.31 μg/g), and benzophenone-related chemicals (2.69 μg/g). Urinary concentrations differed between children and mothers, but the pattern of differences varied between chemical groups. Children exhibited greater urinary levels of mono-PAEs than mothers (510 versus 395 ng/mL, p = 0.152), while the latter population exhibited greater levels of parabens and benzophenones. Regression analyses indicate a lack of association between dust and urinary levels for most chemicals, suggesting that other exposure pathways can complicate human exposure scenarios. Indeed, we estimated that the daily intake via dust ingestion only constituted 0.002 - 0.81% of total daily intake estimated based on urine data for mothers and 0.04 – 5.61% for children. Future efforts are needed to better characterize source-specific exposure for different populations.
Phthalates are water-insoluble organic plasticizers which provide flexibility to PVC-plastics and make them useable in pharmaceutical industry, medical devices, clothing, and food packings. These plasticizers leach out from such articles as they are not chemically bound to polymeric materials and act as toxicants. These contaminants are found everywhere in the environment. Humans are always exposed to different kinds of phthalates through food, inhalation, personal care products, clothing, medication, nutritional supplements, etc. The hand to mouth behavior of infants increases the risk of phthalates exposure at the crucial phase of their growth and development. The phthalates or their metabolites act as agonist or antagonist ligands and disrupt the chemical signaling of the endocrine hormones thus are regarded as endocrine disrupting chemicals (EDCs). So the disrupted messaging by the hormones implicate a number of abnormalities, behavioral issues, and diseases like impaired neurodevelopment, decreased IQ and attention deficit, early puberty and fertility issues, sex anomalies, altered reproductive development, etc. The impaired endocrinal signaling cause perturbation of lipid and glucose homeostasis and result in obesity, overweight and insulin resistance and type II diabetes.
Abstrac
While phthalate esters are commonly used as plasticizers to improve the flexibility and workability of polymeric materials, their presence and detection in various environments has become a significant concern. Phthalate esters are known to have endocrine-disrupting effects, which affects reproductive health and physical development. As a result, there is now increased focus and urgency to develop effective and energy efficient technologies capable of removing these harmful compounds from the environment. This review explores the use of semiconductor photocatalysis as an efficient and promising solution towards achieving removal and degradation of phthalate esters. A comprehensive review of photocatalysts reported in the literature demonstrates the range of materials including commercial TiO2, solar activated catalysts and composite materials capable of enhancing adsorption and degradation. The degradation pathways and kinetics are also considered to provide the reader with an insight into the photocatalytic mechanism of removal. In addition, through the use of two key platforms (the technology readiness level scale and electrical energy per order), the crucial parameters associated with advancing photocatalysis for phthalate ester removal are discussed. These include enhanced surface interaction, catalyst platform development, improved light delivery systems and overall system energy requirements with a view towards pilot scale and industrial deployment.
Previous studies demonstrated that maternal exposure to di-n-butyl phthalate (DBP) resulted in developmental disorder of male reproductive organ, however, the underlying mechanism has not been thoroughly elucidated to date. The present study was aimed to investigate the effects of maternal exposure to DBP on the formation of the Sertoli cells (SCs)-based tight junctions (TJs) in the testes of male offspring mice and the underlying molecular mechanism. By observation of pathological structure and ultrastructure and permeability analysis of in testis of 22-day male offspring in vivo as well as transepithelial electrical resistance measurement of inter-SCs in vitro, we found that formation of TJs between SCs in offspring mice was accelerated, which was paralleled by the accumulation of TJs protein occludin at 50 mg/kg/day DBP exposure in utero and 0.1 mM monobutyl phthalate (MBP, the active metabolite of DBP) in vitro, respectively. Our in vitro results demonstrated that 0.1 mM MBP down-regulated the expression of matrix metalloproteinase-2 (MMP-2) by inhibiting the activation of nuclear factor-κB (NF-κB)/cyclooxygenase-2 (COX-2)/ prostaglandin E2 (PGE2) cascades via attenuated binding of NF-κB to both MMP-2 promoter and COX-2 promoter. Taken together, the data confirmed that maternal exposure to relative low-dose DBP promoted the formation of testicular TJs through down-regulation of NF-κB/COX-2/PGE2/MMP-2, which might promote the development of testis during puberty. Our findings may provide new perspectives for prenatal DBP exposure, which is a potentially environmental contributor leading to earlier puberty in male offspring mice.
Objectives:
Neurotoxic effects of phthalate during pregnancy on immature brain of the offspring or mature brains of the mothers remain unclear. We examined the effect of dibutyl phthalate (DBP) exposure during gestation and lactation on the maternal behavior of mother mice and neurodevelopment in pups.
Methods:
Pregnant mice were treated orally with DBP (0, 50 and 100 mg/kg/day, N = 20 per group) from gestational day 13 to postnatal day (PND) 15. Maternal behavior was measured using pup retrieval and nest shape test at postpartum day 4. For the pups, the neurodevelopment was measured using negative geotaxis, cliff avoidance at PND 7, swimming test and olfactory orientation at PND 14. RNA and protein expressions in the brain cortex of 50 mg/kg/day and control group (0 mg/kg/day) were analyzed using microarray and Western blot analysis. Nissl-stained sections at the coronal level of interaural 2.56 mm, bregma -1,23 mm, were used for counting of dark cortical neurons in mother and pup mice.
Results:
DBP treated mother mice (50 and 100 mg/kg/day) showed poor maternal behavior, poor nesting and retrieval behavior compared to the control group (0 mg/kg/day). In brain cortex, DBP-treated mothers showed decrease in protein expression of Nr4a3, Egr1, Arc, BDNF and phosphorylation of AKT and CREB, were also decreased in cortex of DBP-treated mothers. Pups exposed to DBP showed significantly decreased scores in negative geotaxis at PND 7 and swimming scores and olfactory orientation tests at PND 14. The cortex of the DBP exposed pups showed increase in expression of dopamine receptor D2 gene. Nissl staining showed that the dark neurons were increased in cortex of DBP treated mothers and DBP exposed pups. Suggesting that phthalate may delay pup development indirectly through inadequate mothering as well as direct phthalate exposure on the brain.
Conclusion:
DBP exposure during gestation and lactation cause impairment in maternal behaviors and downregulation of neuronal plasticity and survival signals. Pups of mothers with exposed to DBP, showed delayed neurodevelopment and dark neurons increase in brain cortex, suggesting that phthalate may delay pup development indirectly through inadequate mothering as well as direct phthalate exposure on the brain.
Transformation of di-n-butyl phthalate (DBP) was investigated in anaerobic/anoxic/oxic (A/A/O) leachate treatment processes. Good removal was achieved under A/A/O conditions. Although the DBP removal was affected by the initial DBP concentration, the overall DBP removal efficiencies for this system were high (> 94%). Only traces of DBP remained in the effluent. The results of mass balance calculations indicated that approximately 33.7–50.7% of the DBP was degraded by the activated sludge, 48.9–64.9% accumulated in the system, and 0.4–1.4% was contained in the final effluent. This confirms that biodegradation and adsorption to activated sludge are both major mechanisms for DBP removal from leachate. The results of correlations between the DBP removal efficiencies and leachate contaminants indicated that the total nitrogen (TN) and total phosphorus (TP) may be key factors influencing the biodegradation of DBP. Half of the DBP in the system adsorbs on the activated sludge. This differs from previous studies in which DBP was mostly biodegraded. DBP is not completely removed when it adsorbs onto sludge. Therefore, methods for decreasing DBP adsorption and increasing the biodegradation efficiencies of the leachate treatment processes should be investigated in future.
To estimate realistic exposure to a chemical, the aggregate exposure from multiple consumer products should be considered. A receptor-based aggregate exposure assessment was conducted according to individuals' exposure factors and simultaneous use patterns including co-use and non-use. A product-based aggregate exposure assessment was conducted by product usage rates of population and users’ exposure factors. Two aggregate exposure assessments were compared. Exposure factors for 31 cosmetic products were collected by face-to-face interviews with 1001 members of the Korean population through national representative sampling. The concentrations of phthalates in 214 cosmetic products were analyzed by GC-MS-MS. The average aggregate exposure dose (AED) determined by the receptor-based method for di(2-ethylhexyl)phthalate (DEHP), di-n-butyl phthalate (DnBP), and diethyl phthalate (DEP) were 0.68 ± 0.87, 1.08 ± 5.71, and 2.47 ± 9.05 μg/kg/day, respectively. The cosmetics that contributed most to the receptor-based AED were skin care and body care products for DEHP, nail care products for DnBP, and fragrance and hair care products for DEP. The young female group showed the highest exposure. The product-based aggregate exposure assessment method underestimated high exposure but overestimated average exposure for DnBP and DEP. The receptor-based aggregate exposure assessment method would be used to determine high exposure groups.
Ubiquitous dimethyl phthalate (DMP) has severely threatened environmental safety and the health of organisms. Therefore, it is necessary to degrade DMP, removing it from the environment. Microbiological degradation is an efficient and safe method for degrading DMP. In this study, the response of Arthrobacter QD 15-4 to DMP was investigated. The results showed that the growth of Arthrobacter QD 15-4 was not impacted by DMP and Arthrobacter QD 15-4 could degrade DMP. RNA-Seq and RT-qPCR results showed that DMP treatment caused some changes in the expression of key genes in Arthrobacter QD 15-4. The transcriptional expressions of pstSCAB and phoU were downregulated by DMP. The transcriptional expressions of potACD, gluBC, oppAB, pdhAB, aceAF, gltA were upregulated by DMP. The genes are mainly involved in regulating energy metabolism and ATP-binding cassette (ABC) transporters. The increasing of pyruvic acid and citrate in Arthrobacter QD 15-4 further supported the energy metabolism was improved by DMP. It was clearly shown that Arthrobacter QD 15-4 made response to dimethyl phthalate by regulating energy metabolism and ABC transporters.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.
Although geographic variation in semen quality has been reported, this is the first study in the United States to compare semen quality among study centers using standardized methods and strict quality control. We evaluated semen specimens from partners of 512 pregnant women recruited through prenatal clinics in four U.S. cities during 1999-2001; 91% of men provided two specimens. Sperm concentration, semen volume, and motility were determined at the centers, and morphology was assessed at a central laboratory. Study protocols were identical across centers, and quality control was rigorously maintained. Sperm concentration was significantly lower in Columbia, Missouri, than in New York, New York; Minneapolis, Minnesota; and Los Angeles, California. Mean counts were 58.7, 102.9, 98.6, and 80.8 × 106/mL (medians 53.5, 88.5, 81.8, and 64.8 × 106/mL) in Missouri, New York, Minnesota, and California, respectively. The total number of motile sperm was also lower in Missouri than in other centers: 113, 196, 201, and 162 × 106 in Missouri, New York, Minnesota, and California, respectively. Semen volume and the percent morphologically normal sperm did not differ appreciably among centers. These between-center differences remained significant in multivariate models that controlled for abstinence time, semen analysis time, age, race, smoking, history of sexually transmitted disease, and recent fever (all p-values < 0.01). Confounding factors and differences in study methods are unlikely to account for the lower semen quality seen in this mid-Missouri population. These data suggest that sperm concentration and motility may be reduced in semirural and agricultural areas relative to more urban and less agriculturally exposed areas.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.
Human metabolism of di(2-ethylhexyl)phthalate (DEHP) was studied after a single oral dose of 48.1mg to a male volunteer. To avoid interference by background exposure the D4-ring-labelled DEHP analogue was dosed. Excretion of three metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP), was monitored for 44h in urine and for 8h in serum. Peak concentrations of all metabolites were found in serum after 2h and in urine after 2h (MEHP) and after 4h (5OH-MEHP and 5oxo-MEHP). While the major metabolite in serum was MEHP, the major metabolite in urine was 5OH-MEHP, followed by 5oxo-MEHP and MEHP. Excretion in urine followed a multi-phase elimination model. After an absorption and distribution phase of 4 to 8h, half-life times of excretion in the first elimination phase were approximately 2h with slightly higher half-life times for 5OH- and 5oxo-MEHP. Half-life times in the second phase—beginning 14 to 18h post dose—were 5h for MEHP and 10h for 5OH-MEHP and 5oxo-MEHP. In the time window 36 to 44h, no decrease in excreted concentrations of 5OH- and 5oxo-MEHP was observed. In the first elimination phase (8 to 14h post dose), mean excretion ratios of MEHP to 5oxo-MEHP and MEHP to 5OH-MEHP were 1 to 1.8 and 1 to 3.1. In the second elimination phase up to 24h post dose mean excretion ratios of MEHP to 5oxo-MEHP to 5OH-MEHP were 1 to 5.0 to 9.3. The excretion ratio of 5OH-MEHP to 5oxo-MEHP remained constant through time at 1.7 in the mean. After 44h, 47% of the DEHP dose was excreted in urine, comprising MEHP (7.3%), 5OH-MEHP (24.7%) and 5oxo-MEHP (14.9%).
Fetal exposure of male rats to di (n-butyl) phthalate (DBP) induces testicular changes remarkably similar to testicular dysgenesis syndrome in humans; these include induction of focal areas of dysgenetic tubules in otherwise normal testes. In searching for the fetal origins of the latter, we used image analysis to show that exposure to 500 mg/kg DBP [embryonic day (E)13.5-20.5)] caused abnormal aggregation of Leydig cells centrally in the fetal testis. This aggregation was not due to increase in Leydig cell number, and Leydig cell size was significantly reduced in DBP-exposed animals, as were testosterone levels and immunoexpression of P450 side-chain cleavage enzyme. The Leydig cell aggregates did not exhibit evidence of focal proliferation at E17.5-19.5. Using confocal microscopy and Leydig (3beta-hydroxysteroid dehydrogenase) and Sertoli (anti-Mullerian hormone) cell-specific markers, we show that fetal Leydig cell aggregates in DBP-exposed animals trap isolated Sertoli cells within them at E21.5. These areas of intermingled cells are still apparent on postnatal d 4, after cessation of DBP treatment, when they may form misshapen seminiferous cords that trap (intratubular) Leydig cells within them. These centrally located dysgenetic tubules contain germ cells in early puberty, but by adulthood they are Sertoli cell only, implying that presence of intratubular Leydig cells interferes with spermatogenesis. It is concluded that DBP-induced fetal Leydig cell aggregation may be a key event in formation of focal dysgenetic areas in the testis, and identification of the mechanisms underlying these events may give new insights into the fetal origins of testicular dysgenesis syndrome disorders in the human.
The incidence of testicular cancer was examined in the Nordic and Baltic countries, Poland and Germany by collaboration among 10 cancer registries. Population-based registers were used to analyze a total of 34,309 cases, diagnosed from the start of registration (varying from 1943 in Denmark to 1980 in Latvia and Lithuania) through 1989. An approximately 10-fold geographical variation was found in 1980, with the highest age-standardized incidence rate (7.8 per 10(5); world standard population) in Denmark and the lowest (0.9) in Lithuania. During the entire period of registration, incidence increased rapidly in all countries, by 2.3 to 3.4 per cent annually in the Nordic countries and by about 5 per cent in Poland and Germany; there was some evidence of a slower increase in Denmark and Poland after 1975. The rising trend was more pronounced for ages below 30. The age-specific incidence peaked in all countries at ages 25 to 34, but the geographical variation was considerable. Our data indicate that environmental influences on testicular cancer are strong. Exposure to causal factors mostly takes place early in life, shows substantial geographical variation, and increases over time, so that the age-standardized incidence doubles every 15 to 25 years. New aetiological hypotheses are needed to accommodate these salient features of the descriptive epidemiology, since risk factors considered so far cannot explain the observed pattern.
Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.
The phthalate ester di-n-butylphthalate (DBP) is used extensively in the manufacture of plastics; its reproductive toxicity was tested in rats by the National Toxicology Program's Reproductive Assessment by Continuous Breeding protocol. Levels of 0.1, 0.5, and 1.0% DBP in the diet were selected, and this dosing design yielded average daily DBP intakes of 52, 256, and 509 mg/kg for males and 80, 385, and 794 mg/kg for females, respectively. DBP consumption by F0 rats reduced the total number of live pups per litter in all treated groups by 8-17% and live pup weights in the 0.5% and 1.0% dose groups by < 13%. In tests to determine the affected sex, the number of offspring was unchanged, but the weights of pups from treated females were significantly decreased and offspring from treated males were unchanged. At necropsy, high-dose F0 females had a 14% reduction in body weight, and both sexes had approximately 10-15% increased kidney and liver to body weight ratios compared to controls. Sperm parameters and estrous cyclicity were not affected. In the F1 mating trial, indices of mating, pregnancy, and fertility in the 1.0% dose group were all sharply decreased (one live litter was delivered out of 20 cohabited pairs), concomitant with a 13% decrease in dam body weight. Live F2 pup weights were 6-8% lower in all dose groups. F1 necropsy results revealed that epididymal sperm counts and testicular spermatid head counts were significantly decreased in the 1.0% dose group. Histopathologic investigation showed that 8 of 10 F1 males consuming 1.0% DBP had degenerated seminiferous tubules and 5 of 10 had underdeveloped or otherwise defective epididymides. No ovarian or uterine lesions were observed. In conclusion, this study showed that DBP is a reproductive/developmental toxicant in Sprague-Dawley rats exposed both as adults and during development; it also indicates that the adverse reproductive/developmental effects of DBP on the second generation were greater than on the first generation.
Peroxisome proliferator-activated receptor a (PPARalpha), a member of the steroid hormone receptor superfamily, has been linked to lipid homeostasis and tumorigenesis in tissues with high expression of receptor protein. On the other hand, the role of PPARalpha in tissues with a lower expression is not well known. Here we demonstrate the localization of PPARalpha messenger RNA (mRNA) and protein in developing and adult rat testis. Additionally, we demonstrate the expression of PPARalpha protein in adult human testis. Our experiments with Northern analysis, in situ hybridization and immunocytochemistry reveal a complex distribution of PPARalpha in tubular and interstitial cells of both adult and developing rat testis. The overall expression is rather low but may be modified by exogenous or endogenous stimuli. An up-regulation of PPARalpha mRNA could be observed after stimulation with FSH. In the developing rat testis, a clear expression of PPARalpha mRNA was present from the first days after birth. Additionally, PPARalpha mRNA and protein increased toward adulthood. In adult human testis PPARalpha immunoreactivity (IR) was present in interstitial Leydig cells and tubular cells. In the seminiferous epithelium of adult human testis the expression of PPARalpha-IR could be seen in meiotic spermatocytes, spermatids and myoid peritubular cells. The findings of our study suggest that PPARalpha may be involved in the regulation of growth and differentiation of tubular and interstitial cells in rat and human testis.
In mammals, exposure to antiandrogenic chemicals during sexual differentiation can produce malformations of the reproductive tract. Perinatal administration of AR antagonists like vinclozolin and procymidone or chemicals like di(2-ethylhexyl) phthalate (DEHP) that inhibit fetal testicular testosterone production demasculinize the males such that they display reduced anogenital distance (AGD), retained nipples, cleft phallus with hypospadias, undescended testes, a vaginal pouch, epididymal agenesis, and small to absent sex accessory glands as adults. In addition to DEHP, di-n-butyl (DBP) also has been shown to display antiandrogenic activity and induce malformations in male rats. In the current investigation, we examined several phthalate esters to determine if they altered sexual differentiation in an antiandrogenic manner. We hypothesized that the phthalate esters that altered testis function in the pubertal male rat would also alter testis function in the fetal male and produce malformations of androgen-dependent tissues. In this regard, we expected that benzyl butyl (BBP) and diethylhexyl (DEHP) phthalate would alter sexual differentiation, while dioctyl tere- (DOTP or DEHT), diethyl (DEP), and dimethyl (DMP) phthalate would not. We expected that the phthalate mixture diisononyl phthalate (DINP) would be weakly active due to the presence of some phthalates with a 6-7 ester group. DEHP, BBP, DINP, DEP, DMP, or DOTP were administered orally to the dam at 0.75 g/kg from gestational day (GD) 14 to postnatal day (PND) 3. None of the treatments induced overt maternal toxicity or reduced litter sizes. While only DEHP treatment reduced maternal weight gain during the entire dosing period by about 15 g, both DEHP and DINP reduced pregnancy weight gain to GD 21 by 24 g and 14 g, respectively. DEHP and BBP treatments reduced pup weight at birth (15%). Male (but not female) pups from the DEHP and BBP groups displayed shortened AGDs (about 30%) and reduced testis weights (about 35%). As infants, males in the DEHP, BBP, and DINP groups displayed femalelike areolas/nipples (87, 70, and 22% (p < 0.01), respectively, versus 0% in other groups). All three of the phthalate treatments that induced areolas also induced a significant incidence of reproductive malformations. The percentages of males with malformations were 82% (p < 0.0001) for DEHP, 84% (p < 0.0001) for BBP, and 7.7% (p < 0.04) in the DINP group. In summary, DEHP, BBP, and DINP all altered sexual differentiation, whereas DOTP, DEP, and DMP were ineffective at this dose. Whereas DEHP and BBP were of equivalent potency, DINP was about an order of magnitude less active.
Phthalate esters (PE) such as DEHP are high production volume plasticizers used in vinyl floors, food wraps, cosmetics, medical products, and toys. In spite of their widespread and long-term use, most PE have not been adequately tested for transgenerational reproductive toxicity. This is cause for concern, because several recent investigations have shown that DEHP, BBP, DBP, and DINP disrupt reproductive tract development of the male rat in an antiandrogenic manner. The present study explored whether the antiandrogenic action of DEHP occurs by (1) inhibiting testosterone (T) production, or by (2) inhibiting androgen action by binding to the androgen receptor (AR). Maternal DEHP treatment at 750 mg/kg/day from gestational day (GD) 14 to postnatal day (PND) 3 caused a reduction in T production, and reduced testicular and whole-body T levels in fetal and neonatal male rats from GD 17 to PND 2. As a consequence, anogenital distance (AGD) on PND 2 was reduced by 36% in exposed male, but not female, offspring. By GD 20, DEHP treatment also reduced testis weight. Histopathological evaluations revealed that testes in the DEHP treatment group displayed enhanced 3ss-HSD staining and increased numbers of multifocal areas of Leydig cell hyperplasia as well as multinucleated gonocytes as compared to controls at GD 20 and PND 3. In contrast to the effects of DEHP on T levels in vivo, neither DEHP nor its metabolite MEHP displayed affinity for the human androgen receptor at concentrations up to 10 microM in vitro. These data indicate that DEHP disrupts male rat sexual differentiation by reducing T to female levels in the fetal male rat during a critical stage of reproductive tract differentiation.
Recent reports have indicated a decrease in semen quality of men in some countries, and suggested regional differences. A study was undertaken of semen samples from 1082 fertile men from four European cities (Copenhagen, Denmark; Paris, France; Edinburgh, Scotland; and Turku, Finland). Semen analysis was standardized, inter-laboratory differences in assessment of sperm concentration were evaluated, and morphology assessment centralized. Lowest sperm concentrations and total counts were detected for Danish men, followed by French and Scottish men. Finnish men had the highest sperm counts. Men from Edinburgh had the highest proportion of motile spermatozoa, followed by men from Turku, Copenhagen and Paris. Only the differences between Paris/Edinburgh and Paris/Turku were statistically significant (P < 0.003 and P < 0.002 respectively). No significant differences in morphology were detected. A general seasonal variation in sperm concentration (summer 70% of winter) and total sperm count (summer 72% of winter) was detected. Semen quality of a 'standardized' man (30 years old, fertile, ejaculation abstinence of 96 h) were estimated. Typically, sperm concentrations (x 10(6)/ml) for winter/summer were: Turku 132/93; Edinburgh 119/84; Paris 103/73; and Copenhagen 98/69. These differences in semen quality may indicate different environmental exposures or lifestyle changes in the four populations. However, it remains to be seen whether such changes can account for these differences. These data may also serve as a reference point for future studies on time trends in semen quality in Europe.
Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising
incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended
testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and
different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups,
e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting
a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity,
the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental
and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during
fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus
on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information
may be lost.
Fischer-344 rats treated with 12,500 ppm (728 and 879 mg/kg/d for male and females, respectively) and B6C3F1 mice treated with 6,000 ppm (1,227 and 1,408 mg/kg/d, respectively) di(2-ethylhexyl)phthalate (DEHP) in the diet for 78 weeks were allowed to recover for an additional 26 weeks on control diet. Blood was analyzed at weeks 78 and 104 from 10 animals per sex per group; animals were sacrificed at weeks 79 and 105 for histopathologic examination. The results are compared with data from animals continuously exposed to these dietary levels for 104 weeks (10, 11). Body weights and food consumption were measured monthly. BUN, albumin, and globulin that were significantly different for rats exposed to DEHP throughout 104 weeks, were comparable to controls for the recovery group. Reversibility of chronic effects on erythrocyte count, hemoglobin, and hematocrit values was apparent only for female rats. Chronic exposure demonstrated effects on liver, kidney, and testes weights. All organ weight effects except for testes for the Recovery group of rats, and all organ weight effects for mice, were reversible. Pigmentation of Kupffer cells and renal tubules present in chronically treated rats were not observed for the Recovery group. Lesions in the testes and pituitary gland were not reversible in rats. This may be a reflection of the senescence of the hypothalamic-gonad axis in rats. Cessation of exposure for mice resulted in amelioration of effects in the kidneys, liver, and testes. The extent of reversibility suggests that many chronic effects may be associated with a metabolic phenomenon such as peroxisome proliferation, which also reverted to control levels after 26 weeks of recovery.
Denmark and Norway have a three-fold higher incidence of testicular cancer than Estonia and Finland. Groups of young men from Denmark, Norway, Finland and Estonia were investigated to elucidate whether semen parameters and other related parameters follow a gradient between these countries, as does the gradient in incidence of testicular cancer.
In total, 968 young men from the general population in these four countries were investigated according to the same protocol. Possible confounders were evaluated, and included in the statistical analysis when appropriate. Inter-laboratory differences in assessment of sperm concentrations were controlled by an external quality control programme and morphology assessment was centralized to one person.
The Finnish and Estonian men had an adjusted median sperm concentration of 54 and 57 x 10(6)/ml, respectively and the Norwegian and Danish men 41 x 10(6)/ml. The corresponding total sperm counts were 185, 174, 133 and 144 x 10(6). The frequency of normal sperm in men from Finland was 8.9%, Estonia 9.2%, Norway 6.9% and Denmark 6.4%. Within all four groups of men, a relationship between increasing levels of inhibin-B and increasing sperm counts was observed. However, inhibin-B levels were not predictive of sperm count differences between countries.
It is believed that the men examined were representative of the normal population of young men in all four countries as they were recruited from groups attending a compulsory medical examination, and not selected for known fertility or semen quality. Moreover, the majority of participants had no prior knowledge of their fertility potential. It appears that an east-west gradient exists in the Nordic-Baltic area with regard to semen parameters, this being in parallel with the incidences of testicular cancer. Further investigations are required to determine whether these findings are due to genetic differences, to different environments, or perhaps to a combination of both factors.
The low potency of many man-made estrogenic chemicals, so-called xenoestrogens, has been used to suggest that risks arising from exposure to individual chemicals are negligible. Another argument used to dismiss concerns of health effects is that endogenous steroidal estrogens are too potent for xenoestrogens to contribute significantly to estrogenic effects. Using a yeast reporter gene assay with the human estrogen receptoralpha, we tested these ideas experimentally by assessing the ability of a combination of 11 xenoestrogens to affect the actions of 17ss-estradiol. Significantly, each xenoestrogen was present at a level well below its no-observed-effect concentration (NOEC). To derive accurate descriptions of low effects, we recorded concentration-response relationships for each xenoestrogen and for 17ss-estradiol. We used these data to predict entire concentration-response curves of mixtures of xenoestrogens with 17ss-estradiol, assuming additive combination effects. Over a large range of concentrations, the experimentally observed responses decisively confirmed the model predictions. The combined additive effect of the 11 xenoestrogens led to a dramatic enhancement of the hormone's action, even when each single agent was present below its NOEC. Our results show that not even sub-NOEC levels of xenoestrogens can be considered to be without effect on potent steroidal estrogens when they act in concert with a large number of similarly acting chemicals. It remains to be seen to what degree these effects can be neutralized by environmental chemicals with antiestrogenic activity. Nevertheless, potential human and wildlife responses induced by additive combination effects of xenoestrogens deserve serious consideration.
The disorders comprising human 'testicular dysgenesis syndrome' (TDS) may be increasing in incidence. TDS originates in fetal life but the mechanisms are not known, and discerning them requires an animal model.
The study investigated whether male rats exposed in utero to dibutyl phthalate [DBP; 500 mg/kg on gestational days (GD) 13-21] would provide a suitable model for human TDS. DBP induced a high rate (>60%) of cryptorchidism (mainly unilateral), hypospadias, infertility and testis abnormalities, similar to those in human TDS. Cell-specific immunohistochemistry and confocal microscopy were used to track development of Sertoli [anti-Müllerian hormone (AMH), Wilm's tumour (WT-1) protein, p27(kip)], Leydig [3beta-hydroxysteroid dehydrogenase (3beta-HSD)], germ (DAZL protein) and peritubular myoid (smooth muscle actin) cells from fetal life to adulthood. In scrotal and cryptorchid testes of DBP-exposed males, areas of focal dysgenesis were found that contained Sertoli and Leydig cells, and gonocytes and partially formed testicular cords; these dysgenetic areas were associated with Leydig cell hyperplasia at all ages. Suppression ( approximately 90%) of testicular testosterone levels on GD 19 in DBP-exposed males, coincident with delayed peritubular myoid cell differentiation, may have contributed to the dysgenesis. Double immunohistochemistry using WT-1 (expressed in all Sertoli cells) and p27(kip) (expressed only in mature Sertoli cells) revealed immature Sertoli cells in dysgenetic areas. DBP-exposed animals also exhibited Sertoli cell-only (SCO) tubules, sporadically in scrotal and predominantly in cryptorchid, testes, or foci of SCO within normal tubules in scrotal testes. In all SCO areas the Sertoli cells were immature. Intratubular Leydig cells were evident in DBP-exposed animals and, where these occurred, Sertoli cells were immature and spermatogenesis was absent. Abnormal Sertoli cell-gonocyte interaction was evident at GD 19 in DBP-exposed rats coincident with appearance of multinucleated gonocytes, although these disappeared by postnatal day 10 during widespread loss of germ cells.
Abnormal development of Sertoli cells, leading to abnormalities in other cell types, is our hypothesized explanation for the abnormal changes in DBP-exposed animals. As the testicular and other changes in DBP-exposed rats have all been reported in human TDS, DBP exposure in utero may provide a useful model for defining the cellular pathways in TDS.
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 exposure to environmental chemicals that interfere with the androgen signaling pathway can cause permanent adverse effects on reproductive development in male rats. The objectives of this study were to 1) determine whether a documented antiandrogen butyl benzyl phthalate (BBP) and/or linuron (an androgen receptor antagonist) would decrease fetal testosterone (T) production, 2) describe reproductive developmental effects of linuron and BBP in the male, 3) examine the potential cumulative effects of linuron and BBP, and 4) investigate whether treatment-induced changes to neonatal anogenital distance (AGD) and juvenile areola number were predictive of adult reproductive alterations. Pregnant rats were treated with either corn oil, 75 mg/kg/day of linuron, 500 mg/kg/day of BBP, or a combination of 75 mg/kg/day linuron and 500 mg/kg/day BBP from gestational Day 14 to 18. A cohort of fetuses was removed to assess male testicular T and progesterone production, testicular T concentrations, and whole-body T concentrations. Male offspring from the remaining litters were assessed for AGD and number of areolae and then examined for alterations as young adults. Prenatal exposure to either linuron or BBP or BBP + linuron decreased T production and caused alterations to androgen-organized tissues in a dose-additive manner. Furthermore, treatment-related changes to neonatal AGD and infant areolae significantly correlated with adult AGD, nipple retention, reproductive malformations, and reproductive organ and tissue weights. In general, consideration of the dose-response curves for the antiandrogenic effects suggests that these responses were dose additive rather than synergistic responses. Taken together, these data provide additional evidence of cumulative effects of antiandrogen mixtures on male reproductive development.
In animal studies of the effects of hormonally active agents, measurement of anogenital distance (AGD) is now routine, and serves as a bioassay of fetal androgen action. Although measurement of AGD in humans has been discussed in the literature, to our knowledge it has been measured formally in only two descriptive studies of females. Because AGD has been an easy-to-measure, sensitive outcome in animals studies, we developed and implemented an anthropometric protocol for measurement of AGD in human males as well as females.
We first evaluated the reliability of the AGD measures in 20 subjects. Then measurements were taken on an additional 87 newborns (42 females, 45 males). All subjects were from Morelos, Mexico.
The reliability (Pearson r) of the AGD measure was, for females 0.50, and for males, 0.64. The between-subject variation in AGD, however, was much greater than the variation due to measurement error. The AGD measure was about two-fold greater in males (mean, 22 mm) than in females (mean, 11 mm), and there was little overlap in the distributions for males and females.
The sexual dimorphism of AGD in humans comprises prima facie evidence that this outcome may respond to in utero exposure to hormonally active agents.
Global phthalate ester production has increased from very low levels at the end of World War II to approximately 3.5 million metric tons/year. The aim of the present study was to investigate potential associations between persistent allergic symptoms in children, which have increased markedly in developed countries over the past three decades, and the concentration of phthalates in dust collected from their homes. This investigation is a case-control study nested within a cohort of 10,852 children. From the cohort, we selected 198 cases with persistent allergic symptoms and 202 controls without allergic symptoms. A clinical and a technical team investigated each child and her or his environment. We found higher median concentrations of butyl benzyl phthalate (BBzP) in dust among cases than among controls (0.15 vs. 0.12 mg/g dust). Analyzing the case group by symptoms showed that BBzP was associated with rhinitis (p = 0.001) and eczema (p = 0.001), whereas di(2-ethylhexyl) phthalate (DEHP) was associated with asthma (p = 0.022). Furthermore, dose-response relationships for these associations are supported by trend analyses. This study shows that phthalates, within the range of what is normally found in indoor environments, are associated with allergic symptoms in children. We believe that the different associations of symptoms for the three major phthalates-BBzP, DEHP, and di-n-butyl phthalate-can be explained by a combination of chemical physical properties and toxicologic potential. Given the phthalate exposures of children worldwide, the results from this study of Swedish children have global implications.
Phthalates are a family of multifunctional chemicals widely used in personal care and other consumer products. The ubiquitous use of phthalates results in human exposure through multiple sources and routes, including dietary ingestion, dermal absorption, inhalation, and parenteral exposure from medical devices containing phthalates. We explored the temporal variability over 3 months in urinary phthalate metabolite levels among 11 men who collected up to nine urine samples each during this time period. Eight phthalate metabolites were measured by solid-phase extraction-high-performance liquid chromatography-tandem mass spectrometry. Statistical analyses were performed to determine the between- and within-subject variance apportionment, and the sensitivity and specificity of a single urine sample to classify a subject's 3-month average exposure. Five of the eight phthalates were frequently detected. Monoethyl phthalate (MEP) was detected in 100% of samples; monobutyl phthalate, monobenzyl phthalate, mono-2-ethylhexyl phthalate (MEHP), and monomethyl phthalate were detected in > 90% of samples. Although we found both substantial day-to-day and month-to-month variability in each individual's urinary phthalate metabolite levels, a single urine sample was moderately predictive of each subject's exposure over 3 months. The sensitivities ranged from 0.56 to 0.74. Both the degree of between- and within-subject variance and the predictive ability of a single urine sample differed among phthalate metabolites. In particular, a single urine sample was most predictive for MEP and least predictive for MEHP. These results suggest that the most efficient exposure assessment strategy for a particular study may depend on the phthalates of interest.
Male reproductive tract abnormalities associated with testicular dysgenesis in humans also occur in male rats exposed gestationally to some phthalate esters. We examined global gene expression in the fetal testis of the rat following in utero exposure to a panel of phthalate esters. Pregnant Sprague-Dawley rats were treated by gavage daily from Gestational Days 12 through 19 with corn oil vehicle (1 ml/kg) or diethyl phthalate (DEP), dimethyl phthalate (DMP), dioctyl tere-phthalate (DOTP), dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), dipentyl phthalate (DPP), or benzyl butyl phthalate (BBP) at 500 mg/kg per day. Testes were isolated on Gestational Day 19, and global changes in gene expression were determined. Of the approximately 30 000 genes queried, expression of 391 genes was significantly altered following exposure to the developmentally toxic phthalates (DBP, BBP, DPP, and DEHP) relative to the control. The developmentally toxic phthalates were indistinguishable in their effects on global gene expression. No significant changes in gene expression were detected in the nondevelopmentally toxic phthalate group (DMP, DEP, and DOTP). Gene pathways disrupted include those previously identified as targets for DBP, including cholesterol transport and steroidogenesis, as well as newly identified pathways involved in intracellular lipid and cholesterol homeostasis, insulin signaling, transcriptional regulation, and oxidative stress. Additional gene targets include alpha inhibin, which is essential for normal Sertoli cell development, and genes involved with communication between Sertoli cells and gonocytes. The common targeting of these genes by a select group of phthalates indicates a role for their associated molecular pathways in testicular development and offers new insight into the molecular mechanisms of testicular dysgenesis.
Peroxisome proliferator-activated receptor α (PPARα), a member of the steroid hormone receptor superfamily, has been linked to lipid homeostasis and tumorigenesis in tissues with high expression of receptor protein. On the other hand, the role of PPARα in tissues with a lower expression is not well known. Here we demonstrate the localization of PPARα messenger RNA (mRNA) and protein in developing and adult rat testis. Additionally, we demonstrate the expression of PPARα protein in adult human testis. Our experiments with Northern analysis, in situ hybridization and immunocytochemistry reveal a complex distribution of PPARα in tubular and interstitial cells of both adult and developing rat testis. The overall expression is rather low but may be modified by exogenous or endogenous stimuli. An up-regulation of PPARα mRNA could be observed after stimulation with FSH. In the developing rat testis, a clear expression of PPARα mRNA was present from the first days after birth. Additionally, PPARα mRNA and protein increased toward adulthood. In adult human testis PPARα immunoreactivity (IR) was present in interstitial Leydig cells and tubular cells. In the seminiferous epithelium of adult human testis the expression of PPARα-IR could be seen in meiotic spermatocytes, spermatids and myoid peritubular cells. The findings of our study suggest that PPARα may be involved in the regulation of growth and differentiation of tubular and interstitial cells in rat and human testis.
The retention, distribution, excretion and metabolism of dibutyl phthalate 7 14C were investigated in the rat. Of a single oral dose 80 to 90% is metabolized and excreted in the urine within 48 hr. Phthalic acid, monobutyl phthalate, mono(3 hydroxybutyl) phthalate, and mono(4 hydroxybutyl) phthalate were identified as metabolites in the urine. Rats fed for 12 weeks on a diet containing dibutyl phthalate at 1 g/kg of feed did not accumulate either dibutyl phthalate or monobutyl phthalate in tissues or organs.
Adequate distinction between an abnormality in androgen secretion or in target cell response is important in the diagnosis and management of male pseudohermaphroditism. Hormone serum levels give reasonable information on steroid secretion, but there are no simple methods, in clinical practice, to evaluate target cell response to androgens. In this work, we have evaluated the validity of the acute decrease in serum (SHBG) after administration of hCG or exogenous testosterone, as an indicator of androgen sensitivity in prepubertal subjects. The results were expressed as percentage of basal values. In control subjects, after hCG, SHBG dropped below 85% of basal, mean 55 +/- 17, and, after exogenous testosterone, below 80%, mean 62.18 +/- 8.85. In 23 patients studied with the hCG test, 10 positive and 13 negative results were found, but most of the negative responses became positive after exogenous testosterone. Of 25 patients studied with the exogenous testosterone test, 19 positive and 6 negative results were found. Clinical analysis of these 6 patients with negative responses showed that 4 subjects had a confirmed androgen insensitivity syndrome, while clinical information was compatible with this diagnosis in the other 2 patients. Furthermore, in 4 additional patients with the androgen insensitivity syndrome, but with high basal serum testosterone, this test was also negative. It is concluded that determination of serum SHBG after hCG is not reliable as an androgen sensitivity test, but the detection of the decrease in serum SHBG after exogenous testosterone is a useful and simple test of androgen sensitivity.
Analysis of reports in the world's literature suggests that average sperm densities for groups of unselected males were relatively constant at about 108 million cells per ml prior to 1950. Subsequent to that time mean sperm densities appear to have declined. Regression analysis indicates the existence of significant negative correlations between mean sperm densities and production of synthetic organic chemicals among other parameters. Phthalate esters are one class of large volume organic chemicals that are known to disturb testicular function in laboratory animals. These compounds are also the most abundant man-made chemicals in the environment. Plots of the concentration of dibutylphthalate in the cellular fraction of ejaculates against either the sperm density or the total number of sperm for the same ejaculates gave two clusters of points. These clusters suggest the existence of two or more populations vis à vis phthalate metabolism; both of which show a negative correlation between phthalate concentration and sperm production.
Oral administration of di-n-butylphthalate (DBP) produced uniformly severe seminiferous tubular atrophy in rats and guinea pigs but caused only focal atrophy in mice. Hamsters showed no testicular changes with DBP and only minor changes in response to di-(2-ethylhexyl)phthalate (DEHP) and di-n-pentylphthalate (DPP). The rate of intestinal monohydrolysis of DEHP was slower in hamsters than in rats and this may be important, as mono-(2-ethylhexyl)phthalate (MEHP) did cause focal seminiferous tubular atrophy in hamsters. However, mono-n-butylphthalate (MBP) had no such effect. The decrease in testicular zinc concentration and enhancement of urinary zinc excretion produced in rats by DEHP and DPP was not observed in hamsters. Thus, species differ widely in their sensitivity to the testicular toxicity of phthalate esters.
Phthalate esters are widely used in the manufacture of plastics and have been shown to cause testicular toxicity, purportedly, by targeting the Sertoli cell alone. Recent evidence, however, indicates that a paracrine control exists between Sertoli and Leydig cells and the breakdown of one component of this relationship is therefore detrimental to normal function. However, no data that explore the influence of testicular toxins on Leydig cell structure and function have been published hitherto. The preliminary studies reported here were initiated to test the hypothesis that phthalate intoxication may adversely alter Leydig cell structural and functional integrity. Four phthalate esters, namely, di(2-ethylhexyl) phthalate (DEHP, di-n-pentyl phthalate (DPP)., di-n-octyl phthalate (DOP), and diethyl phthalate (DEP) were investigated in vivo and their monoesters (MEHP, MPP, MOP, and MEP, respectively) in vitro for indications of Leydig cell toxicity in the rat. Rats were dosed by oral gavage with 2 g phthalate diester/kg/day in corn oil vehicle for 2 days, while Leydig cell primary cultures were incubated with 1,000 microM monoester for 2 hr. Light and electron microscopy were undertaken to determine the type and degree of any changes. Phthalate esters exerted a direct effect on Leydig cell structure and function (as determined by testosterone output) with correlation of the in vitro and in vivo effects of MEHP (DEHP) and MOP (DOP). No effects on Leydig cell structure or function were seen with MPP (DPP), although Sertoli cell cytoplasmic rarefaction and vacuolation were observed in vivo. DEP produced Leydig cell ultrastructural alterations in vivo. We conclude that individual phthalate esters may exert effects on both Sertoli and Leydig cells or one cell type alone.
Di(n-butyl) phthalate (DBP), a widely used plasticizer suspected of having estrogenic properties, was investigated for its effects on the prenatal and early neonatal development of the reproductive tract. Pregnant CD rats (n = 10) were given DBP at 0, 250, 500, or 750 mg/kg/day (p.o.) throughout pregnancy and lactation until their offspring were at postnatal day 20. Maternal body weights throughout the dosing period were comparable in all groups. At 750 mg/kg/day, the number of live pups per litter at birth was decreased and maternal effects on pregnancy and postimplantation loss are likely to have occurred. Anogenital distance was decreased at birth in the male offspring at 500 and 750 mg/kg/day. The epididymis was absent or underdeveloped in 9, 50, and 71% of adult offspring (100 days old) at 250, 500, and 750 mg/kg/day, respectively, and was associated with testicular atrophy and widespread germ cell loss. Hypospadias occurred in 3, 21, and 43% of males and ectopic or absent testes in 3, 6, and 29% of males at 250, 500, and 750 mg/kg/day, respectively. Absence of prostate gland and seminal vesicles as well as small testes and seminal vesicles were noted at 500 and 750 mg/kg/day. Vaginal opening and estrous cyclicity, both estrogen-dependent events, were not affected in the female offspring, although low incidences of reproductive tract malformations were observed at 500 and 750 mg/kg/day. In the male offspring, DBP produced the same spectrum of effects elicited by the antiandrogen flutamide. Thus, DBP specifically impaired the androgen-dependent development of the male reproductive tract, suggesting that DBP is not estrogenic but antiandrogenic in the rat at these high dose levels. For human risk assessment, determining if this toxicity is metabolite-mediated will be critical, since marked species differences in metabolism exist.