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The increasing global prevalence of gestational diabetes mellitus (GDM) has been hypothesized to be associated with maternal exposure to environmental chemicals. Here, among 420 women participating in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study, we examined associations between GDM and second trimester blood or urine concentrations of endocrine disrupting chemicals (EDCs): bisphenol-A (BPA), bisphenol-S (BPS), twelve phthalate metabolites, eight perfluoroalkyl acids (PFAAs), and eleven trace elements. Fifteen (3.57%) of the women were diagnosed with GDM, and associations between the environmental chemical exposures and GDM diagnosis were examined using multiple logistic and LASSO regression analyses in single- and multi-chemical exposure models, respectively. In single chemical exposure models, BPA and mercury were associated with increased odds of GDM, while a significant inverse association was observed for zinc. Double-LASSO regression analysis selected mercury (AOR: 1.51, CI: 1.12-2.02), zinc (AOR: 0.017, CI: 0.0005-0.56), and perfluoroundecanoic acid (PFUnA), a PFAAs, (AOR: 0.43, CI: 0.19-0.94) as the best predictors of GDM. The combined data for this Canadian cohort suggest that second trimester blood mercury was a robust predictor of GDM diagnosis, whereas blood zinc and PFUnA were protective factors. Research into mechanisms that underlie the associations between mercury, zinc, PFUnA, and the development of GDM is needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Endocrine-disrupting chemicals (EDCs) might increase the risk of childhood diseases by disrupting hormone-mediated processes that are critical for growth and development during childhood, however, the association among the exposure level of EDCs such as Nonylphenol (NP), Bisphenol A (BPA), Dimethyl phthalate (DMP) in children and environmental risk factors, as well as hepatic function has not been elaborated. This study aimed to discuss this interesting relationship among NP, BPA, DMP concentrations in serum, environmental risk factors, hepatic function of 5- to 14-year-old children in industrial zone, residential zone and suburb in northern district of Guizhou Province, China. In Zunyi city, 1006 children participated in cross-sectional health assessments from July to August 2018, and their parents completed identical questionnaires on the environmental risk factors of EDCs exposure to mothers and children. Serum NP, BPA and DMP concentrations were measured by high performance liquid chromatography (HPLC). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT, total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) were detected with automatic biochemical analyzer. The median concentrations of serum NP, BPA, and DMP in the participants were 45.85 ng/mL, 26.31 ng/mL and 31.62 ng/mL, respectively, which were higher than the environmental concentration limits of the U.S. National Environmental Protection Agency (EPA). Hair gels used during pregnancy, types of domestic drinking water, nail polish and cosmetics used by children were significantly positive correlated with serum NP concentration (P < 0.05). Gender, feeding pattern, plastic water cup used during pregnancy, hair spray and perfume use for children, duration of children birth, materials for baby bottle or cup and ways to plastic products were significantly positively correlated with serum BPA concentration (P < 0.05). Gender, perms used during pregnancy, hair spray and perfume use for children, using plastic lunch box during pregnancy, duration of children birth, exposure to pesticides, parents' occupations were significantly positively correlated with serum DMP concentrations (P < 0.05). Serum NP (β = 0.296, P = 0.036) and DMP (β = 0.316, P = 0.026) concentrations and TBIL level were significantly positively correlated. Serum NP concentration and the levels of IBIL (β = 0.382, P = 0.006) are significantly positively correlated. Cosmetics used during pregnancy significantly increased AST level (β = 2.641, P = 0.021). There was a positive correlation between the frequency of hair spray and perfume use for children and the AST (β = 4.241, P = 0.022). NP, BPA and DMP, which were commonly detected in the serum of children aged 5-14 years old in Zunyi City, Northern Guizhou Province, China, were closely related to the environmental risk factors of exposure environment during pregnancy, infancy and school age. Exposure to NP, BPA and DMP would have negative effects on hepatic function, and these effects showed differences in gender and geographical location. Notably,The relationships were more evident in girls than in boys., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Bisphenol A (BPA) is an endocrine disruptor that it is present in numerous products of daily use. The aim of this study was to assess the potential association of serum BPA concentrations and the risk of incident breast and prostate cancer in a sub-cohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: We designed a case-cohort study within the EPIC-Spain cohort. Study population consisted on 4812 participants from 4 EPIC-Spain centers (547 breast cancer cases, 575 prostate cancer cases and 3690 sub-cohort participants). BPA exposure was assessed by means of chemical analyses of serum samples collected at recruitment. Borgan II weighted Cox regression was used to estimate hazard ratios., Results: Median follow-up time in our study was 16.9 years. BPA geometric mean serum values of cases and sub-cohort were 1.12 ng/ml vs 1.10 ng/ml respectively for breast cancer and 1.33 ng/ml vs 1.29 ng/ml respectively for prostate cancer. When categorizing BPA into tertiles, a 40% increase in risk of prostate cancer for tertile 1 (p = 0.022), 37% increase for tertile 2 (p = 0.034) and 31% increase for tertile 3 (p = 0.072) was observed with respect to values bellow the limit of detection. No significant association was observed between BPA levels and breast cancer risk., Conclusions: We found a similar percentage of detection of BPA among cases and sub-cohort from our population, and no association with breast cancer risk was observed. However, we found a higher risk of prostate cancer for the increase in serum BPA levels. Further investigation is needed to understand the influence of BPA in prostate cancer risk., (© 2021. The Author(s).)

Aim: Bisphenol-A (BPA) is an endocrine disrupting compound and may exacerbate or induce allergic diseases. To the best of our knowledge, there is little evidence regarding the effects of BPA exposure on allergic rhinitis (AR) in children. In the present study, we sought to examine whether exposure to BPA in children is associated with AR., Methods: This study was designed as a case controlled clinical study. 140 children diagnosed as allergic rhinitis and 140 healthy children as control group were recruited. BPA, interleukin-4, interleukin-13, total IgE and interferon-gamma levels were determined. Skin prick tests were performed in patient group. Total nasal symptom score and ARIA classification were used to predict disease severity., Results: Serum IL-4, IgE and BPA levels of children with allergic rhinitis were found to be significantly higher than the control group. BPA and IL-4 levels were significantly higher in moderate to severe-persistent group. There was a positive correlation between total nasal symptom scores and Bisphenol A levels in children with allergic rhinitis., Conclusions: The present study is the first to observe statistically significant relationship between BPA concentrations and allergic rhinitis in children. Also increased levels of BPA are associated with disease severity.

The aim of this study was to newly identify and investigate the gender differences in pharmacokinetics (PKs) and tissue distribution of 4-n-nonylphenol (4-n-NP) in both male and female Sprague-Dawley rats. For this study, a UPLC-ESI-MS/MS system for 4-n-NP was developed as a sensitive and rapid analysis method and validated according to the accepted criteria of the international guidelines. The method was finally applied to the analysis of plasma, urine, feces, and nine different tissue samples of rats. PK parameters were calculated after single oral or intravenous administration of 4-n-NP at a dose of 10 or 50 mg/kg. Mean half-life of 4-n-NP in female rats was shorter and its clearance was larger for all doses than those in male rats. There were statistically significant differences in excretion patterns of urine and feces between male and female rats. Distribution of nine different tissues for 4-n-NP was greater in male than in female, and 4-n-NP was highly distributed in the liver or kidney. It was also specific that the distribution of 4-n-NP into brain was considerable. These results suggest that there are gender differences in the PKs of 4-n-NP in rats. Although, 4-n-NP is known to be a reproductive toxicant, reports on its PKs, excretion pattern, tissue distribution, and gender difference are limited. Therefore, our results will be useful data for gender differences as well as toxicokinetic information for 4-n-NP. In addition, it is expected to be very important for future risk assessment and PBPK model establishment of 4-n-NP.

Bisphenol A (BPA) and phthalates are endocrine disruptors that can induce oxidative stress. Serum bilirubin has antioxidant properties and may serve as a biomarker of oxidative stress. The objective of this study was to explore the relationship of BPA and phthalates with serum bilirubin levels in a Korean population. Urinary concentrations of BPA and six phthalate [mono-n-butyl phthalate (MnBP), mono-iso-butyl phthalate (MiBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5- hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono-benzyl phthalate (MBzP)] were measured in 709 participants. Serum concentrations of BPA and three phthalate metabolites [MnBP, MiBP, and mono-(2-ethylhexyl) phthalate (MEHP)] were measured in 752 participants. After excluding missing variables, associations between above chemicals and serum bilirubin levels were analyzed using multivariate linear regression with age, sex, BMI, GGT, GOT, GPT, and alcohol intake adjustment. Participants were further stratified by sex. Among the urinary chemicals, BPA and four phthalate metabolites (MnBP, MEOHP, MEHHP and MECPP) were inversely associated with serum bilirubin levels (BPA: β = - 0.071, P < 0.0001; MnBP: β = - 0.055, P = 0.025; MEOHP: β = - 0.101, P < 0.0001; MEHHP: β = - 0.106, P < 0.0001; MECPP: β = - 0.052, P = 0.003). In a case of serum chemicals, only MiBP showed significantly positive association (β = 0.036, P = 0.016). After stratification by sex, the associations of urinary BPA remained both in male and female, of which urinary phthalates disappeared in female. The association of serum MiBP was disappeared after stratification. Urinary BPA and phthalate metabolites were inversely associated with serum bilirubin levels, whereas serum MiBP showed positive association with bilirubin. These results could provide clues for understanding the mechanisms of endocrine disruptor from oxidative stress to excretion from our body.

Some obese individuals have normal metabolic profile, and some normal-weight persons have impaired metabolic status. Our hypothesis was that one of the potential underlying factors for such differences in cardiometabolic profiles might be the exposure to some environmental chemicals. This study aimed to investigate the association of serum bisphenol A (BPA) and phthalate metabolites with cardiometabolic risk factors in children and adolescents independent of their weight status. This case-control study was conducted on a subsample of 320 participants of a national school-based surveillance program in Iran. We measured serum BPA and phthalate metabolites by gas chromatography mass spectrophotometry. We compared them in children and adolescents with and without excess weight and those with and without cardiometabolic risk factors (80 in each group). We categorized the concentrations of chemicals to tertiles and then we applied logistic regression models after adjustment for potential confounding factors. The concentrations of BPA and some metabolites of phthalates were significantly different in the four groups studied. MEHP concentration was associated with higher odds ratio of cardiometabolic risk factors in participants with normal weight (OR, 95% CI 2.82, 1.001-7.91) and those with excess weight (OR, 95% CI 3.15, 1.27-7.83). MBP concentration increased the odds ratio of cardiometabolic risk factors only in normal weight children and adolescents (OR, 95% CI 6.59, 2.33-18.59, P < 0.001). In participants without cardiometabolic risk factor, MMP and MEHHP were significantly associated with increased risk of excess weight (OR, 95% CI 5.90, 1.21-28.75 and 7.82, 1.5-41.8, respectively). This study showed that the association of BPA and phthalate with cardiometabolic risk factors is independent of the weight status. Our findings suggest that the metabolic impairment in some normal weight children and normal metabolic profile of some obese children can be, in part, related to exposure to these environmental chemicals. Graphical abstract.

In the present study, concentrations of bisphenol A (BPA) and its six alternatives were quantified in serum samples collected from elder population living around an e-waste recycling facilities as well as an reference area in China. BPA, bisphenol AF (BPAF), and bisphenol F (BPF) were frequently detected (detection rates: > 65%) in serum samples collected from residents living near e-waste dismantling facilities, with geometric mean (GM) concentrations of 3.2, 0.0074, and 0.062 ng/mL, respectively. The detection frequencies of other four bisphenols (BPs) in serum samples were lower than 25%, regardless of the sampling areas. Significant difference (Mann-Whitney U-test, p < 0.05) was observed in the serum concentration of BPA, but not BPAF and BPF, between the e-waste recycling and reference areas. This finding indicated e-waste dismantling activities are correlated with human BPA exposure. Significant higher (p < 0.05) detection rates of donors who had abnormal fasting blood glucose (FBG) levels were found in e-waste recycling areas (45%) than those found in reference area. Our results suggested BPA and BPAF exposure might associated with abnormal FBG in participants living in e-waste sites. To our knowledge, this study is first determination of BPs in serum samples and assessment of health risk of elderly people from BPs exposure in e-waste dismantling area., (Copyright © 2018. Published by Elsevier Inc.)

Evaluating the biological significance of human-relevant exposures to environmental estrogens involves assessing the individual and total estrogenicity of endogenous and exogenous estrogens found in serum, for example from biomonitoring studies. We developed a method for this assessment by integrating approaches for (i) measuring total hormone concentrations by mass spectrometry (Fleck et al., 2018), (ii) calculating hormone bioavailable concentrations in serum and, (iii) solving multiple equilibria between estrogenic ligands and receptors, and (iv) quantitatively describing key elements of estrogen potency. The approach was applied to endogenous (E1, E2, E3, E4), environmental (BPA), and dietary Genistein (GEN), Daidzein (DDZ) estrogens measured in the serum of thirty pregnant women. Fractional receptor occupancy (FRO) based estrogenicity was dominated by E1, E2 and E3 (ER-α, 94.4-99.2% (median: 97.3%), ER-β, 82.7-97.7% (median: 92.8%), as was the total response (TR), which included ligand specific differences in recruitment of co-activator proteins (RCA). The median FRO for BPA was at least five orders of magnitude lower than E1, E2 and E3, and three orders of magnitude lower than the fetal derived E4 and GEN and DDZ. BPA contributed less than 1/1000th of the normal daily variability in total serum estrogenicity in this cohort of pregnant women., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pollutants represent potential threats to the human health, being ubiquitous in the environment and exerting toxicity even at low doses. This study aims at investigating the role of fifteen multiclass organic pollutants, assumed as markers of environmental pollution, most of which exerting endocrine-disrupting activity, in thyroid cancer development. The increasing incidence of differentiated thyroid cancer (DTC) may be related to the rising production and environmental dissemination of pollutants. Fifty-five patients, twenty-seven with diagnosis of benign thyroid nodules and twenty-eight suffering from differentiated thyroid cancer, were enrolled and the concentration levels of seven bisphenols, two phthalates (i.e. di(2-ethylhexyl) phthalate (DEHP) and its main metabolite, mono-(2-ethyl-hexyl) phthalate) (MEHP)), two chlorobenzenes, (1,4-dichlorobenzene and 1,2,4,5-tetrachlorobenzene), and 3 phenol derivatives (2-chlorophenol, 4- nonylphenol, and triclosan) were determined in their serum by using a validated analytical method based on high performance liquid chromatography with ultraviolet tandem fluorescence detection. A significant relationship was found between malignancy and the detection in the serum of both bisphenol AF and DEHP. Indeed, their presence confers a more than fourteen times higher risk of developing differentiated thyroid cancer. Relationship between these two pollutants and the risk of malignancy was dose-independent and not mediated by higher thyroid stimulating hormone levels. Even if a conclusive evidence cannot still be drawn and larger prospective studies are needed, the exposure to low doses of environmental endocrine-disrupting contaminants can be considered consistent with the development of thyroid cancer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Maternal immune system regulation is critical for maintenance of a healthy pregnancy and fetal development. Exposure to phenols and parabens is widespread, and may be linked to systemic inflammation and alteration of circulating immunological biomarkers., Objective: We sought to characterize associations between repeated measures of individual urinary phenols, parabens and plasma inflammatory markers across pregnancy., Methods: In the LIFECODES prospective birth cohort, we conducted a nested preterm birth case-control study, including 130 cases and 352 controls. In urine samples collected from each participant at up to four study visits during pregnancy, we measured concentrations of six phenols and four parabens, as well as five plasma inflammatory markers. We used multivariable linear mixed models to analyze repeated measures of exposures on inflammatory markers. We created and applied inverse probability weights to account for the sampling approach., Results: We observed bidirectional associations between select phenols and parabens and inflammatory markers. An interquartile range increase in triclosan (55.2 ng/mL) was associated with a 12.5% (95% CI: 3.67, 22.0) increase in C-reactive protein, a 7.95% (95% CI: 1.95, 14.3) increase in interleukin 10, and a 7.93% (95% CI: 3.82, 12,2) increase in tumor necrosis factor-α. Additionally, an interquartile range increase in 2,5-dichlorophenol (11.0 ng/mL) was associated with a 10% increase in C-reactive protein (95% CI: 1.92, 18.7). Conversely, an interquartile range increase in ethyl paraben (10.4 ng/mL) was associated with a 7.7% decrease in interleukin‑1β (95% CI: -14.1, -0.86)., Conclusions: Our findings can be organized into two thematic frameworks, one where concentrations of urinary phenols and parabens during pregnancy reflected a pro-inflammatory relationship with immunological biomarkers, and the other contrary theme - an anti-inflammatory relationship. These findings have implications for fetal development and reproductive outcomes, and emphasize the need for further research on immunological mechanisms of phenol and paraben action during pregnancy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Studies of circulating levels in difference sex and age classes, and maternal transfer of bisphenol A, 4-tert-octylphenol and 4- nonylphenol in the Baltic grey seal were performed from 2014-2017. Blood was collected from long-term captive adult males, pregnant females and pups. Milk was collected from nursing females. The aim of this study was not only to determine the concentrations of phenol derivatives, i.e. bisphenol A (BPA), 4-tert-octylphenol (OP) and 4-nonylphenol (NP), but also to try to evaluate the transfer of these compounds to the next generation in the final stage of foetal life and in the first few weeks of life in juvenile marine mammals. The measurements were carried out using high performance liquid chromatography. The obtained data show that all phenol derivatives are present in the blood of males, females and pups (range <0.07-101 ng·cm -3 ) and in female milk (range <0.1-406.3 ng·cm -3 ). The main source of phenol derivatives in organisms is food exposure. Gender, age, or number of births were not observed to have a significant effect on changes in phenol derivative levels in seal blood within the breeding group. In the prenatal stage of life, a small amount of BPA and alkylphenols was passed on to the offspring through the placenta. In the blood of the offspring the concentration of these compounds exceeded the concentration in the mother's blood 1.5-fold. During nursing, females detoxified their systems. Level of phenol derivatives in the pups blood increased linearly with its increasing concentrations in the mother's milk. On the other hand, the seafood diet which started after the physiological fasting stage of the pup, stabilised the levels of phenol derivatives below 10 ng ∙ cm -3 ., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Chemicals showing structural or functional similarity to bisphenol A (BPA), commonly called BPA analogues, have recently drawn scientific attention due to their common industrial and commercial application as a substitute for BPA. In the European Union, the use of BPA has been severely restricted by law due to its endocrine disrupting properties. Unfortunately, it seems that all BPA analogues show comparable biological activity, including hormonal disruption, toxicity and genotoxicity. Until now, the knowledge about human exposure to BPA analogues is scarce, mainly due to the lack of the data concerning their occurrence in human derived biological samples. This study presents the development of an analytical method for determination of trace levels of eleven BPA analogues in human blood serum samples. The method involves fast and simple liquid-liquid extraction, using low sample and solvent volumes. Chromatographic separation of analytes was optimized using one-factor-at-a-time approach (mobile phase composition, gradient shape, chromatographic column selection, separation temperature, etc.). The method allows for effective separation of the analytes, even in the case of configurational isomers (bisphenol M and bisphenol P). The calibration curves for all analytes were linear in the range tested. The limits of detection and quantitation were in the range of 0.0079÷0.039ng/mL and 0.024÷0.12ng/mL respectively. Compound-dependent recovery values were in the rage of 88÷138%. Matrix effects were mitigated with the help of matrix-matched calibration curves prepared for every batch of samples. Results obtained after the analysis of 245 real human blood serum samples indicate that human beings are exposed to different BPA analogues, that are present in the environment and in common, daily use products., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To explore the long-term effects of maternal pregnancy bisphenol A (BPA) exposure on emotional and behavioral problems appeared in their preschool children. Methods: The study sample was a subset of the China-Anhui Birth Cohort Study (C-ABCS). A unified questionnaire was used to collect basic information on both pregnant women and their children. Free BPA concentration in maternal serum was determined by high-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS). The parent-report version of the Strengths and Difficulties Questionnaire (SDQ) was used to estimate the emotional and behavioral problems in preschool children. A total of 1 713 pairs of mothers and children were included in this study. Association between BPA exposure during pregnancy and the emotional and behavioral problems in preschool children was evaluated with multinomial logistic regression model. Results: Prevalence rates in 1 713 preschool children appeared as: 6.48% of emotional problems, 8.11% for conduct problems, 8.35% for hyperactivity/inattention, 2.86% for peer problems, 11.38% for prosocial behaviors and 7.94% for total difficulties. Subjects were divided according to the degrees of exposure and the results showed as: low exposure group (≤0.120 ng/ml), medium exposure group (0.120

Background: Pregnant women are exposed to a mixture of endocrine disrupting chemicals (EDCs). Gestational EDC exposures may be associated with changes in fetal growth that elevates the risk for poor health later in life, but few studies have examined the health effects of simultaneous exposure to multiple chemicals. This study aimed to examine the association of gestational exposure to five chemical classes of potential EDCs: phthalates and bisphenol A, perfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) with infant birth weight., Methods: Using data from the Health Outcomes and Measures of Environment (HOME) Study, we examined 272 pregnant women enrolled between 2003-2006. EDC concentrations were quantified in blood and urine samples collected at 16 and 26 weeks gestation. We used Bayesian Hierarchical Linear Models (BHLM) to examine the associations between newborn birth weight and 53 EDCs, 2 organochlorine pesticides (OPPs) and 2 heavy metals., Results: For a 10-fold increase in chemical concentration, the mean differences in birth weights (95% credible intervals (CI)) were 1 g (-20, 23) for phthalates, -11 g (-52, 34) for PFAS, 0.2 g (-9, 10) for PCBs, -4 g (-30, 22) for PBDEs, and 7 g (-25, 40) for OCPs., Conclusion: Gestational exposure to phthalates, PFAS, PCBs, PBDEs, OCPs or OPPs had null or small associations with birth weight. Gestational OPP, Pb, and PFAS exposures were most strongly associated with lower birth weight.

Background: Prenatal chemical exposures may adversely affect neurodevelopment, but few studies have examined the persistence of these associations. We examined whether associations between prenatal bisphenol A (BPA) or polybrominated diphenyl ether (PBDE) exposures persist or resolve as children age., Methods: We followed 346 mother-child pairs (enrolled 2003-2006) from Cincinnati, OH from pregnancy until children were 8 years old. We measured BPA in urine collected at 16 and 26 weeks gestation and PBDE-47 in serum collected at 16 weeks gestation. We administered repeated measures of children's behavior, mental/psychomotor development, and IQ from ages 1-8 years. We determined if associations of BPA or PBDE-47 with child neurobehavior persisted or resolved as children aged using linear mixed models and estimated neurobehavioral measure reproducibility using intraclass correlation coefficients (ICCs)., Results: Higher BPA in girls and higher PBDE-47 in both boys and girls were associated with more externalizing behaviors; these associations persisted from ages 2-8 years (exposure×age interaction p-values≥0.36). Higher PBDE-47 concentrations were associated with decreases in MDI from ages 1-3 years (PBDE-47x age interaction p-value=0.03) and persistently lower IQ at ages 5 and 8 years (PBDE-47×age interaction p-value=0.56). Mental/psychomotor abilities had fair reproducibility from ages 1-3 years (ICCs∼0.4), cognitive abilities from ages 5 to 8 years had excellent reproducibility (ICCs=0.7-0.8), and parent-reported behaviors from ages 2-8 years had poor to good reproducibility (ICCs=0.38-0.59)., Conclusions: Prenatal BPA and PBDE-47 concentrations were persistently associated with more externalizing behaviors. PBDE-47 concentrations were inversely associated with cognitive abilities that strengthened over time., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Prenatal and postnatal exposure to bisphenol A (BPA) may affect early brain development. Rodent studies suggest that prenatal and postnatal neurodevelopmental toxicity from BPA exposure may manifest as social deficits in offspring. We investigated the association between prenatal and postnatal exposure to BPA and social impairments in a sample of 4-year-old children., Methods: We recruited second-trimester pregnant women between 2008 and 2011, and measured their creatinine-adjusted prenatal urine BPA levels. In 2014-2015, a subset of 4-year-old children born to these women underwent neurobehavioral assessment and physical examination. We collected urine and blood from the children and assessed social impairments, including deficits in social interaction, social communication, and other behavior patterns using the Korean version of the Social Communication Questionnaire (K-SCQ) (n = 304). We examined social impairments associated with prenatal exposure at mid-term pregnancy and postnatal exposure to BPA at 4 years of age, using linear and piecewise linear regression models., Results: The relationship between prenatal BPA exposure and social communication was non-linear and statistically significant at or above the flexion point for BPA levels of 3.0 μg/g creatinine in girls (58.4%, 95% confidence interval [CI], 6.5% to 135.8%). Each 2-fold increase in postnatal BPA exposure was significantly associated with an 11.8% (95% CI, 0.6% to 24.3%) increase in impairment in social communication in 4-year old girls, as indicated by the linear regression model., Conclusion: Prenatal and postnatal BPA exposure is associated with social impairment at 4 years of age, particularly in girls.

Background: Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment., Objectives: A complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes., Methods: Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 μg BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS)., Results: The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100 μg/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses., Conclusions: Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose-specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. https://doi.org/10.1289/EHP1050.

The aim of this study was to (1) optimize a method for the measurement of parabens and phenols in adipose tissue, (2) evaluate the stability of chemical residues in adipose tissue samples, and (3) study correlations of these compounds in urine, serum, and adipose tissue. Samples were obtained from adults undergoing trauma surgery. Nine phenols and seven parabens were determined by isotope diluted TurboFlow-LC-MS/MS. The analytical method showed good accuracy and precision. Limits of detection (LOD) for parabens and phenols ranged from 0.05 to 1.83ng/g tissue. Good recovery rates were found, even when biological samples remained defrosted up to 24h. Benzophenone-3 (BP-3; range of values: 70% of adipose tissue samples, while bisphenol-A (BPA; 40% of adipose tissue samples. In general, levels were similar between adipose tissue and serum, while a correlation between adipose tissue and urine was only found for BP-3. In conclusion, adipose tissue samples in this study were found to contain environmental chemicals considered to be non-persistent, whose levels were weakly or not at all correlated with the urine burden. Therefore, adipose tissue may potentially provide additional information to that obtained from other biological matrices. Further investigations are warranted to explore whether adipose tissue might be a suitable matrix for assessment of the consequences for human health of mid/long-term exposure to these chemicals., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Body weight (BW) and body composition were examined in CD-1 mice exposed perinatally or perinatally and peripubertally to 0, 0.25, 2.5, 25, or 250μg BPA/kg BW/day. Our goal was to identify the BPA dose (s) and the exposure window(s) that increased BW and adiposity, and to assess potential sex differences in this response. Both perinatal exposure alone and perinatal plus peripubertal exposure to environmentally relevant levels of BPA resulted in lasting effects on body weight and body composition. The effects were dose specific and sex specific and were influenced by the precise window of BPA exposure. The addition of peripubertal BPA exposure following the initial perinatal exposure exacerbated adverse effects in the females but appeared to reduce differences in body weight and body composition between control and BPA exposed males. Some effects of BPA on body weight and body composition showed a non-linear dose response., (Copyright © 2016. Published by Elsevier Inc.)

It was recently discovered that bisphenol A (BPA) and phthalates are cardiovascular disruptors. Inflammation is central to the initiation and progression of cardiovascular disease (CVD). This study evaluated whether BPA and different phthalate metabolites are associated with the inflammation marker high-sensitivity C-reactive protein (hs-CRP) in healthy Korean adults. This research is part of an ongoing, population-based study of Korean adults (30-64 years of age) conducted at the Cardiovascular and Metabolic Diseases Etiology Research Center (CMERC). The study enrolled 200 healthy volunteers (96 men, 104 women). Plasma hs-CRP was measured as an inflammation marker. BPA and five phthalate metabolites in urine were analyzed by using liquid chromatography/tandem mass spectrometry. BPA and monobenzyl phthalate (MBzP) differed significantly between the low-hs-CRP (<2 mg/L) and high-hs-CRP (≥2 mg/L) groups. BPA and MBzP were related to hs-CRP in an inverted L-shaped manner. High BPA levels (≥75th percentile) had significant odd ratios (ORs) for high hs-CRP even after adjusting for confounding factors related to obesity and insulin resistance, such as visceral fat volume, body mass index (BMI), adiponectin, high-density lipoprotein (HDL) cholesterol, hemoglobin A1c (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR) (OR = 2.85; 95 % CI, 1.16-6.97). However, there was no significant association for MBzP ≥75th percentile. BPA was significantly related to high hs-CRP, even after adjusting for factors related to obesity and insulin resistance. Therefore, BPA could have a direct relationship with systemic inflammation regardless of obesity or insulin resistance.

Bisphenol A (BPA) is one of the synthetic monomer which can be found in the environment. Limited animal and human studies have demonstrated that BPA alters endocrine and or metabolic functions. The aims of the present study were to evaluate serum BPA level in marketing seller women with polycystic ovary syndrome (PCOS) and hormonal and metabolic effects of this exposure compared to a control paired group. In a case-control study, 62 PCOS women who work as marketing sellers and 62 healthy women with similar jobs were included. The two groups were body mass index (BMI)- and age-matched. Serum samples were analyzed for BPA content, fasting blood sugar (FBS), triglyceride, cholesterol, HDL and LDL levels, thyroid stimulating hormone (TSH) concentration, and LH:FSH ratio. Significant higher serum BPA content (0.48 ± 0.08 vs. 0.16 ± 0.04 ng/ml), triglyceride (103.05 ± 13.10 vs. 91.65 ± 12.52 mg/dl), cholesterol (165.05 ± 10.79 vs. 161.21 ± 10.31 mg/dl) levels and LH:FSH ratio (3.64 ± 0.86 vs. 0.62 ± 0.14) and significant lower TSH concentration (1.56 ± 0.68 vs. 2.15 ± 1.09 IU/ml) were detected in case against control group, respectively (P < 0.05). No significant differences were detected in FBS, LDL, and HDL levels between the two groups. Also, there were no significant associations between serum TSH concentration and BPA level neither in case (P = 0.269) nor in control (P = 0.532) groups. In BPA-exposed PCOS women, BPA level was higher than healthy women and this difference maybe the cause of significant differences in levels of triglyceride, cholesterol, TSH, and LH:FSH ratio. These observations confirm the potential role of BPA in PCOS pathophysiology.

Objective: The objective of this study is to determine if BPA exposure, as measured by maternal plasma (MP) and amniotic fluid (AF) BPA concentrations is associated with an increased risk of spontaneous preterm birth (PTB) and preterm premature rupture of membranes (pPROM)., Methods: In this nested case-control study, MP samples from women in term labor (n = 30), preterm labor that ended with preterm delivery (n = 25), or who had pPROM (n = 30) and amniotic fluid samples from term labor (n= 45), preterm labor (n = 60), and pPROM (n = 35) were assayed for BPA by enzyme immunoassay., Results: BPA was detectible in 100% of MP and AF samples. Women with MP BPA concentrations in the fourth quartile were at increased risk of PTB (cOR = 4.12, 95% CI = 1.32-12.87; aOR = 4.78, 95% CI = 1.14-20) but not pPROM. High (fourth quartile) AF BPA values also tended to increase the risk of pPROM (cOR = 2.47, 95% CI = 0.96-6.37) but results were not statistically significant., Conclusions: Increased BPA concentration is associated with an increased risk for PTB or pPROM depending on the maternal-fetal compartment(s) affected. High MP plasma BPA concentrations are associated with PTB with intact membranes but high AF BPA concentrations may weakly be associated with pPROM.

Epidemiologic studies of in utero phthalate exposure and birth outcomes have had conflicting findings. The objective of this study was to characterize maternal phthalate exposure across pregnancy, examine associations between maternal phthalate levels and infant size and gestational age at birth, and investigate relationships between concurrent bisphenol A (BPA) and phthalate exposure and birth outcomes. Women in the Michigan Mother-Infant Pairs cohort provided urine and blood samples during their first trimester and at delivery. Urinary phthalate metabolites and serum BPA were measured at both time points, and birth weight, length, head circumference, and gestational age were recorded from medical records. Maternal DEHP metabolite concentrations were significantly higher at delivery compared to the first trimester (p<0.05), suggesting increased DEHP exposure late in pregnancy. A number of phthalate metabolites were associated with birth size and gestational age in patterns that varied by sex and timing of exposure, independent of BPA exposure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are attracting more and more attention for the neurodevelopment toxicity effects. We evaluated the concentrations of 15 individual OH-PBDEs and 3 bromophenol (BRP) congeners in 30 mother-newborn paired placenta, breast milk, fetal cord blood, and neonatal urine samples collected from South China. The geometric mean (GM) concentrations of ∑OH-PBDEs were 37.6, 61.3, and 76.8pgg(-1) ww in placenta, breast milk, and cord blood, respectively. The GM concentrations of ∑BRPs were 47.6, 119, and 30.2pgg(-1) ww in placenta, breast milk, and cord blood, respectively. The GM concentrations of ∑OH-PBDEs and ∑BRPs in neonatal urine were 72.0 and 79.8pgml(-1), respectively. Of the 15 OH-PBDE congeners analyzed, the three most frequently detected congeners were 2'-OH-BDE-68 (72.1%), 6-OH-BDE-47 (67.6%), and 2'-OH-BDE-28 (65.8%). The estimated daily intake (EDI) of OH-PBDEs for the breast-fed infants was 9.31±4.00ngkg(-1) bw day. The accumulation of OH-PBDEs in newborns was much lower than the estimated lowest observed-effect concentration (LOEC) of neurotoxicity. The present study provided the first systematic fundamental data that exposure to OH-PBDEs for newborn and their mothers in South China., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Despite its very low oral bioavailability and rapid elimination, multiple reports of unexpectedly high bisphenol A (BPA) concentrations in the serum of pregnant mothers or cord blood have raised questions about BPA exposures during pregnancy. Thirty healthy pregnant women recruited to the study were evaluated for total BPA exposure over a 30-h period comprising one-half day in the field and one day in a clinical setting. BPA and its metabolites were measured in serum and total BPA was measured in matching urine samples. The mean total exposure was similar to the 50(th) percentile of exposure for U.S. women and pregnant women in a large North American cohort. Twenty volunteers had total daily exposures equal to or exceeding the U.S. mean, and six volunteers had exposures exceeding the 75th percentile. Women working as cashiers did not have higher total BPA exposure. BPA was detected in some serum samples (0.25-0.51 ng/ml), but showed no relationship to total BPA in corresponding urine samples, no relationship to total BPA exposure, and had unconjugated BPA fractions of 60-80%, consistent with established criteria for sample contamination. We conclude that typical exposures of North American pregnant women produce internal exposures to BPA in the picomolar range., (Copyright © 2016. Published by Elsevier Ltd.)

Phthalates and bisphenol A (BPA) are endocrine disruting chemicals (EDCs) that are suggested to exert neurotoxic effects. This study aimed to determine plasma phthalates and BPA levels along with oxidant/antioxidant status in autistic children [n=51; including 12 children were diagnosed with "Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS)]. Plasma levels of BPA, di (2-ethylhexyl)-phthalate (DEHP) and its main metabolite mono (2-ethylhexyl)-phthalate (MEHP); thiobarbituric acid reactive substance (TBARS) and carbonyl groups; erythrocyte glutathione peroxidase (GPx1), thioredoxin reductase (TrxR), catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) activities and glutathione (GSH) and selenium levels were measured. Plasma BPA levels of children with PDD-NOS were significantly higher than both classic autistic children and controls (n=50). Carbonyl, selenium concentrations and GPx1, SOD and GR activities were higher (p<0.05); CAT activity was markedly lower in study group. BPA exposure might be associated with PDD-NOS. Intracellular imbalance between oxidant and antioxidant status might facilitate its neurotoxicity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Dioxins, PCBs, chlorinated pesticides, brominated flame retardants, bisphenol A, triclosan, perfluorinated compounds and phthalates are known as endocrine disrupting chemicals (EDCs)., Objectives: The aim of our study was to investigate whether higher exposure to EDCs is associated with increased subfertility in men., Methods: We measured biomarkers of exposure in 163 men, recruited through four fertility clinics. According to WHO guidelines, we used a total motility count (TMC) of 20 million as cut-off value. We assigned patients to the case group when two semen samples - collected at least one week apart - had a TMC<20 and to the control group when both samples had a TMC≥20. To estimate the risk of subfertility and alteration in sex hormone concentrations we used multivariable-adjusted analysis, using logistic and linear regressions, respectively., Results: For an IQR increase in serum oxychlordane, the odds ratio for subfertility was 1.98 (95% CI: 1.07; 3.69). Furthermore, men with serum levels of BDE209 above the quantification limit had an odds of 7.22 (1.03; 50.6) for subfertility compared with those having values below the LOQ. Urinary levels of phthalates and triclosan were negatively associated with inhibin B and positively with LH. Urinary bisphenol A correlated negatively with testosterone levels., Conclusions: Our study in men showed that internal body concentrations of endocrine disrupting chemicals are associated with an increased risk of subfertility together with alterations in hormone levels. The results emphasize the importance to reduce chemicals in the environment in order to safeguard male fertility., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA., Objective: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration., Methods: We exposed six men and eight women to 100 μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates., Results: Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 ± 0.50h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 ± 2.0 h and 6.2 ± 2.6h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h., Conclusions: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h., (Published by Elsevier Ltd.)

Background: Studies from several countries report increases in rates of gestational diabetes mellitus (GDM) over recent decades. Exposure to environmental chemicals could contribute to this trend., Objectives: To determine the associations between plasticisers and metals measured in early pregnancy with impaired glucose tolerance (IGT) and GDM in a Canadian pregnancy cohort., Methods: Women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study were included if they had a singleton delivery and did not have pre-existing diabetes. Eleven phthalate metabolites and total bisphenol A (BPA) were measured in first-trimester urine samples, and four metals (lead, cadmium, mercury and arsenic) were measured in first-trimester blood samples. IGT and GDM were assessed in accordance with standard guidelines by chart review. Chemical concentrations were grouped by quartiles, and associations with outcomes were examined using logistic regression with adjustment for maternal age, race, pre-pregnancy BMI, and education. Restricted cubic spline analysis was performed to help assess linearity and nature of any dose-response relationships., Results: Of 2001 women recruited into the MIREC cohort, 1274 met the inclusion criteria and had outcome data and biomonitoring data measured for at least one of the chemicals we examined. Elevated odds of GDM were observed in the highest quartile of arsenic exposure (OR = 3.7, 95% CI = 1.4-9.6) in the adjusted analyses. A significant dose-response relationship was observed in a cubic spline model between arsenic and odds of GDM (p < 0.01). No statistically significant associations were observed between phthalates or BPA or other metals with IGT or GDM., Conclusions: Our findings add to the growing body of evidence supporting the role of maternal arsenic exposure as a risk factor for gestational diabetes., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Critical care medicine has largely benefited from plastic-containing medical devices. However, bisphenol-A (BPA) and phthalates present in the plastics can leach from such devices. We hypothesized that intensive care unit (ICU) patients are exposed to BPA and phthalates through (plastic) medical devices. Serum (n = 118) and urine (n= 102) samples of adult ICU patients (n = 35) were analyzed for total BPA and phthalate metabolites (PMs). Our results showed that adult ICU patients are continuously exposed to phthalates, such as di(2-ethylhexyl)phthalate (DEHP), as well as to BPA, albeit to a lesser extent. This exposure resulted in detectable high serum and urinary levels in almost every patient and at every studied time point. Moreover, these levels were significantly higher than in controls or compared to referenced literature. The chronology of exposure was demonstrated: pre-operative urinary and serum levels of the DEHP metabolites were often below the detection limit. Plastic-containing medical devices were the main source of DEHP exposure: post-operative patients on hemofiltration, extracorporeal membrane oxygenation or both showed serum levels 100-or 1000-fold higher than the levels in the general population reported in the literature. The serum and some of the urinary levels of the DEHP metabolites are the highest ever reported in humans; some at biologically highly relevant concentrations of ≥ 10-50 μM. Despite the continuously tightening regulations, BPA and DEHP appear to be still present in (some) medical devices. Because patient safety is a concern in the ICU, further research into the (possibly toxic and clinical) effects of these chemicals released from medical devices is imperiously necessary., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Phenols and parabens show some evidence for endocrine disruption in laboratory animals. The goal of the Methods Advancement for Milk Analysis (MAMA) Study was to develop or adapt methods to measure parabens (methyl, ethyl, butyl, propyl) and phenols (bisphenol A (BPA), 2,4- and 2,5-dichlorophenol, benzophenone-3, triclosan) in urine, milk and serum twice during lactation, to compare concentrations across matrices and with endogenous biomarkers among 34 North Carolina women. These non-persistent chemicals were detected in most urine samples (53-100%) and less frequently in milk or serum; concentrations differed by matrix. Although urinary parabens, triclosan and dichlorophenols concentrations correlated significantly at two time points, those of BPA and benzophenone-3 did not, suggesting considerable variability in those exposures. These pilot data suggest that nursing mothers are exposed to phenols and parabens; urine is the best measurement matrix; and correlations between chemical and endogenous immune-related biomarkers merit further investigation., (Published by Elsevier Inc.)

Background: This study aimed to determine serum Bisphenol A (BPA) concentrations in patients with dilated cardiomyopathy (DCM) as well as the association between serum BPA and several hormonal parameters in DCM patients compared with a healthy control group., Materials and Methods: Eighty-eight DCM patients and 88 age- and gender-matched healthy controls were included. Serum BPA levels and several hormonal parameters (including total testosterone (T), sex hormone-binding globulin (SHBG) and estradiol (E2) were measured by using corresponding ELISA Kits. The free androgen index (FAI) was calculated by the formula: total T in nmol/L × 100/SHBG in nmol/L., Results: BPA levels in the total DCM group were significantly higher compared with that in the controls (6.9 ± 2.7 ng/mL vs. 3.8 ± 1.9 ng/mL, p < 0.001). Significant difference was also observed in SHBG and FAI between DCM patients and controls, (76.9 ± 30.9 nM/L vs. 41.0 ± 15.6 nM/L and 2.9 ± 3.5 vs.5.3 ± 2.6, respectively, both of p < 0.001). Similar trends were observed in the male and female subgroup. Mean T level was lower in DCM group than in control group (540.8 ± 186.0 pg/mL vs. 656.3 ± 112.9 pg/mL, p < 0.001). Linear regression analysis has shown that increasing serum BPA levels were statistically significantly associated with increased SHBG levels. However, no statistical difference was noted for E2., Conclusion: Our findings firstly demonstrated that BPA exposure increased in DCM patients compared with that in healthy controls, while FAI and T levels decreased. SHBG presented a positive association with BPA. It is concluded that hormone disorder induced by BPA exposure might be an environmental factor in the pathology of DCM.

The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02 kg (mice) to 495 kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79 L/min (equivalent to 25.6 mL/kg.min) with a 95% prediction interval of 0.36 to 8.83 L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Bisphenol-A (BPA) can alter endocrine function in animals, yet the relationship between human exposure to BPA and male reproductive function is not well understood. We collected serum samples from 281 male workers exposed to BPA and 278 controls. Serum BPA concentrations were analyzed by gas chromatography-mass spectrometry after derivatization. The serum levels of sex hormone-binding globulin (SHBG) and total testosterone (TT) were detected by radioimmunoassay and levels of inhibin B (INB) and androstenedione (AD) by enzyme-linked immunosorbent assay. We examined the association of BPA exposure and male sex hormone levels by multivariable linear regression. Both serum BPA concentrations and detection rates were greater in males exposed than those not exposed to BPA, but the two groups did not differ in levels of SHBG, TT, INB, or AD. Compared with exposure for ≤5 years, exposure for >5 years was associated with increased serum BPA and SHBG 1evels and decreased AD levels. Compared with undetectable BPA and BPA ≤ 18.75 ng/mL, BPA level >18.75 ng/mL was associated with low AD and high SHBG levels (P < 0.05). On adjusted multivariable regression, increased serum BPA level was associated with decreased mean serum AD level (0.18 ng/mL; 95% confidence interval CI -0.22 to -0.13) and increased mean serum SHBG level (2.79 nmol/L; 95% CI 2.11-3.46). Serum BPA levels were increased after occupational exposure. BPA exposure was negatively associated with serum AD level but positively associated with serum SHBG level.

Background: Polycystic Ovary Syndrome (PCOS) is an endocrine-metabolic disorder that affects approximately 6-10% of women of child-bearing age. Although preliminary studies suggest that certain pollutants may act as endocrine disruptors in animals, little is known about their potential association with PCOS. The objective of this case-control pilot study is to determine whether women with PCOS have higher concentrations of specific environmental contaminants compared to women who have not developed PCOS., Methods: Fifty-two PCOS case-patients (diagnosed using the National Institutes of Health 1990 definition) and 50 controls were recruited in 2007-2008, from an urban academic medical center in Los Angeles, CA. Brominated diphenyl ethers, polychlorinated biphenyls (PCBs), organochlorine pesticides, and perfluorinated compounds (PFCs) were measured in serum, and phthalates metabolites and bisphenol A (BPA) in urine., Results: PCOS case-patients had significantly higher geometric mean (GM) serum concentrations of two PFCs: perfluorooctanoate (PFOA) (GMcases = 4.1 μg/L, GMcontrols = 2.3 μg/L; p = 0.001) and perfluorooctane sulfonate (PFOS) (GMcases = 8.2 μg/L, GMcontrols = 4.9 μg/L; p = 0.01), and lower urinary concentrations of monobenzyl phthalate (mBzP) (GMcases = 7.5 μg/g creatinine, GMcontrols = 11.7 μg/g creatinine; p = 0.02). Logistic regression, controlling for body mass index, age and race, identified an increased likelihood of PCOS in subjects with higher serum concentrations of PFOA and PFOS (adjusted-ORs = 5.8-6.9, p < 0.05), and with lower urine concentrations of mBzP and mono-n-butyl phthalate (mBP) (aORs = 0.14-0.25, p < 0.05)., Conclusions: Our data suggest that PCOS case-patients may differ from controls in their environmental contaminant profile. PCOS subjects had higher serum concentrations of two PFCs, PFOA and PFOS, and lower urine concentrations of mBP and mBzP. Future studies are needed to confirm these preliminary findings and determine if these chemicals or their precursors may have a role in the pathogenesis of PCOS.

Within the PREVIENI project, infertile and fertile women were enrolled from metropolitan, urban and rural Italian areas. Blood/serum levels of several endocrine disrupters (EDs) (perfluorooctane sulfonate, PFOS; perfluorooctanoic acid, PFOA; di-2-ethylhexyl-phthalate, DEHP; mono-(2-ethylhexyl)-phthalate, MEHP; bisphenol A, BPA) were evaluated concurrently with nuclear receptors (NRs) gene expression levels (ERa, ERb, AR, AhR, PPARg, PXR) in peripheral blood mononuclear cells (PBMCs). Infertile women from the metropolitan area displayed significantly higher levels of: BPA compared to fertile women (14.9 vs. 0.5 ng/mL serum); BPA and MEHP compared to infertile women from urban and rural areas; enhanced expression levels of NRs, except PPARg. Infertile women from urban and rural areas had PFOA levels significantly higher than those from metropolitan areas. Our study indicates the relevance of the living environment when investigating the exposure to EDs and the modulation of the NR panel in PBMC as a suitable biomarker of the effect, to assess the EDs impact on reproductive health.

Childhood obesity, a major public health concern, has increased worldwide. Endocrine-disrupting chemicals (EDCs) have recently received attention as a cause of obesity. A cross-sectional study using logistic regression was conducted to investigate the association between some endocrine disrupting chemicals and obesity in young girls. Endogenous steroids expected to be associated with EDCs were also investigated. The target compounds included 7 phthalates (MEP, DBP, MBP, DEHP, MEHP, PA and MBzP), 2 alkylphenols (4-NP and t-OP), bisphenol A and 9 endogenous steroids (DHT, epi-T, T, DHEA, A, P, E1, E2 and E3). PA in urine and MEP, DBP and PA in serum showed statistically significant differences between the control and obese groups, those compounds were considered to be associated with obesity. In addition, DHEA in serum showed a statistically significant difference between obese and control groups. We concluded that these substances can affect the development of obesity., (Copyright © 2014. Published by Elsevier B.V.)

We determined bisphenol A (BPA) concentrations of 61 pregnant women (PW), their fetuses and 26 nonpregnant women (NPW) in Eastern Townships of Canada; and evaluated potential correlations between maternal and fetal blood, and between peripheral blood and peritoneal fluid. In PW, BPA levels were ranged from non-detected to 4.46ng/ml and from non-detected to 4.60ng/ml for maternal and fetal serum, respectively. In NPW, BPA levels were ranged from 1.30 to 8.17ng/ml and from 0.19 to 13.45ng/ml for serum and peritoneal fluid, respectively. Positive correlation was found between maternal and fetal serum, and between serum and peritoneal fluid. In conclusion, our findings highlight a continuous distribution of BPA between the mother and its fetus and reveal a role of pregnancy in underestimating the actual levels of blood BPA. Our study also provides a temporal-spatial reference on BPA exposure, which is a useful tool in monitoring, comparing and correcting., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Identification of maternal environmental factors influencing preterm birth risks is important to understand the reasons for the increase in prematurity since 1990. Here, we utilized a health survey, the US National Health and Nutrition Examination Survey (NHANES) to search for personal environmental factors associated with preterm birth. 201 urine and blood markers of environmental factors, such as allergens, pollutants, and nutrients were assayed in mothers (range of N: 49-724) who answered questions about any children born preterm (delivery <37 weeks). We screened each of the 201 factors for association with any child born preterm adjusting by age, race/ethnicity, education, and household income. We attempted to verify the top finding, urinary bisphenol A, in an independent study of pregnant women attending Lucile Packard Children's Hospital. We conclude that the association between maternal urinary levels of bisphenol A and preterm birth should be evaluated in a larger epidemiological investigation., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

This publication describes a method for the determination of total bisphenol A (BPA and conjugated BPA) following enzyme hydrolysis and is intended as a companion to our previously developed analytical method for the determination of free BPA (the aglycone) in human blood and urine using high-performance liquid chromatography-tandem mass spectrometry ( 1). That free BPA method provided a means to account for and/or eliminate background contamination and demonstrated accuracy and reproducibility in both matrices fortified with BPA or a surrogate analyte ((13)C BPA) at a low method quantitation limit (MQL) of 0.1-0.2 ng/mL. In contrast to the free BPA method results and based on stringent accuracy, precision and confirmation criteria set for the MQLs of the method developed for total BPA, the MQL achieved in blood was 1.020-2.550 and 0.510-1.020 ng/mL in urine. These data showed higher MQLs than the desired MQLs of 0.5 ng/mL (blood) and 0.2 ng/mL (urine) with increased variability between analyses which demonstrates the importance of generating method validation data with each analysis. In contrast, the MQL achieved for (13)C BPA-G (monoglucuronide as a surrogate analyte in blood was 0.2-0.5 and 0.2 ng/mL in urine illustrating that the method is capable of meeting lower MQL requirements if the contribution from exogenous BPA can be well controlled. This method for the determination total BPA in human blood and urine is intended to be used in conjunction with the free BPA method ( 1) to obtain accurate and complete BPA biomonitoring data to support human exposure assessments.

Background: Human exposure to bisphenol A (BPA) is ubiquitous, yet there are concerns about whether BPA can be measured in human blood. This Round Robin was designed to address this concern through three goals: 1) to identify collection materials, reagents and detection apparatuses that do not contribute BPA to serum; 2) to identify sensitive and precise methods to accurately measure unconjugated BPA (uBPA) and BPA-glucuronide (BPA-G), a metabolite, in serum; and 3) to evaluate whether inadvertent hydrolysis of BPA-G occurs during sample handling and processing., Methods: Four laboratories participated in this Round Robin. Laboratories screened materials to identify BPA contamination in collection and analysis materials. Serum was spiked with concentrations of uBPA and/or BPA-G ranging from 0.09-19.5 (uBPA) and 0.5-32 (BPA-G) ng/mL. Additional samples were preserved unspiked as 'environmental' samples. Blinded samples were provided to laboratories that used LC/MSMS to simultaneously quantify uBPA and BPA-G. To determine whether inadvertent hydrolysis of BPA metabolites occurred, samples spiked with only BPA-G were analyzed for the presence of uBPA. Finally, three laboratories compared direct and indirect methods of quantifying BPA-G., Results: We identified collection materials and reagents that did not introduce BPA contamination. In the blinded spiked sample analysis, all laboratories were able to distinguish low from high values of uBPA and BPA-G, for the whole spiked sample range and for those samples spiked with the three lowest concentrations (0.5-3.1 ng/ml). By completion of the Round Robin, three laboratories had verified methods for the analysis of uBPA and two verified for the analysis of BPA-G (verification determined by: 4 of 5 samples within 20% of spiked concentrations). In the analysis of BPA-G only spiked samples, all laboratories reported BPA-G was the majority of BPA detected (92.2 - 100%). Finally, laboratories were more likely to be verified using direct methods than indirect ones using enzymatic hydrolysis., Conclusions: Sensitive and accurate methods for the direct quantification of uBPA and BPA-G were developed in multiple laboratories and can be used for the analysis of human serum samples. BPA contamination can be controlled during sample collection and inadvertent hydrolysis of BPA conjugates can be avoided during sample handling.

The temporal trend in serum concentrations of phenolic organohalogen contaminants (POCs) were investigated in two age groups of men from Kyoto, Japan, from 1989 to 2010. These concentrations and trends were compared with neutral contaminants including polychlorinated biphenyls (PCBs) and pesticides. Serum concentrations of pentachlorophenol (PenCP) and 4-hydroxy-PCB187 were age-dependent and decreased to approximately one-half during the two decades, whereas no contamination trends were observed for 2,4,6-tribromophenol (TriBP), tetrabromobisphenol A (TBBPA) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47). 6-OH-BDE47 was found in all samples (up to 3000 pg/g wet weight), whereas TBBPA was detected in 17 of 60 serum samples (up to 950 pg/g wet weight). The concentrations of TriBP, TBBPA and 6-OH-BDE47 were not correlated to those of PenCP or 4-OH-PCB187 in either age group, suggesting the different kinetics on exposure routes and fate between these brominated and chlorinated POCs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A novel, simple and sensitive method was developed for the simultaneous determination of eight phenolic environmental estrogens in blood by using the dispersive micro-solid-phase extraction (d-µ-SPE) procedure combined with ultra-fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS). The excellent nanomaterials tetraethylenepentamine-functionalized magnetic polymer was used as an adsorbent, and the main factors affecting the extraction efficiency were investigated in detail. All target compounds showed good linearities in the tested range with correlation coefficients (r) higher than 0.999. The mean recoveries were in the range of 85.0-105.0%. The intra-day and inter-day relative standard deviations (RSDs) were lower than 4.9% and 5.2%, respectively. The limits of quantification for the eight phenolic environmental estrogens were between 0.075 and 0.42 µg L(-1). The developed method can be applied to the routine analyses for the determination of the eight phenolic environmental estrogens in blood samples., (Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.)

In this study we report the human plasma concentrations of some common endocrine disrupting chemicals (EDCs) in the Hong Kong population. We have analyzed 153 plasma samples for the contaminants by methods involving labeled standards spiked into the samples. Quantification was performed using high performance liquid chromatography tandem mass spectrometry for bisphenol-A (BPA) and perfluorinated compounds (PFCs), and gas chromatography mass spectrometry methods for phthalates. We found BPA, several types of PFCs and phthalates in over 90% of the plasma samples. Perfluorooctane sulfonate (PFOS) was the dominant PFC, followed by perfluroroctanoic acid (PFOA) and perfluorohexane sulfonate (PFHxS). Eight out of ten phthalates were detected, with bis(2-ethylhexyl) phthalate (DEHP) as the most abundant, followed by bis(2-methoxyethyl) phthalate (DMEP) and dioctyl phthalate (DnOP). The levels of PFOS, PFOA, PFHxS and perfluorohexanoic acid (PFHxA) were significantly higher in the male plasma samples (p<0.05), while the mean plasma levels of DEHP and n-butyl benzyl phthalate (BBP) were significantly higher in the young age group (p<0.02). The presence of the selected EDCs in human blood plasma indicates common exposure routes among different population cohorts. Although the plasma levels of the EDCs were comparable to other countries, regular monitoring of human blood EDC contamination levels is necessary to provide a time-trend database for the estimation of exposure risk and to formulate appropriate public health policy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to explore the association between NP exposure and parity and their effect on neonatal birth weight., Methods: A cohort of pregnant women was established in a medical center in North Taiwan. Urinary NP concentration was determined by high-performance liquid chromatography coupled with fluorescent detection and adjusted using creatinine. A multivariable regression model was fit to determine the association between the maternal NP level in each trimester and neonatal birth weight. The odds ratios (ORs) of infant birth weight below the 10th, 25th, and 50th percentiles, comparing pregnant women with the different NP exposure levels, was estimated using a logistic regression., Results: Of the 162 pregnant women in the study, 99 were multiparas and 63 were primiparas. After adjusting for other covariates, the NP level in the second trimester had a significant association with birth weight in the primiparas (β = -182.49 g, p value = 0.02). The OR of low infant birth weight, comparing pregnant women with different NP levels, was increased by decreasing the cutoff percentile for birth weight (OR = 1.18 for the 50th percentile, 2.12 for the 25th percentile, and 7.81 for the 10th percentile). The odds of primiparas with high NP level having a low neonatal birth weight increased to 3.87, 11.77, and 9.40 for the three different percentiles (p value < 0.05)., Conclusion: Maternal NP exposure level is associated with an increased risk of low neonatal weight. Primiparas are especially at risk, and the second trimester of pregnancy may be the critical stage of exposure., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Low level chronic exposure to toxicants is associated with a range of adverse health effects. Understanding the various factors that influence the chemical burden of an individual is of critical importance to public health strategies. We investigated the relationships between socioeconomic status (SES) and bio-monitored chemical concentration in five cross-sectional waves of the U.S. National Health and Nutrition Examination Survey (NHANES). We utilised adjusted linear regression models to investigate the association between 179 toxicants and the poverty income ratio (PIR) for five NHANES waves. We then selected a subset of chemicals associated with PIR in 3 or more NHANES waves and investigated potential mediating factors using structural equation modelling. PIR was associated with 18 chemicals in 3 or more NHANES waves. Higher SES individuals had higher burdens of serum and urinary mercury, arsenic, caesium, thallium, perfluorooctanoic acid, perfluorononanoic acid, mono(carboxyoctyl) phthalate and benzophenone-3. Inverse associations were noted between PIR and serum and urinary lead and cadmium, antimony, bisphenol A and three phthalates (mono-benzyl, mono-isobutyl, mono-n-butyl). Key mediators included fish and shellfish consumption for the PIR, mercury, arsenic, thallium and perfluorononanoic acid associations. Sunscreen use was an important mediator in the benzophenone-3/PIR relationship. The association between PIR and cadmium or lead was partially mediated by smoking, occupation and diet. These results provide a comprehensive analysis of exposure patterns as a function of socioeconomic status in US adults, providing important information to guide future public health remediation measures to decrease toxicant and disease burdens within society., (© 2013.)

Background: Bisphenol A (BPA) risk assessment is currently hindered by the rejection of reported higher-than-expected plasma BPA concentrations in humans after oral ingestion. These are deemed incompatible with the almost complete hepatic first-pass metabolism of BPA into its inactive glucurono-conjugated form, BPA glucuronide (BPAG)., Objectives: Using dogs as a valid model, we compared plasma concentrations of BPA over a 24-hr period after intravenous, orogastric, and sublingual administration in order to establish the absolute bioavailability of BPA administered sublingually and to compare it with oral bioavailability., Methods: Six dogs were sublingually administered BPA at 0.05 mg/kg and 5 mg/kg. We compared the time course of plasma BPA concentrations with that obtained in the same dogs after intravenous administration of the same BPA doses and after a 20-mg/kg BPA dose administrated by orogastric gavage., Results: The data indicated that the systemic bioavailability of BPA deposited sublingually was high (70-90%) and that BPA transmucosal absorption from the oral cavity led to much higher BPA internal exposure than obtained for BPA absorption from the gastrointestinal tract. The concentration ratio of BPAG to BPA in plasma was approximately 100-fold lower following sublingual administration than after orogastric dosing, distinguishing the two pathways of absorption., Conclusions: Our findings demonstrate that BPA can be efficiently and very rapidly absorbed through the oral mucosa after sublingual exposure. This efficient systemic entry route of BPA may lead to far higher BPA internal exposures than known for BPA absorption from the gastrointestinal tract.

Dried blood spots (DBS), collected as part of the newborn screening program (NSP) in the USA, is a valuable resource for studies on environmental chemical exposures and associated health outcomes in newborns. Nevertheless, determination of concentrations of environmental chemicals in DBS requires assays with great sensitivity, as the typical volume of blood available on a DBS with 16-mm diameter disc is approximately 50 μL. In this study, we developed a liquid-liquid extraction and high-performance liquid chromatography/tandem mass spectrometry method for the detection of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and bisphenol A (BPA) in DBS. The method was validated for accuracy, precision, and sensitivity, by spiking of target chemicals at different levels on Whatman 903 filter cards, which is used in the collection of DBS by the NSP. Contamination arising from collection, storage, and handling of DBS is an important issue to be considered in the analysis of trace levels of environmental chemicals in DBS. For the evaluation of the magnitude of background contamination, field blanks were prepared from unspotted portions of DBS filter cards collected by the NSP. The method was applied for the measurement of PFOS, PFOA, and BPA in 192 DBS specimens provided by NSP of New York State. PFOS and PFOA were detected in 100 % of the specimens analyzed. The concentrations of PFOS and PFOA measured in DBS were similar to those reported earlier in the whole blood samples of newborns. BPA was also found in 86 % of the specimens at concentrations ranging from 0.2 to 36 ng/mL (excluding two outliers). Further studies are needed to evaluate the sources of BPA exposures and health outcomes in newborns.