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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.

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... DEHP is often exposed to by the human bodies. After exposure, DEHP is easily metabolized, crosses the placenta, and is detected at higher concentrations in children than in adults [7]. ...
... DEHP is considered as antiandrogenic endocrine disruptors because of its possible effect on animal gonads and reproduction [8,9]. A growing number of research has been focused on its role in the disruption of the reproductive and developmental processes [7]. On the other hand, very few studies focused on the thyroid-disrupting effects of DEHP [10,11]. ...
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Di-(2-ethylhexyl)phthalate (DEHP) was a widely used chemical with human toxicity. Recent in vivo and in vitro studies suggested that DEHP-exposure may be associated with altered serum thyroid hormones (THs) levels, but the underlying molecular mechanisms were largely unknown. To explore the possible molecular mechanisms, 128 Wistar rats were dosed with DEHP by gavage at 0, 150, 300, and 600 mg/kg/day for 3 months (M) and 6 M, respectively. After exposure, expression of genes and proteins in the thyroid, pituitary, and hypothalamus tissues of rats were analyzed by Q-PCR and western blot, while the sera and urine samples were assayed by radioimmunoassay and ELISA. Results showed that serum THs levels were suppressed by DEHP on the whole. DEHP treatment influenced the levels of rats’ thyrotropin releasing hormone receptor (TRHr), Deiodinases 1 (D1), thyroid stimulating hormone beta (TSHβ), sodium iodide symporter (NIS), thyroid stimulating hormone receptor (TSHr), thyroperoxidase (TPO), thyroid transcription factor 1 (TTF-1), and thyroglobulin (TG) mRNA/protein expression in the hypothalamus-pituitary-thyroid (HPT) axis and decreased urine iodine. Taken together, observed findings indicate that DEHP could reduce thyroid hormones via disturbing the HPT axis, and the activated TSH/TSHR pathway is required to regulate thyroid function via altering TRHr, TSHβ, NIS, TSHr, TPO, TTF-1 and TG mRNA/protein expression of the HPT axis.
... They may also be associated with certain cancers and adverse reproductive effects. [29][30][31][32][33][34][35][36][37] Table 1 illustrates some of the chemicals of concern in nail salons that may pose problems for reproductive health. ...
... 52 In a study of hairdressers and cosmetologists, the risk of babies being born small for gestational age and the risk of perinatal death were elevated for cosmetologists when compared to a control group of teachers. 36 Herdt-Losavio et al. 35 found a slightly increased risk for low-birth weight babies among cosmetologists compared to a group of realtors. 35 The risk was greater among non-White women in each comparison in the latter study. ...
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The issue of pregnant women’s exposures to everyday chemicals and the implications for the health of future children are receiving increased attention in popular media and in the academic press. In response, health profession organizations are developing clinical practice guidelines for warning pregnant women about the risks associated with exposures to certain toxics. We evaluate different sides of a risk-avoidance approach for pregnant women in the context of a hypothetical case study involving phthalates and women who work in nail salons. We consider the ubiquitous nature of low-dose exposures and both the positive aspects and limitations of promoting avoidance measures with respect to phthalate exposures. We conclude that a risk-disclosure approach has both practical limitations and equity dimensions which must be factored in to public health guidelines and messaging and the development of clinical practice guidelines. Upstream solutions including regulatory action on chemicals and heightened attention to environmental justice would result in optimal management of this issue.
... The FDA has set a tolerable intake level of DEHP for parenteral exposure of 0.6 mg/kg/day [4]. However, the amount of phthalates released by medical devices does not appear to vary according to age groups, so that the dose of DEHP reported to the patient's weight is greater as a child is younger, which explains that children are more vulnerable compared to adults [7]. Thus, the most exposed children to high doses of DEHP are those on life support, transfusion and under extracorporeal circulation [1]. ...
... Therefore, even if the exposure in PICU remains the same regardless of weight or age, it is still proportionally higher in patients whose weight is lower. Infants also have a more important oral exposure due to their higher caloric intake per kg of body weight when compared to older children or adolescents [7]. Furthermore, frequent oral contacts such as mouthing and sucking objects containing or contaminated with phthalates or BPA (toys, pacifiers, plastic containers, etc.) in addition to ingestion of contaminated dust, breast milk, infants formula, cow's milk or food packaging can also lead to increased exposure in this population [21]. ...
... Phthalate diesters are reported to have antiandrogenic and weak estrogenic effects [8][9][10]. Among phthalate diesters, di-(2-ethylhexyl) phthalate (DEHP) is the most widely used [11]. ...
... SHBG can be regulated by sex hormones as androgen decreases and estrogen increases SHBG concentration [38,39]. The positive association of SHBG with DEHP exposure may be due to the anti-androgenic effects of DEHP because testosterone has an inhibitory influence on SHBG [9]. Our results were consistent with antiandrogenic effects of phthalate exposure, and a negative association was found between DEHP and TT concentrations in general, even though the association became statistically non-significant after multiple adjustments due to the limited sample size. ...
Article
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In May 2011, a major incident involving phthalates-contaminated foodstuffs occurred in Taiwan. Di-(2-ethylhexyl) phthalate (DEHP) was added to foodstuffs, mainly juice, jelly, tea, sports drink, and dietary supplements. Concerns arose that normal pubertal development, especially reproductive hormone regulation in children, could be disrupted by DEHP exposure.To investigate the association between phthalate exposure and reproductive hormone levels among children following potential exposure to phthalate-tainted foodstuffs.A total of 239 children aged
... 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]. ...
Article
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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.
... Secondly, chemicals may influence sex hormone regulations, and can eventually affect normal fetal brain development (Colborn, 2004;Schug et al., 2015). For example, estradiol plays a critical role in male brain development, therefore antiandrogenic compounds like DEHP and DEP (Lottrup et al., 2006;Main et al., 2006) may affect normal development of the neural system. In addition, thyroid hormone disruption by chemical exposure may explain adverse consequences in neurodevelopment of the developing brain (Laurberg, 2009). ...
Article
Exposure of the developing fetus and infants to toxic substances can cause serious lifelong health consequences. Several chemicals have been associated with adverse neurodevelopmental disorders in the early life stages of humans. However, most epidemiological studies have focused on a limited number of chemicals, and hence may exclude important chemicals from consideration or result in conclusions built on associations by chance. In the present study, we investigated the chemical exposure profile of the women, and associated these with the early neurodevelopmental performance of their offspring at 13-24months of age. The chemicals assessed include four phthalates, bisphenol A, three heavy metals, 19 polychlorinated biphenyls (PCBs), 19 organochlorine pesticides, and 19 polybrominated diphenyl ethers, which were measured from urine, whole blood, serum, and/or breastmilk of the pregnant or lactating women. For neurodevelopmental performance, the Bayley Scales of Infant Development-II (BSID-II), Social Maturity Scale (SMS), and Child Behavior Checklist (CBCL) were measured from a total of 140 toddlers. Among the measured chemicals, monoethyl phthalate (MEP) in maternal urine was significantly associated with early mental, psychomotor, and social development. In addition, breast milk di-ethylhexyl phthalate (DEHP) metabolite and blood lead concentrations were inversely associated with mental and psychomotor development indices, respectively. Maternal blood PCB153, heavy metals, and urinary MEP levels were also higher among the children with behavioral problems, as indicated by the CBCL range. Taken together, maternal exposure to several EDCs such as PCBs and DEHP was associated with adverse neurodevelopmental performances among the children aged 1-2years. Confirmation of these association in larger populations, as well as longer-term consequences of such exposure warrant further investigation.
... Furthermore, chemicals may influence sex hormone regulation and can eventually affect normal fetal brain development (Schug et al., 2015). Most importantly, antiandrogenic compounds such as DEHP and DEP are known to affect normal fetal brain development (Lottrup et al., 2006). ...
Article
Phthalates are a family of synthetic chemicals that are used in producing a variety of consumer products. Di-(2-ethylhexyl) phthalate (DEHP) is an widely used phthalate and poses a public health concern. Prenatal exposure to DEHP has been shown to induce premature reproductive senescence in animal studies. In this study, we tested the hypothesis that prenatal exposure to DEHP impairs neurobehavior and recognition memory in her male offspring and we investigated one possible mechanism—oxidative damage in the hippocampus. Pregnant CD-1 female mice were orally administered 200μg, 500mg, or 750mg/kg/day DEHP or vehicle from gestational day 11 until birth. The neurobehavioral impact of the prenatal DEHP exposure was assessed at the ages of 16 to 22 months. Elevated plus maze and open field tests were used to measure anxiety levels. Y-maze and novel object recognition tests were employed to measure memory function. The oxidative damage in the hippocampus was measured by the levels of oxidative DNA damage and by SLIM microscopic counting of hippocampal neurons. Adult male mice that were prenatally exposed to DEHP exhibited anxious behaviors and impaired spatial and short-term recognition memory. The number of hippocampal pyramidal neurons was significantly decreased in the DEHP mice. Furthermore, DEHP mice expressed remarkably high levels of cyclooxygenase-2, 8-hydroxyguanine, and thymidine glycol in their hippocampal neurons. DEHP mice also had lower circulating testosterone concentrations and displayed a weaker immunoreactivity than the control mice to androgen receptor expression in the brain. This study found that prenatal exposure to DEHP caused elevated anxiety behavior and impaired recognition memory. These behavioral changes may originate from neurodegeneration caused by oxidative damage and inflammation in the hippocampus. Decreased circulating testosterone concentrations and decreased expression of androgen receptor in the brain also may be factors contributing to the impaired neurobehavior in the DEHP mice.
... Phthalates negatively impact human reproduction: they are associated with reduced semen quality, endometriosis and shorter gestation periods during pregnancy (Sharpe and Irvine, 2004;Weuve et al., 2010). Phthalates have been linked to both prenatal and postnatal effects, including anomalous development of the male reproductive system (Lottrup, 2006;Martino-Andrade et al., 2009;Rider et al., 2010), with potentially irreversible anti-androgenic effects in fetuses (Kortenkamp, 2010;Albert and Je´gou, 2014). There are also indications that early menopause may result from exposure to certain phthalates (Grindler et al., 2015). ...
Article
Endocrine-disrupting chemicals have been identified as posing risks to reproductive health and may have intergenerational effects. However, responses to the potential harms they pose frequently rely on medicalised understandings of the body and normative gender identities. This article develops an intersectional feminist framework of intergenerational justice in response to the potential risks posed by endocrine-disrupting chemicals. We examine critiques of endocrine disruptors from feminist, critical disability and queer standpoints, and explore issues of race and class in exposures. We argue that responding to the risks posed by endocrine disruptors such as brominated flame retardants (BFRs) and phthalates requires developing a theory of intergenerational justice that recognises relationality and transcorporeality, and that also recognises harm in terms of suffering, not in terms of difference.
... Several studies have shown that children's phthalate exposure are closely related to improper sexual development (Col on et al., 2000; Swan et al., 2005), such as premature breast development in girls younger than eight years old (Col on et al., 2000); effects on the immune system (Wang et al., 2014), neuropsychological development (Cho et al., 2010;T ellez-Rojo et al., 2013) and adverse respiratory outcomes including bronchial obstruction and asthma (Hoppin et al., 2004). On the other hand, the effects on adults are considered to be associated with increase in body weight and obesity (Stahlhut et al., 2007;Hatch et al., 2008), diabetes (Svensson et al., 2011), insulin resistance (Trasande et al., 2013), impact on production of reproductive hormones (Duty et al., 2005a;Lottrup et al., 2006;Main et al., 2006), early puberty (Koch et al., 2003), abnormal pregnancy duration (Latini et al., 2003;Whyatt et al., 2009), preterm birth (Meeker et al., 2009), increased risk of breast cancer (due to exposure to DEP) (L opez-Carrillo et al., 2010), influence on normal pulmonary function for males (Hoppin et al., 2004), and androgen-responsive brain development (Swan et al., 2010). ...
... As one of environmental endocrine disruptors (EEDs), it plays a role similar to that of oestrogen in the body and interferes with the body's normal endocrine function, especially causing a negative influence to the male reproductive system. 22 Therefore, DMP has been listed as a priority pollutant by the China National Environmental Monitoring Center. 23 Due to its widespread usage and intractable biodegradability, it has been detected in the atmosphere, freshwater and ocean. ...
Article
The photochemical transformation of dimethyl phthalate (DMP) with N(III)(NO2-/HONO/H2ONO+) was investigated under 365 nm steady-state irradiation and 355 nm laser flash photolysis (LFP) techniques. The results showed that N(III) concentration, DMP initial concentration and pH values all strongly affected the oxidation efficiency of DMP. The primary step of the reaction was mainly due to the attack of •OH radicals on the aromatic ring to form a DMP-OH adduct, and the bimolecular rate constant was determined as (5.5 ± 0.4) × 109 M-1 s-1. The DMP-OH adduct not only underwent monomolecular self-decay with a rate constant of (1.6 ± 0.3) × 104 s-1 but also interacted with HONO, H2ONO+ and O2 with rate constants of (6.4 ± 0.4) × 106 M-1 s-1, (8.8 ± 0.5) × 106 M-1 s-1 and (1.6 ± 0.1) × 108 M-1 s-1, respectively. Major transformation products including methyl salicylate, monomethyl phthalate, dimethyl 4-hydroxyphthalate and dimethyl 4-nitrophthalate were identified by GC-MS and characteristics of these secondary contaminants required extra attention.
... Although not all metabolites selected had been associated with AMH level, and some correlations were only found in age group over 60 years of age, on the whole, phthalate exposure had a certain impact on male AMH secretion. Phthalates had been known to have negative effects on the testis, including inhibiting the development of sperm, altering reproductive hormone levels, and even disturbing the functions of active substances in the body such as thyroxine and vitamin D [28][29][30][31][32]. This accumulating evidence could partly explain relationship between phthalates and AMH, but the mechanism underlying had not been very clear yet. ...
Article
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Anti-Müller hormone (AMH) plays an important role in reproductive development and has a wide potential clinical application value. Phthalates have been widely found in human living environment and have negative effects on human reproduction. This study aimed to explore the relationship between urinary phthalate metabolites and serum AMH level in the general male population. Cross-sectional analyses were performed with a population of 489 men aged more than 12 years who participated in National Health and Nutrition Examination Survey (NHANES) 2003-2004 by Centers for Disease Control and Prevention, the United States. NHANES public data (demographic and socioeconomic information, examinations, and laboratory tests) were analyzed using Kruskal-Wallis test, Wilcoxon test and multivariable regression. Results showed that the urine concentration of mono (3-carboxypropyl) phthalate (MCPP) of 12-20 age group was significantly positively correlated with serum AMH concentration in the model without any covariates (p < 0.05). In the 60-year-old group, the monomethyl phthalate (MEP), mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) concentrations were significantly correlated with serum AMH concentrations in models both with and without covariates (all p < 0.05). It could be concluded that exposure to phthalates might have negative effects on AMH level, especially in seniors. AMH could be used as a marker of exposure to phthalates in aged males. How exposure to phthalates affected AMH level and what the potential long-term health consequences of their relationship are needs more investigation.
... Antiandrogen effect of phthalates is well described on animal models (Foster et al. 2001;Gray et al. 2000) since they inhibit the synthesis of testosterone (Welsh et al. 2008) followed by reduced anogenital distance and genital size (Foster 2006). In humans, phthalates decrease sperm quality (Hauser et al. 2006) and affect normal development of the reproductive system (Lottrup et al. 2006). Hepatic steatosis is associated with IR (as its cause and symptom); DEHP exposure on animal models caused accelerated progression of non-alcoholic fatty liver disease (NAFLD) (Chen et al. 2016) and may lead to liver steatoses followed by enhanced transaminase levels (Burgert et al. 2006). ...
Article
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Phthalates are ubiquitous environmental contaminants, massively used in industry as plasticizers and additives in cosmetics, which may impair the human endocrine system inducing fertility problems, respiratory diseases, obesity, and neuropsychological disorders. The aim of this study was to examine the influence of the monoethyl phthalate (MEP) and mono-(2-ethylhexyl) phthalate (MEHP) on the liver function and cardiometabolic risk factors in males. In this research, 102 male participants (51 normal weight and 51 overweight/obese) were enrolled and examined for phthalate metabolites exposure in urine samples after 12 h of fasting. MEP was found in 28.43% (29/102) volunteers, while MEHP was detected among 20.59% (21/102) participants. Statistically significant increment in transaminase serum levels was observed in MEP-positive normal weight subgroup. Linear correlation was obtained between MEP concentration in urine samples and triglyceride (TG) serum levels (r² = 0.33; p < 0.01), visceral adiposity index (VAI) (r² = 0.41; p < 0.01), lipid accumulation product (LAP) (r² = 0.32; p < 0.01), and TG to high-density lipoprotein (HDL) ratio (r² = 0.40, p < 0.01) among the obese. The MEHP-positive normal weight volunteers had statistically significant increment of body mass index (p = 0.03) compared to MEHP-negative participants. Urine MEHP concentrations were negatively correlated with HDL serum levels (r² = 0.31; p < 0.05) in the normal weight subgroup. The phthalates exposure may be related to statistically significant ALT and AST serum levels increment as well as with increased BMI, while the phthalate levels in the urine may be correlated with increased TG and decreased HDL cholesterol serum levels and associated with indicators of cardiometabolic risk and insulin resistance as LAP and VAI.
... Contradictory evidence has been reported for the effects of phthalates in humans. On the one hand, according to Lottrup et al. [38], two recent studies indicated that human testicular development might be susceptible to phthalates. One study analysed phthalate monoesters in breast milk and reproductive hormone levels in infants. ...
Pregnant women are exposed to various chemical products at home and at work. Some of these products contain endocrine-disrupting chemicals (EDCs) such as cosmetics, pesticides, industrial chemicals, heavy metals, plastics or medications that could alter sexual differentiation and increase the risk of hypospadias. We evaluated maternal occupational and household exposures that could constitute risk factors for hypospadias. From 2011 to 2014, we enrolled 57 full-term newborns with hypospadias and three randomly selected controls per case (162 control newborns), matched for gestational age, from 11 maternity units in Picardy, France. Neonatal and parental data were collected at birth (personal characteristics, maternal lifestyle, and medical history). Maternal occupational exposure was assessed by a job-exposure matrix for EDCs from a job history questionnaire completed by mothers. Odds ratios (OR) and 95% confidence intervals (CI) were calculated with univariate and multivariable logistic regression, and adjusted for relevant covariates. Multivariate analysis showed a strong association between hypospadias and potential maternal occupational exposure to EDCs and maternal household use of hair cosmetics (OR 6.1, 95% CI: 1.1–34.9; OR: 9.6, 95% CI: 1.4–66.1, respectively). Our results suggest that maternal occupational exposure to EDCs is a risk factor for hypospadias and suggests a possible influence of household use of hair cosmetics during early pregnancy on the incidence of hypospadias in the offspring. A larger study with more accurate exposure assessment should evaluate the impact of EDCs in hair cosmetics on the incidence of hypospadias.
... No studies were found on the effects of exposure to microbes in damp buildings on reproductive responses. One group of indoor air contaminants, phthalates, are, however, potential reproductive and developmental toxicants (Lottrup et al., 2006). ...
Book
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Microbial pollution is a key element of indoor air pollution. It is caused by hundreds of species of bacteria and fungi, in particular filamentous fungi (mould), growing indoors when sufficient moisture is available. This document provides a comprehensive review of the scientific evidence on health problems associated with building moisture and biological agents. The review concludes that the most important effects are increased prevalences of respiratory symptoms, allergies and asthma as well as perturbation of the immunological system. The document also summarizes the available information on the conditions that determine the presence of mould and measures to control their growth indoors. WHO guide-lines for protecting public health are formulated on the basis of the review. The most important means for avoiding adverse health effects is the prevention (or minimization) of persistent dampness and microbial growth on interior surfaces and in building structures. http://www.who.int/airpollution/guidelines/dampness-mould/en/
... Humans can be contaminated with EDCs via the food chain, inhalation of contaminated dust or dermal contact with pesticides or herbicides, plastics, pharmaceutical, or dietary components (Frye et al., 2012). Phthalate is an EDC that can cross the placenta and, thus, can affect intrauterine development; phthalate has been found in higher concentrations in children than in adults (Lottrup et al., 2006). Experimental studies with laboratory mice showed that females treated in vivo with phthalate increased in body and fat mass (Kl€ oting et al., 2015). ...
Article
Objectives: During the early 1990s, the economic and political situation in eastern Germany changed overnight. Here, we use the rare chance of an experiment-like setting in humans and aim to test whether the rapid change of environmental conditions in eastern Germany in the 1990s led to a change in the sex-specific fat distribution pattern, an endocrine-influenced phenotypic marker. Methods: Based on a cross-sectional data set of 6- to 18-year-old girls and boys measured between 1982-1991 and 1997-2012, we calculated a skinfold ratio of triceps to subscapular and percentage of body fat. Using linear regressions, we tested for differences in percentage of body fat and skinfold ratio between these two time periods. Results: We found that the percentage of body fat increased in boys and girls, and they accumulated relatively more fat on extremities than on the trunk in all BMI groups measured after 1997 as compared to those measured between 1982 and 1991. Conclusions: Concurrent with drastic and rapid changes of environmental conditions, the body fat distribution of children and adolescents changed to a more feminized pattern during the early 1990s in an East German population. The changes in this endocrinologically mediated pattern might be associated with the increased exposure of individuals to endocrine-disrupting chemicals which are known to influence the endocrine, reproductive, and immune systems in animals and humans.
... During foetal gonad differentiation, neonatal testicular development and final maturation and differentiation of the testes during puberty, proper androgen levels are very important for normal development (36). Puberty is an important part of reproductive health, marking the sexual maturation of the hypothalamic-pituitary-gonadal (HPG) axis that culminates in adult hormonal profiles and physiological changes that are essential for reproductive fitness (37). ...
Article
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Humans are exposed to phthalates continuously throughout life. The aim of this study was to evaluate the genotoxic effects induced in male mice following 8 weeks of subchronic exposure to di-n-butyl phthalate (DBP) during their puberty and to investigate the possibility of transmission of mutations to subsequent generations via the sperm. Pzh:Sfis outbred male mice aged 4.5 weeks were exposed to DBP by gavage for 8 weeks, 3 days per week to doses of 1/16 LD50 or 1/4 LD50 each time. Six to seven males from each dosage group were sacrificed at 4, 8 and 12 weeks after the start of exposure for examination of sperm count and quality. Immediately after the end of exposure, the remaining males were caged for 1 week with two unexposed females each. Group of females were sacrificed 1 day before expected parturition, whilst other females were allowed to deliver and rear litters. F1 generation males at 8-9 weeks of age were caged with females from the same group, but from a different litter, for examination of prenatal development of the F2 generation. The remaining F1 generation males were sacrificed at the same age to check the sperm count and quality. Our results confirmed the toxic effects of DBP on the reproductive organs and germ cells of pubertally exposed males. The changes induced in male gametes might be transmitted to the next generation via the sperm. The most important effects were induced in the F1 generation. Exposure of F0 males to DBP induced skeletal malformations in surviving foetuses, caused significant mortality in postnatal life and a disturbance in the sex ratio (superior survival of females in F1), as well as increased frequency of DNA damage in the germ cells of F1 males. The present study did not confirm higher sensitivity to DBP of pubescent males compared to adult males, but the effects induced in the F1 generation differed from that after exposure of adult F0 males.
... In humans, phthalate exposure has been associated with adverse effects on male reproductive system. Negative associations between urinary phthalate metabolites and anogenital index (AGI), semen quality, or reproductive hormones have been reported [14][15][16]. In addition, associations with decreased semen quality (MBzP and MEP) [17], and with DNA damage and decreased motility of sperm (MEP) have been reported [18][19][20]. ...
Article
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Low molecular weight phthalates, such as diethyl phthalate (DEP), benzyl butyl phthalate (BBzP), or diisobutyl phthalate (DiBP), are suspected to disrupt endocrine system. However, their adverse effects on sex steroid hormones and underlying mechanisms are not well-documented. The aim of this study is to investigate the effects of major low molecular weight phthalates (LMWPs), i.e., DEP, BBzP, and DiBP, and their hydrolytic metabolites, on sex steroid hormone system, employing male zebrafish and/or a human adrenocortical carcinoma (H295R) cell. In male zebrafish, 14-day exposure to DEP, BBzP, or DiBP significantly decreased testosterone (T) concentrations. All test compounds significantly up-regulated cyp19a gene expression, and down-regulated star and 3β hsd genes in the male fish. In H295R cell, all test compounds except monoisobutyl phthalate (MiBP) reduced T concentrations and increased E2/T ratio. Gene expression changes in H295R cell, e.g., significant down-regulation of StAR gene and up-regulation of CYP19A gene, supported depressed synthesis of sex hormones in the adrenal cell. Our results show that not only DEP, BBzP, and DiBP, but also their hydrolytic metabolites disrupt sex hormone balances through modulating key steroidogenic genes in the human adrenal cells and in zebrafish.
... A well-known case is phthalates which display adverse effects on the male reproductive function, including hypospadias, cryptorchidism, reduced testosterone production and decrease sperm counts. These antiandrogenic effects are not the consequences of an antagonism towards the androgen receptor, but are due to a disruption of the androgen biosynthesis, as revealed by animal phthalate exposure studies (Lottrup et al, 2006). ...
Article
Endocrine activity of 65 compounds migrating from polycarbonate replacement plastic baby bottles was assessed using in vitro cell based assays (reporter gene assays) involving 7 nuclear receptors, i.e. human steroid hormones receptors (oestrogen, androgen, progesterone and glucocorticoid receptors), human thyroid beta and peroxisome proliferator-activatedgamma receptors, and the mouse aryl hydrocarbon receptor. The chemicals were tested at 4 concentrations ranging from 0.001mM to 1mM. Only twelve chemicals did not show anyactivity towards any of the nuclear receptors, while fifty three compounds showed a possible endocrine activity. Most of the agonistic activities were observed towards theoestrogen receptorwhile the PPARγ was the target for most of the recorded antagonistic activities. Agonistic activities were recorded for several phthalates, benzophenones, aromatic hydrocarbons and phenols, while compounds such as benzaldehydes, ketones and esters of fatty acid showed antagonistic activities. Thirty five chemicals were able of agonistic activities on 1 to 4 receptors and antagonistic activities were recorded for 35 compounds as well, towards 1 to 7 receptors. Sixteen compounds were able of both agonistic and antagonistic activities, but not on the same receptors, except in 2 cases for the oestrogen receptor and 4 cases for the PPARγ.
... The products of hair dye contain large parts of chemical substances, such as aromatic amines, organic solvents, phthalates, formaldehyde, et al. Some studies indicated that the reproductive toxicity of chemical substances had adverse effect on birth outcomes in animal experiments [17,18]. Previous epidemiological studies showed that occupational hair-dressers and cosmetologist had reproductive risks on abnormal pregnancy outcomes such as LBW, preterm birth, abortion, preeclampsia [19][20][21][22]. ...
Article
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Background: Limited evidences were reported about the risk of pre-pregnancy hair dye use or irregular menstruation with abnormal birth weight during pregnancy, and their joint effects were also unknown. The aim of our study was to explore whether the pre-pregnancy exposure of hair dye and irregular menstruation were associated with the risk of abnormal birth weight. Methods: We conducted a nested case-control study from a prospective cohort of 6203 pregnant women. Low birth weight study included 315 mother-infant pairs (105 LBW cases and 210 matched controls), and macrosomia study included 381 mother-infant pairs (127 macrosomia cases and 254 matched controls). Meanwhile, lifestyle information including hair dying custom and menstrual history were collected by face-to-face questionnaires and birth outcomes were extracted from the medical records. The logistic regressions models were used to analyze the join effect of irregular menstruation and hair dye use. Results: Pre-pregnancy hair dye use was associated with increased risk of LBW (adjusted OR = 1.71, 95% CI: 1.01-2.92, P = 0.048). Irregular menstruation had high risk of LBW (adjusted OR = 2.79, 95% CI: 1.53-5.09, P = 0.001) and macrosomia (adjusted OR = 1.93, 95% CI: 1.09-3.44, P = 0.023). Additionally, in the LBW study, women who used hair dye with pre-pregnancy BMI < 18.5 kg/m2 had higher OR than those with only one risk factor (3.07 vs 2.53, P trend = 0.015), and women with both hair dye use and irregular menstruation also had higher risk than those with only one factor (4.53 vs 2.07, P trend = 0.05). Moreover, in macrosomia study, women with irregular menstruation and pre-pregnancy BMI ≥ 24 kg/m2 had higher risk than those with one factor (13.31 vs 2.09, P trend = 0.001). Conclusion: Our study showed that either pre-pregnancy hair dye use or irregular menstruation was associated with abnormal birth weight, especially, their joint effects could furthermore increase the risk of low birth weight infants when these two factors existed simultaneously.
... Témoins d'une exposition humaine, des phtalates et leurs métabolites ont été retrouvés dans les urines humaines (Koch et al. 2007), le lait maternel (Lottrup et al. 2006) et le liquide amniotique (Silva M. J. et al. 2004). Par ailleurs, ces derniers peuvent franchir la barrière placentaire (Ghittino et al. 2003). ...
... EDCs exhibit anti-androgenic and xeno-estrogenic actions (well described in other sections of this review); androgens and estrogens are involved in the regulation of lipid and glucose metabolism and in the regulation of adipose tissue also [133,134]. Therefore, EDCs may exert their obesogenic action inhibiting the androgen receptor pathway, enhancing the estrogen pathway or reducing androgen conversion through the up-regulation of the aromatase enzyme [135][136][137]. Thyroid hormones have a pivotal role in the regulation of basal metabolic rate and energy expenditure [138]. ...
Article
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Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.
... 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]. ...
Article
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.
... 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]. ...
Article
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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]. ...
Article
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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]. ...
Article
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 landll leachate is mainly distributed in humic acid (HA), fulvic acid (FA) and hydrophilic organic components (HyI). ...
Article
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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 . ...
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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 2 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 3 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.
... Most PAEs are identified as endocrine disruptor chemicals (EDCs) and have in vitro estrogenic potential for the human, especially leading to more toxicity to the male reproductive system (Harris et al. 1997;Lottrup et al. 2006). A worrying fact is that phthalates and their metabolites have been detected to be the highest median concentration of 47.1 ng mL −1 in urine of Chinese schoolchildren (Wang et al. 2015). ...
Article
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The photochemical oxidation of di-n-butyl phthalate (DBP) by •OH radicals from nitrous acid (HONO) in atmospheric hydrometeors was explored by two techniques, steady-state irradiation, and laser flash photolysis (LFP). The effects of atmospheric liquid parameters on DBP transformation were systematically evaluated, showing that DBP does not react with HONO directly and •OH-initiated reactions are crucial steps for consumption and transformation of DBP. Two reaction channels are operative: •OH addition and hydrogen atom abstraction. The overall rate constant for the reaction of DBP with •OH is 5.7 × 109 M-1 s-1, and its specific rate constant for addition is 3.7 × 109 M-1 s-1 determined by using laser flash photolysis technique. Comparing the individual reaction rate constant for aromatic ring addition with the total rate constant, the majority of the •OH radicals (about 65%) attack the aromatic ring. The major transformation products were identified by GC-MS, and the trends of their yields derived from both ring addition and H-abstraction with time are discussed. These results provide important insights into the photochemical transformation of DBP in atmospheric hydrometeors and contribute to atmospheric aerosol chemistry.
... Li and Wang [26] detected DEP on the aerosols in Chinese cities with concentrations ranged from ND to 23 ng m −3 . As a kind of environmental endocrine disruptors (EEDs), DEP has many potential adverse effects on living organisms, especially exhibits negative influence to male reproductive system [27]. Therefore, it has been listed as a priority pollutant by the China National Environmental Monitoring Center [28,29]. ...
Article
Diethyl phthalate (DEP) and N (III) are both ubiquitous pollutants in atmospheric hydrometeors. The cross-reaction pathways and kinetic parameters between DEP and N (III) in the atmospheric aqueous environment are explored by using 355 nm laser flash photolysis techniques combined with 365 nm UV light steady-state irradiation. Quantum yields of H 2 ONO + , HONO and NO 2 − under 355 nm illuminations are measured as 0.116, 0.231 and 0.036, respectively. Species-specific reaction rate constants of DEP with H 2 ONO + , HONO and NO 2 − are determined to be 0.039, 0.07 and 0.008 L mol −1 s −1 , respectively. Laser flash photolysis studies indicated HO% radicals originating from N (III) photolysis mainly attack aromatic ring of DEP to produce %DEP-OH adducts with a second-order rate constant of (4.2 ± 0.1) × 10 9 L mol −1 s −1. The major transformation products, ethyl salicylate and diethyl 4-hydroxyphthalate (m-OH-DEP) are produced from the attacking of HO% on the aromatic ring of DEP, while a small amount of dimethyl phthalate is generated by the hydrogen abstraction on the side chain. %DEP-OH is identified as a dominated intermediate which undergoes several decay pathways containing monomolecular decay, interaction with N (III), NO 2 and oxygen, the nitration processes of %DEP-OH by N (III) and NO 2 are crucial to the formation of nitro-compounds. The atmospheric implication of reactions between DEP and HO% in bulk water and surface water are also discussed.
... 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). ...
Article
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). ...
Article
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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. ...
Article
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). ...
Article
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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.
... The initial effects of diesel particulate extracts were moderate with respect to percent motile sperm but higher exposure the effects became more pronounced. Later Lottrup et al. (2006) reported that phthalates adversely affect the male reproductive system in animals, inducing hypospadias, and cryptorchidism, reduced testosterone production and declined sperm counts. Exposre to phthalate effects are much more severe after in utero than adult exposure. ...
Article
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Human and all the living beings are exposed to certain chemical, physical, biological, environmental as well as occupational factors during their day to day activities. Some of them may have adverse impact upon health including reproduction. There are reports which suggest that deterioration of reproductive health occurs in industrialized countries in recent decades. Thus, exposure to certain synthetic chemicals and changing life styles might be one of the cause behind the deterioration of reproductive health in recent decades. The available data indicated that occupational/environmental exposure especially to some of the organic solvents, pesticides, metals, plasticizers such as phthalates; ionizing and nonionizing radiations, extreme heat, stress might have adverse effects on male reproduction and associated function which depends upon the dose, duration of exposure, age, time of exposure, and health status of exposed person, nutrition etc. Some of the life styles factors such as tobacco smoking and chewing, excessive use of alcohol, certain illicit drugs and sedentary life style, working in hot environment etc. may also have some impact upon male reproduction in addition to host factors. Human are exposed to some of them simultaneously so that there may be of synergistic effects of these factors behind the cause of deterioration of reproductive health. Hence it is difficult to pinpoint a single compound or factor responsible for the cause of declining semen quality. There is a need for awareness among the society about the adverse effects of these factors behind the cause for the deterioration in semen quality and associated reproductive health impairments observed in recent decades so that preventive measure can be adopted to safeguard reproductive health.
... A few studies examined associations between phthalates and the human sex hormone system. In one study, lactational exposure to phthalate metabolites was found to be associated with reproductive hormone levels in the sera of healthy infant boys, and male infants exposed to higher levels of phthalate metabolites through breast milk demonstrated reduced androgen activity and Leydig cell function (Lottrup et al. 2006). Further, free testosterone levels in male children (aged <12 years) was reported to be negatively associated with urinary concentrations of MEHP and MBP (Pan et al. 2006). ...
Article
Risk assessment and hormone evaluation were carried out for di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), endocrine disrupting chemicals (EDCs), in 302 Korean children (n = 223) and adolescents (n = 79) (< age 19). Urinary and serum concentrations of DEHP, MEHP (mono(2-ethylhexyl) phthalate), DBP, MBP (monobutyl phthalate), and PA (phthalic acid, a common final metabolite of phthalates) were detected in children and adolescents. Daily exposure levels were estimated to be 16.45 ± 36.50 μg/kg b.w./day for DEHP, which is one-third of the tolerable daily intake (TDI) value (50 μg/kg b.w./day), but 14 out of 302 participants had a hazard index (HI = intake/TDI) value >1. The mean daily exposure level of DBP was 1.23 ± 1.45 μg/kg b.w./day, which is one-eighth of the TDI value (10 μg/kg b.w./day), but 1 out of 302 participants had a HI value > 1. Positive correlations were observed between serum DBP or MEHP, and serum estradiol (E2) and/or luteinizing hormone (LH) in prepubescent children. In addition, serum MBP levels were found to be negatively correlated with serum triiodothyronine (T3) or thyroxine (T4) in male participants, and serum DEHP levels with serum thyroid stimulating hormone (TSH) in female adolescents. Low-density lipoprotein (LDL) levels were positively correlated with serum PA levels in children and adolescents. DEHP, DBP or its metabolites may be associated with altered hormone levels in children and adolescents. Data suggest that exposure levels of DEHP and DBP in Korean children need to be reduced to levels below TDI to protect them from EDC-mediated toxicities. Abbreviations: DBP: dibutyl phthalate; DEHP: di(2-ethylhexyl) phthalate; E2: estradiol; EDC: endocrine disrupting chemical; EFSA: European Food Safety Authority; FSH: follicle stimulating hormone; HDL: high density lipoprotein; HI: hazard index; LDL: low density lipoprotein; LH: luteinizing hormone; MEHP: mono(2-ethylhexyl) phthalate; MBP: monobutyl phthalate; PA: phthalic acid; PPAR: peroxisome proliferator-activated receptor gamma; PVC: polyvinyl chloride; T3: triiodothyronine; T4: thyroxine; TDI: tolerable daily intake; TG: triglyceride; TSH: thyroid stimulating hormone; UPLC/MS/MS: Ultra Performance Liquid Chromatography/Tandem Mass Spectrometry; WWF: World Wildlife Fund.
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Background The occurrence of inflammatory bowel disease (IBD) and hypospadias has been concurrently increasing, possibly through shared environmental risk factors such as endocrine disrupting compounds. Also, maternal IBD may disturb the normal development of the fetal reproductive tract. However, whether maternal IBD increases the risk of hypospadias in male offspring is unknown. We compared hypospadias risk in sons of mothers with and without IBD. Methods We used Danish nationwide population-based registries to conduct a longitudinal prevalence study including all live-born boys from 1979 through 2009. We computed HRs, as estimates of prevalence ratios (PRs), with 95% CIs for hypospadias, using Cox proportional hazards regression, while adjusting for measured confounding. Results Among 966 038 live-born boys, 4688 (0.5%) had a mother with a history of IBD diagnosis before the relevant childbirth. Among the boys with maternal IBD, 36 (0.8%) were diagnosed with hypospadias any time after birth, whereas 6112 (0.6%) sons of mothers without IBD diagnosis had hypospadias (adjusted PR: 1.20, (95% CI 0.86 to 1.67). Adjusted PRs for maternal Crohn's disease and ulcerative colitis were 1.38 (95% CI 0.83 to 2.29) and 1.10 (95% CI 0.71 to 1.68), respectively. Analyses defining hypospadias diagnosis recorded <6 months postpartum showed similar results. Conclusions We found no convincing evidence of an association between maternal IBD and hypospadias.
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Children today live in a world that is vastly different from a few generations ago. While industrialization has maximized (for many) children’s opportunities to survive, develop and enjoy high levels of health, education, recreation, and fulfillment, it has also added significant challenges to their development.
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RECOMMENDATION FROM THE SCIENTIFIC COMMITTEE ON OCCUPATIONAL EXPOSURE LIMITS FOR DI-N-BUTYL PHTHALATE 8-hour TWA: 0.05 ppm (0.58 mg/m3) STEL: None BLV: None BGV: 70 μg mono-n-butyl phthalate/l urine Additional categorisation: No Notation: No The present Recommendation was adopted by SCOEL on 2016-12-14. This evaluation is based on ACGIH (2001), ATSDR (2001), ECB (2000), ECB (2003), NTP (2000), WHO (1997), Hartwig (2010) and the references cited in these reviews. Further literature update (covering 2009-2013) was performed in June 2013. RECOMMENDATION EXECUTIVE SUMMARY Critical endpoints for occupational exposure to DBP are irritation and reproductive toxicity. There were no adequate human data on DBP to derive a recommended OEL. Local effects In an animal subacute study with aerosol inhalation exposure according to OECD guidelines, DBP was irritating to the upper respiratory tract of rats (LOAEC 1.2 mg/m3, no NOAEC; Gamer et al 2000). Systemic effects including reproductive toxicity The study by Gamer et al (2000) reveals a reliable NOAEC of 509 mg/m3 for systemic effects after repeated inhalation exposure. After repeated oral exposure, DBP produced effects on liver, kidney and blood in rats and mice. The LOAEL and NOAEL in the most valid study by Schilling et al (1992) were 752 and 152 mg/kg bw/day for rats, respectively. DBP like diethyl hexyl phthalate induces effects in the liver and the reproductive organs (testes), which may result from the same mechanisms of action. These mechanisms, which are associated with proliferative effects in the liver and the testes and which induce reproductive toxicity are disturbances in intercellular communication or signal transduction, changes in the activities of enzymes involved in steroid metabolism (which probably leads to a reduction in the testosterone level), increased expression of nuclear factor-kappa B (NF-κB) (can lead to the activation of Kupffer’s cells), and reduced gene expression (PPAR induced or PPAR independent) (Hartwig 2010). On the basis of the available data, the effects on the testes are regarded as relevant for humans. Swan et al (2005) provided indications that the development of the reproductive organs in humans is influenced by DBP. Also, Schultz et al (1999) suggested that the presence of PPAR α in human germ cells has a greater influence on human fertility as compared to rats. The lowest relevant LOAEL (sperm abnormalities) from studies with repeated administration (4 weeks) in rats is 31.25 mg/kg bw and day. A NOAEL for the effects on the testes cannot be derived (Mitsuhashi et al 2004). A benchmark calculation resulted in a lower confidence limit (BMDL) of 1.5 mg/kg bw/day. The findings by Mitsuhashi et al (2004) are supported by the occurrence of testicular effects at higher doses in numerous studies. Concerning developmental effects, the relevant exposure situation at the workplace is prenatal exposure combined with postnatal investigation of the offspring. Such studies resulted in a NOAEL of 50 mg/kg bw and day (Mylchreest et al 2000). At the LOAEL of 100 mg/kg bw and day, retention of the areola or nipple (Barlow et al 2004, Mylchreest et al 2000) and effects on the testes (Mahood et al 2007) in rats were observed. Applying route-to-route extrapolation and allometric scaling the NOAEL corresponds to an air NOAEC of 87.5 mg/m3 (assuming a human body weight of 70 kg and a respiratory volume of 10 m3, the species-specific correction factor for rats of 4, an assumed oral and inhalation absorption of 100 %). In summary, with respect to systemic and reproductive toxicity, the BMDL for the most sensitive endpoint, i.e. for sperm abnormalities in rats, is 1.5 mg/kg bw/day, resembling after allometric scaling as described above and additionally the consideration of 5 day exposure of humans as apposed to 7 day weekly exposure in animals an airconcentration of 3.6 mg/m3. This is about 6-fold higher than the recommended OEL (see below). Genotoxicity and carcinogenicity DBP was considered a non-genotoxic substance, as the only clear positive in vitro result (mouse lymphoma assay; Hazleton 1986) and a weak positive result in vivo (Comet Assay) (Dobrzyńska et al 2010) were not confirmed in (negative) in vivo micronucleus tests (BASF 1990, NTP 1995). Adequate long-term studies on carcinogenic effects were not available. Published studies in rodents (Krauskopf 1973, Nikonorow et al 1973, Smith 1953, Kim and Cho 2009a,b), which were all inadequate in methods or conduction, provide no indication for increased tumour incidences. In developmental toxicity studies by Mylchreest et al (1999, 2000), the incidence of Leydig cell adenomas was slightly increased in 30-day old rats and the incidence of Leydig cell hyperplasia was increased in around 100 to 110-day-old rats, which were exposed prenatally (gestation day 12 – 21) to 500 mg/kg bw/day (dams). No carcinomas were observed. Other phthalate esters have been shown to produce hepatic cancers in rodents, which are attributed to an increased sensitivity of rodents to the induction of peroxisome proliferation compared to monkeys or humans (ECB 2003). Several peroxisome proliferators produce tumours also outside the liver, shown for Leydig cells or pancreatic acinar cells in rats (Biegel et al 2001). DBP leads to the same effects as diethylhexyl phthalate (liver peroxisome proliferation, induction of lipid metabolism enzymes, liver enlargement, malformation of the reproductive organs after prenatal exposure, reduced testosterone concentrations, Leydig cell hyperplasia and multinuclear germ cells), which are the result of proliferative effects on the liver and testes. Based on mechanistic data, there is therefore some remaining suspicion for non-genotoxic formation of tumours. However, the recommended OEL of 0.05 ppm (0.58 mg/m3) is far below the NOAEC for systemic effects. Overall assessment The recommended OEL is based on the data showing irritating of the upper respiratory tract of rats at 1.2 mg/m3 of DBP aerosol (LOAEC; no NOAEC) (Gamer et al 2000). Within this study, epithelial-like metaplasia in the larynx and hyperplasia of the goblet cells in the nasal cavity were observed at 1.2 mg/m3. These effects were hardly more pronounced after 500 mg/m3, an aerosol concentration that is more than two orders of magnitude higher. Also, the local deposition in the nose and larynx is probably higher with exposure in aerosol form, which is not present below concentrations of 1 mg/m3 DBP. Therefore at concentrations below 1 mg/m3, an increase in severity of the observed effects are not expected. Based on the comparatively weak effects at the LOAEC of 1.2 mg/m3 and a flat dose-response-relationship, an OEL of 0.05 ppm (0.58 mg/m3) is proposed. No STEL is proposed to limit short-term exposure as irritation was only observed after subacute exposure duration, and developmental effects are observed only at higher exposure concentrations compared to the recommended OEL.
Chapter
Advances in materials sciences and engineering during the last decades have led to a widespread use of phthalates (phthalic acid esters) in a wide range of industrial products. Phthalates are used as plasticizers that impart flexibility and durability to polyvinylchloride (PVC) products. They are also used in solvents, lubricating oils, fixatives, and as detergents in personal care products. When incorporated into PVC, phthalates are not covalently bound and are therefore easily released to the surroundings, leading to contamination of the external environment. Phthalates are detected in several media including food, water, house dust, and air, thereby exposing animals and humans.
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We studied the removal of two phthalic acid diesters (PAEs), di-n-butyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP), from leachates of a municipal solid waste landfill treatment facility. The leachates originated from the adjusting unit, the anaerobic unit, the aerobic unit, the ultrafiltration membrane unit, and the reverse osmosis membrane unit. The initial concentrations of DBP and DEHP were 225.8 and 260.9 µg/L, respectively, which were reduced to 5.8 and 3.2 µg/L in the effluent, representing 97.4% removal of DBP and 98.8% removal of DEHP. DBP was removed stepwise during the process, mainly via degradation by microorganisms. Approximately, 70.1% of the DEHP was removed by the membrane processes, owing to physical retention of the compound by the membranes. The dissolved organic carbon occurred mostly in the 1–100 kDa molecular weight fraction. The positive correlation between dissolved organic carbon and DBP/DEHP concentrations in raw leachate and in effluents from each treatment unit showed that the interaction between dissolved organic matter and PAEs facilitated the removal of organic pollutants. Large amounts of PAEs can accumulate over long periods of time in the concentrated leachate product, which may make further leachate treatment more difficult and may lead to adverse impacts on the environment.
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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.
Chapter
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.
Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long-term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions. This article is protected by copyright. All rights reserved.
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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.
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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.
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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%).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Article
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.
Article
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.
Article
The migration of di-2-ethylhexyl phthalate (DEHP) from dialyzers was studied in 21 patients with chronic renal failure undergoing maintenance hemodialysis. The circulating concentrations of DEHP were measured by high performance liquid chromatography in blood of patients obtained from the inlet and the outlet of the dialyzer during a 4-h dialysis session. During treatment of renal failure using plasticized tubing, the plasma level of DEHP increased. On average, an estimated 75.2 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 44.3-197. 1 mg. On the other hand, the total amount of DEHP retained by the patient during the dialysis session was evaluated by the difference between the AUCout and the AUCin and ranged from 3.6 to 59.6 mg. The rate of extraction of DEHP from the dialyzer was correlated (r=0.705, P<0.05) with serum lipid content (cholesterol and triglyceride).So, we confirmed that patients on hemodialysis are always regularly exposed to considerable amounts of DEHP. However, several metabolic effects have been reported in various animal species following treatment with DEHP, such as changes in lipid metabolism and in hepatic microsomal drug-metabolizing enzyme activities. DEHP is now a well-known hepatic peroxisomal proliferator in rodents and an inducer of many peroxisomal and non-peroxisomal enzymes. So, lipid metabolism modifications and hepatic changes observed in hemodialysis patients could be explained from chronic exposition to DEHP. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of hemodialysis tubing.
Article
Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicular nondescent, while in contrast, finasteride, an inhibitor of 5 alpha-dihydrotestosterone (DHT) synthesis, rarely, if ever, induces such malformations. In this regard, it was recently proposed that dibutyl phthalate (DBP) alters reproductive development by a different mechanism of action than flutamide or vinclozolin (V), which are AR antagonists, because the male offsprings display an unusually high incidence of testicular and epididymal alterations--effects rarely seen after in utero flutamide or V treatment. In this study, we present original data describing the reproductive effects of 10 known or suspected anti-androgens, including a Leydig cell toxicant ethane dimethane sulphonate (EDS, 50 mg kg-1 day-1), linuron (L, 100 mg kg-1 day-1), p,p'-DDE (100 mg kg-1 day-1), ketoconazole (12-50 mg kg-1 day-1), procymidone (P, 100 mg kg-1 day-1), chlozolinate (100 mg kg-1 day-1), iprodione (100 mg kg-1 day-1), DBP (500 mg kg-1 day-1), diethylhexyl phthalate (DEHP, 750 mg kg-1 day-1), and polychlorinated biphenyl (PCB) congener no. 169 (single dose of 1.8 mg kg-1). Our analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects. Vinclozolin, P, and DDE, known AR ligands, produce similar profiles of toxicity. However, p,p'-DDE is less potent in this regard. DBP and DEHP produce a profile distinct from the above AR ligands. Male offsprings display a higher incidence of epididymal and testicular lesions than generally seen with flutamide, P, or V even at high dosage levels. Linuron treatment induced a level of external effects consistent with its low affinity for AR [reduced anogenital distance (AGD), retained nipples, and a low incidence of hypospadias]. However, L treatment also induced an unanticipated degree of malformed epididymides and testis atrophy. In fact, the profile of effects induced by L was similar to that seen with DBP. These results suggest that L may display several mechanisms of endocrine toxicity, one of which involves AR binding. Chlozolinate and iprodione did not produce any signs of maternal or fetal endocrine toxicity at 100 mg kg-1 day-1. EDS produced severe maternal toxicity and a 45% reduction in size at birth, which resulted in the death of all neonates by 5 days of age. However, EDS only reduced AGD in male pups by 15%. Ketoconazole did not demasculinize or feminize males but rather displayed anti-hormonal activities, apparently by inhibiting ovarian hormone synthesis, which resulted in delayed delivery and whole litter loss. In summary, the above in vivo data suggest that the chemicals we studied alter male sexual differentiation via different mechanisms. The anti-androgens V, P, and p,p'-DDE produce flutamide-like profiles that are distinct from those seen with DBP, DEHP, and L. The effects of PCB 169 bear little resemblance to those of any known anti-androgen. Only in depth in vitro studies will reveal the degree to which one can rely upon in vivo studies, like those presented here, to predict the cellular and molecular mechanisms of developmental toxicity.
Article
Di(n-butyl) phthalate (DBP) is a commercially important plasticizer and ubiquitous environmental contaminant. Since previous, limited dose-response studies with DBP that reported alterations in male reproductive development and function failed to establish a NOAEL (no-observed-adverse-effect level), an extensive dose-response study was conducted. Pregnant CD rats were given DBP by gavage at 0, 0.5, 5, 50, or 100 mg/kg/day (n = 19-20) or 500 mg/kg/day (n = 11) from gestation day 12 to 21. In male offspring, anogenital distance was decreased at 500 mg DBP/kg/day. Retained areolas or nipples were present in 31 and 90% of male pups at 100 and 500 mg/kg/day, respectively. Preputial separation was not delayed by DBP treatment in males with normal external genitalia, but cleft penis (hypospadias) was observed in 5/58 rats (4/11 litters) at 500 mg/kg/day. Absent or partially developed epididymis (23/58 rats in 9/11 litters), vas deferens (16/58 animals in 9/11 litters), seminal vesicles (4/58 rats in 4/11 litters), and ventral prostate (1/58 animals) occurred at 500 mg/kg/day. In 110-day-old F(1) males, the weights of the testis, epididymis, dorsolateral and ventral prostates, seminal vesicles, and levator ani-bulbocavernosus muscle were decreased at 500 mg/kg/day. At 500 mg/kg/day, widespread seminiferous tubule degeneration was seen in 25/58 rats (in 9/11 litters), focal interstitial cell hyperplasia in 14/58 rats (in 5/11 litters), and interstitial cell adenoma in 1/58 rats (in 1/11 litters). For this 10-day prenatal (embryonic and fetal) exposure to DBP, the NOAEL and LOAEL (lowest-observed-adverse-effect level) were 50 and 100 mg/kg/day, respectively. This is currently the lowest NOAEL described for the toxicity of DBP.
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Extravagant claims have been made repeatedly in recent years that human sperm counts are falling and that global exposure to environmental estrogens are responsible. The basis for these two distinct claims is reviewed. The claims of falling human sperm output, reviving an old debate, are prompted by a paper by Carlsen et al. (1992). This meta-analysis, however, is marred by numerous flaws that invalidate its claims. Major defects include severe heterogeneity of component studies, rendering them unsuitable for aggregation, and defective data analysis based on arithmetic mean rather than median, which showed no significant changes over time. This debate is likely to remain unresolved until valid, representative population-based studies of human sperm output can be achieved. None have been reported, or seem feasible in the near future, and so alternative strategies, based on surrogate variables for human male fertility not requiring sperm counts, need to be developed and validated. The plausible hypothesis that prenatal estrogen exposure might influence development of the human testis through effects on Sertoli cell replication and sperm carrying capacity has, however, been conclusively refuted by studies of boys born to women exposed to high doses of oral diethylstilbestrol during pregnancy. Neither fertility nor sperm output were adversely influenced by massive maternal estrogen exposure during pregnancy, although minor urogenital malformations did occur. The still wider claims of deteriorating male reproductive health, notably changes in prevalence or incidence of hypospadias or cryptorchidism, also lack convincing population-based evidence, although cancer registry data indicate a gradual increase in testis cancer in some countries. In summary, the available evidence does not support claims of falling sperm counts or any general deterioration in male reproductive health. Population-based studies of valid surrogate variables for male fertility not requiring semen analysis are needed. If population-based evidence regarding male fertility or sperm output could be generated, it is highly unlikely that prenatal estrogen exposure could be a valid explanation of any deterioration as massive maternal exposure to oral estrogen has negligible effects on male fertility or sperm output.
Article
Adult male rats previously exposed on gestation days (GD) 12-21 to di(n-butyl) phthalate (DBP) have reproductive tract malformations, particularly agenesis of the epididymis, decreased sperm production, and Leydig cell hyperplasia and adenomas. Although similar effects are produced by the potent androgen receptor (AR) antagonist flutamide and are indicative of disruption of male sexual differentiation via an antiandrogenic mechanism, DBP is not an AR antagonist. The purpose of the study was to determine whether DBP causes pathologic changes and alterations in androgen status in the testis during the prenatal period of male reproductive tract differentiation. Pregnant CD rats were given corn oil, DBP (500 mg/kg/day), or flutamide (100 mg/kg/day) p.o. on GD 12-21. At GD 16-21, DBP caused hyperplasia of Leydig cells, many of which were 3beta-hydroxysteroid dehydrogenase- and/or AR-positive. Focal areas of hyperplasia had increased numbers of Leydig cells positive for proliferating cell nuclear antigen (PCNA). At GD 21, testis atrophy was apparent, seminiferous cords in DBP-exposed fetuses were enlarged and contained multinucleated gonocytes that, unlike controls, were PCNA-positive. DBP, but not flutamide, markedly decreased testicular testosterone levels at GD 18 and 21. Fewer epididymal ducts and reduced AR staining in some ducts were evident with DBP treatment, whereas decreased overall AR staining was seen with flutamide in the presence of mild Leydig cell hyperplasia. Leydig cell proliferation is likely a compensatory mechanism to increase testicular steroidogenesis triggered by testosterone insufficiency. The overall decrease in androgen concentration is not corrected and results in reproductive tract malformations. The multinuclearity and proliferation of gonocytes suggests an underlying Sertoli cell dysfunction.
Article
Dibutyl phthalate is a phthalate ester with extensive use in industry in such products as plastic (PVC) piping, various varnishes and lacquers, safety glass, nail polishes, paper coatings, dental materials, pharmaceuticals, and plastic food wrap. Concomitant with this extensive worldwide use is the high potential for human exposure to dibutyl phthalate in the workplace and the home environment through direct sources as well as indirectly, through contamination of water, air, and foodstuffs. Because existing toxicity information was considered inadequate, the effects of exposure to dibutyl phthalate were examined in male and female F344/N rats and B6C3F1 mice in 13-week feed studies. Furthermore, due to concern over the potential for pervasive exposure of humans to dibutyl phthalate, additional perinatal studies examined rats and mice exposed as pups in utero, for the 4 weeks of lactation, and for an additional 4 weeks postweaning. Additional studies examined the effects on rats of combining perinatal and adult subchronic exposure. Due to the recognized biologic activity of this and other phthalates, hepatic peroxisome proliferation during the in utero and lactational phases and testicular toxicity during the perinatal period were also examined. Finally, reproductive assessment by continuous breeding (including crossover mating trials and offspring assessment) and genetic toxicity studies were also conducted. In the maximum perinatal exposure (MPE) determination study in rats, dibutyl phthalate was administered in the diet to dams during gestation and lactation, and to the pups postweaning for four additional weeks, at concentrations of 0, 1,250, 2,500, 5,000, 7,500, 10,000, and 20,000 ppm. Decreased weight gains were noted in dams exposed to 20,000 ppm during gestation and to dams exposed to 10,000 ppm during lactation. The gestation index (number of live pups per breeding female) was significantly lower in the 20,000 ppm group than in the controls, and pup mortality in this group was marked (100% by Day 1 of lactation); however, survival was 89% or greater in all other treatment groups. The mean body weight of pups in the 10,000 ppm group at Day 28 of lactation was approximately 90% of the mean weight of control pups. Pups were weaned onto diets containing dibutyl phthalate at the same concentrations fed to dams. After an additional 4 weeks of dietary administration, final mean body weights of pups in the 10,000 ppm groups were 92% of the control value for males and 95% of the control value for females. Hepatomegaly (increased relative liver weight) was observed in males in all exposed groups and in females receiving 2,500 ppm or greater. No gross lesions were observed at necropsy. Moderate hypospermia of the epididymis was diagnosed in all male rats in the 7,500 and 10,000 ppm groups; mild hypospermia of the epididymis was diagnosed in 2 of 10 males in the 5,000 ppm group. No degeneration of the germinal epithelium was detected in the testis of these rats. Thus, although toxicologically important, the epididymal hypospermia was not considered to be life threatening, and 10,000 ppm was recommended as the MPE concentration for male and female rats. In the subsequent subchronic toxicity study of dibutyl phthalate with perinatal exposure, dams were administered diets containing 0 or the MPE concentration (10,000 ppm) during gestation and lactation, and weaned pups were administered the same diets as their dams received for an additional 4 weeks, until the beginning of the 13-week exposure phase. Male and female rats then received diets containing dibutyl phthalate at concentrations of 0, 2,500, 5,000, 10,000, 20,000, and 40,000 ppm for 13 weeks. No mortality or toxicity was observed in dams during the perinatal phase of the study; however, before pups were culled at 4 days postpartum, the percentage of live pups per litter was 86% to 93% that of the controls. Through weaning, litter weights of exposed pups ranged from 89% to 92% of the control values. Ten control and ten exposed pups per sex were examined at the time of trol and ten exposed pups per sex were examined at the time of weaning; hepatomegaly and markedly increased peroxisomal enzyme activities (approximately 9-fold greater than the control values) were observed in exposed pups. Body weights of the perinatally exposed pups remained lower than those of the controls throughout the 4-week period before the 13-week adult exposures began. During the 13-week adult exposure phase, the final mean body weight of males in the MPE: 0 ppm control group (MPE rats, returned to the base diet for 13 weeks), was 95&percnt; that of the controls. The body weight gain of females in the MPE:0 ppm group was greater than that of the unexposed controls, and the final body weights of these two groups were similar. Body weight gains of rats treated with dibutyl phthalate as adults decreased with increasing exposure concentration; for rats that received the MPE concentration followed by 40,000 ppm for 13 weeks, final body weights were 51&percnt; of the control value for males and 74&percnt; of the control value for females. Hepatomegaly apparently regressed in rats in the MPE:0 ppm groups but was observed in male rats receiving 5,000 ppm or greater and in females receiving 2,500 ppm or greater. In males that received 20,000 ppm as adults, testis and epididymal weights were less than in the controls; males in the 40,000 ppm group also had a lower testis weight than the controls. Results of hematologic analyses conducted at the end of the 13-week exposure period suggested a mild anemia in male rats administered 10,000 ppm or greater as adults and female rats administered 40,000 ppm as adults. Hypocholesterolemia and hypotriglyceridemia were observed in male and female rats at the higher exposure concentrations. Hypotriglyceridemia was detected in females receiving 20,000 or 40,000 ppm and in males receiving 10,000 ppm or greater. Elevations in alkaline phosphatase activities and bile acid concentrations in male and female rats receiving 20,000 or 40,000 ppm as adults were indicative of cholestasis. Microscopic examination revealed hepatocellular cytoplasmic alteration, consistent with glycogen depletion, in male and female rats receiving a concentration of 10,000 ppm or greater. In the liver of rats receiving 40,000 ppm, small, fine, eosinophilic granules were also observed in the cytoplasm of hepatocytes. Ultrastructural examination suggested the presence of increased numbers of peroxisomes. Lipofuscin accumulation was detected in rats that received 10,000 ppm or greater. Consistent with the regression of the hepatomegaly in rats in the MPE:0 and MPE:2,500 ppm groups, peroxisomal enzyme activity was not elevated in these groups. Marked elevations of peroxisomal enzyme activity were detected, however, in males receiving 5,000 ppm or greater and in females receiving 10,000 ppm or greater; at the 40,000 ppm concentration, the highest concentration tested, enzyme activities were approximately 20 fold greater than the control values. Histopathologic examination of the testes revealed degeneration of the germinal epithelium, a mild to moderate focal lesion in rats in the 10,000 and 20,000 ppm groups and a marked, diffuse lesion in all males receiving 40,000 ppm; at 40,000 ppm, an almost complete loss of the germinal epithelium resulted. Testicular zinc concentrations were lower in the 40,000 ppm group than in the controls, a finding consistent with the marked loss of germinal epithelium at this exposure concentration. Spermatogenesis was evaluated in rats in the 0, 2,500, 10,000, and 20,000 ppm groups; rats administered 20,000 ppm had fewer spermatid heads per testis than the unexposed controls, and epididymal spermatozoal concentration was less than that in the MPE:0 ppm group. For comparison with the perinatal subchronic study, a standard 13-week evaluation of the toxicity of dibutyl phthalate in male and female rats was also conducted. In this study, rats received dibutyl phthalate at the same dietary concentrations used in the 13-week exposure phase of the study with perinatal exposure: 0, 2,500, 5,000, 10,000, 20,000, and 40,000 ppm. No deaths occurred in the standard study. Markedly reduced final mean body weights were observed in males and females in the 40,000 ppm groups (45&percnt; and 73&percnt; of control body weights, respectively); final mean body weights of males receiving 10,000 ppm or greater and females receiving 20,000 ppm or greater were lower than those of the controls. Hepatomegaly was observed in males that received 5,000 ppm or greater and in females that received 10,000 ppm or greater. Testis and epididymal weights of males in the 20,000 and 40,000 ppm groups were lower than those of the controls. A minimal anemia was detected in male rats receiving 5,000 ppm or greater. Hypocholesterolemia was observed in male and female rats receiving 20,000 or 40,000 ppm, and hypotriglyceridemia was detected in males in all exposed groups and in females receiving 10,000 ppm or greater. Elevations in alkaline phosphatase activity and bile acid concentration in male and female rats were considered indicative of cholestasis. Morphologic evaluation again confirmed the toxicity of dibutyl phthalate to the liver and testes of rats. Microscopic examination of the liver revealed hepatocellular cytoplasmic alterations, consistent with glycogen depletion, in male and female rats receiving 10,000 ppm or greater. In the liver of rats in the 40,000 ppm groups, small, fine, eosinophilic granules were also observed in the cytoplasm of hepatocytes. Ultrastructural examination suggested the presence of increased numbers of peroxisomes, and peroxisomal enzyme activity was elevated in the livers of male and female rats administered 5,000 ppm or greater; the enzyme activities in the 40,000 ppm groups were approximately 13-fold greater than the control value for males and 32-fold greater than the control value for females. Lipofuscin accumulation was detected in rats receiving 10,000 ppm or greater. Histopathologic examination of the testes revealed degeneration of the germinal epithelium, a mild to marked focal lesion in the 10,000 and 20,000 ppm groups and a marked, diffuse lesion in all males in the 40,000 ppm group; at 40,000 ppm, an almost complete loss of the germinal epithelium resulted. Testicular zinc concentrations were lower in the 20,000 and 40,000 ppm groups than in the controls. Serum testosterone values were also lower at these concentrations than in the controls. Spermatogenesis was evaluated in males in the 0, 2,500, 10,000, and 20,000 ppm groups; at 20,000 ppm, spermatid heads per testis and per gram testis, epididymal spermatozoal motility, and the number of epididymal spermatozoa per gram epididymis were lower than in the controls. All of these findings are consistent with the marked loss of germinal epi