Faculty Bibliography

RATIONALE AND OBJECTIVE/OBJECTIVE:Exposure to Bisphenol A (BPA) and phthalates is ubiquitous among adults and children in the United States. Among children and adolescents, those with chronic kidney disease (CKD) are potentially at greater risk of adverse effects from BPA and phthalate exposure. The objective of this study was to evaluate BPA and phthalate exposure among children with CKD and evaluate associations with three measures of kidney function. STUDY DESIGN/METHODS:Cross sectional study. SETTING, PARTICIPANTS, AND MEASUREMENTS/UNASSIGNED:The CKD population was represented by the Chronic Kidney Disease in Children (CKiD) Study, a multicenter, prospective cohort study of children with impaired kidney function in the US. The main outcome was assessment of the relationship between chemical exposures and clinical laboratory findings at enrollment into CKiD. Data collected at baseline from participants 1 to 17 years old (N = 538) were analyzed. Urinary BPA and phthalate levels were evaluated at this time point. Data from the National Health and Nutrition Examination Survey (NHANES), a nationally representative pediatric population, were used for comparison to the CKiD cohort. RESULTS:Urinary BPA and phthalate levels in the CKiD population were consistently lower than levels detected in healthy children. Additionally, BPA was not significantly associated with blood pressure, proteinuria, or estimated glomerular filtration rate (eGFR). Within the CKiD population, for select individual and combined phthalates, there was an inverse relationship with the urinary protein:creatinine ratio (LMW phthalates, - 9.53% change; 95% CI: - 14.21, - 4.21; p = 0.001), and in most cases, a positive relationship with eGFR (LMW phthalates, a 3.46 unit increase in eGFR, 95% CI: 1.85, 5.07; p < 0.001). LIMITATIONS/CONCLUSIONS:Lack of longitudinal data, limited assessment of diet and nutritional status. CONCLUSION/CONCLUSIONS:In the study cohort, children with CKD did not have increased exposure to BPA and phthalates. Longitudinal studies with repeated measures are likely to be more informative about the possible health effects of prolonged exposure to BPA and phthalates in pediatric patients with CKD.

BACKGROUND:Some non-persistent endocrine disruptors (EDCs) are adversely associated with semen quality and few studies have measured those EDCs in seminal plasma. OBJECTIVE:To find an association between EDCs in seminal plasma and semen quality parameters. METHODS:Five chemical classes of non-persistent EDCs were quantified in seminal plasma from 339 male partners who participated in a prospective pregnancy study. Bisphenols, benzophenone UV-filters, antimicrobials and phthalate diesters and their monoester metabolites were measured using high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Semen samples underwent next day analysis using a standardized protocol for the quantification of 35 endpoints. Linear mixed-effects models of EDCs that were log transformed and rescaled by their standard deviations or dichotomized at the 75th percentile for each exposure and outcomes with covariate adjustment were performed. EDCs in seminal plasma were also assessed relative to clinical reference values of semen quality endpoints using logistic regression or generalized estimating equations. RESULTS:The most consistent findings supporting adverse associations between seminal EDCs and semen quality were observed for some phthalate metabolites. For example, seminal plasma mono-ethyl, mono-n-butyl, mono-2-isobutyl and mono-benzyl phthalate concentrations were associated with decreased odds of having semen volume above clinical reference values (mEP: aOR=0.46; 95%CI= 0.32, 0.66; mBP: aOR=0.40; 95%CI= 0.28, 0.57; miBP: aOR=0.39; 95%CI= 0.27, 0.56), and mBzP: aOR= 0.34; 95%CI= 0.24, 0.49). CONCLUSIONS:Environmentally relevant concentrations of specific phthalates in seminal plasma were associated with diminished semen volume, sperm motility, viability, and morphological alterations in sperm heads such that semen volume and sperm viability fall below reference values.

BACKGROUND:Little is known about the associations of bisphenol A, chlorophenols, benzophenones, and parabens with reproductive hormone levels in women. Our goal was to evaluate the associations between repeated measures of these chemicals and their mixtures with reproductive hormones in women. METHODS:Longitudinal urine samples from healthy, premenopausal women (n = 143 with 3-5 urine samples each) were measured for bisphenol A, five chlorophenols (2,4-dichlorophenol (2,4-DCP), 2,5-dichlorophenol, 2,4,5-trichlorophenol, 2,4,6-trichlorophenol, triclosan), two ultraviolet (UV) filters (benzophenone-1, benzophenone-3), and eight parabens and their metabolites (benzyl, butyl, ethyl, heptyl, methyl, propyl, 4-hydroxybenzoic acid (4-HB), 3,4-dihydroxybenzoic acid (3,4-DHB)) over two menstrual cycles. Estradiol, progesterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured in blood up to 8 times each menstrual cycle. Linear mixed models were used for both single and multi-chemical exposures estimated using principal component analysis. Four factors were identified including: paraben; paraben metabolites and BPA, phenols, and UV filters. Models were adjusted for creatinine, age, race, and body mass index and weighted with inverse probability of exposure weights to account for time varying confounding. RESULTS:In single-chemical models, 3,4-DHB was associated with estradiol (0.06 (95% confidence interval (CI): 0.001, 0.12)), 2-4-DCP with increased progesterone 0.14 (0.06, 0.21) and decreased FSH -0.08 (-0.11, -0.04), and 4-HB was associated with increased FSH 0.07 (0.01, 0.13). In multi-chemical models, all factors were associated with increased progesterone (beta coefficient range: 0.15 for UV filter factor to 0.32 for paraben factor). The paraben factor and the paraben metabolite and BPA factor were associated with increased estradiol [0.21 (0.15, 0.28); 0.12 (0.07, 0.18)]. The phenol and UV filter factors were associated with decreased estradiol, FSH, and LH. The UV filter factor showed the strongest inverse association with estradiol -0.16 (-0.22, -0.10), FSH -0.12 (-0.17, -0.07), and LH -0.17 (-0.23, -0.10). CONCLUSION:Mixtures of phenols were associated with changes in reproductive hormones. Such changes could contribute to adverse health in women but additional research is necessary.

Fish consumption is an important route of exposure to persistent organic pollutants (POPs) in dolphins as well as humans. In order to assess the potential risks associated with these contaminants, 39 whole fish and 37 fillets from fish representing species consumed by dolphins and humans captured from Charleston Harbor and tributaries, South Carolina, USA, were measured for a suite of POPs. Polychlorinated biphenyls (PCBs) were the predominant contaminant with concentrations ranging from 5.02 to 232.20 ng/g in whole fish and 5.42-131.95 ng/g in fillets (weight weight ww) followed by total organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs). Total POPs levels varied by location and species with general trends indicating significantly higher levels in fish from the Cooper (93.4 ng/g ww) and Ashley Rivers (56.2 ng/g ww) compared to Charleston Harbor (31.6 ng/g ww). Mullet and spot were found to have significantly higher PCBs, OCPs and total POPs, 2-3 times higher than red drum; mullet were also significantly higher in OCPs compared to seatrout. PCB concentrations in whole fish and fillets exceeded EPA human screening values for cancer risk in all fish sampled. For PCBs in fillets, all samples had values of maximum allowable meals per month that were less than the EPA, FDA guidelines for recommended fish meals per month, suggesting lower (more stringent) allowable fish meals per month. All fish exceeded PBDE wildlife values and all fish except two exceeded the level where 95% of the dolphin population would have tissue levels below the health effect threshold. Considering that POP concentrations in fish potentially consumed by humans exceed human health effect thresholds levels, consumption advisories should be considered as a prudent public health measure.

We evaluated whether bisphenol-A (BPA) could be quantified in breast adipose tissue samples provided by 36 breast cancer mastectomy patients and 14 reduction mammoplasty patients. Samples of breast adipose tissue were collected and BPA concentration was quantified using HPLC-ESI-MS/MS. BPA was detectable above the limit of quantitation of 0.38 ng/g in 30.6% of samples. BPA concentrations varied within- and between breasts and were similar between cases and controls (0.39 vs 0.41 ng/g, p = 0.74).

A few epidemiologic studies suggest that exposure to bisphenol A (BPA) is associated with type 2 diabetes mellitus (T2DM). However, little is known about association between other phenolic endocrine disrupting chemicals (EDCs) and T2DM. In this case-control study, we measured urinary concentrations of 23 phenolic EDCs in 101 individuals from Jeddah, Saudi Arabia, to examine the association of parabens, antimicrobials, bisphenols, benzophenones and bisphenol A diglycidyl ethers with T2DM. Urine samples were collected from 54 T2DM cases and 47 non-diabetic individuals (controls), aged 28-68 years old, during 2015-2016. Unconditional logistic regression was performed to estimate odd ratios (ORs) for the association between diabetes and EDC exposures after adjusting for confounders including age, gender, nationality, smoking status and occupation. Age from 40 to 59 years (OR 5.56, 95% CI 2.20-14.0) and smoking status (OR 2.92, 95% CI 1.25-6.79) showed significant positive associations with T2DM. After adjusting for potential confounders, we found that T2DM cases had high urinary levels of parabens (i.e., methyl- (MeP), ethyl- (EtP), propyl- (PrP) and 4-hydroxy benzoic acid (4-HB)), bisphenols (i.e., bisphenols A (BPA) and F (BPF)), and benzophenone (i.e., 4-hydroxybenzophenone (4-OH-BP)) relative to the controls. Individuals in the 4th quartile for urinary concentrations of MeP, EtP, PrP, 4-HB and BPF and in the 3rd quartile for BPA and 4-OH-BP showed over a 6-fold increase in the odds of having diabetes compared with those in the first quartile. Overall, our study shows that urinary levels of multiple phenolic EDCs were associated with increased risk for diabetes. Further prospective studies are required to verify these associations.

BACKGROUND:Intrauterine exposure to endocrine disrupting chemicals (EDCs) has been equivocally associated with birth weight, length and head circumference with limited attention to anthropometric endpoints such as umbilical circumference and limb lengths. OBJECTIVE:To explore 76 prenatal maternal plasma EDC concentrations in a healthy obstetric cohort and 7 neonatal anthropometric endpoints by maternal race/ethnicity. METHODS:The study cohort comprised 2106 (564 White, 549 Black, 590 Hispanic, 403 Asian) healthy pregnant women recruited from 12 U.S. clinical sites between 2009 and 2012 who were followed through delivery. Neonates underwent standardized anthropometric assessment (weight, length, head and umbilical circumference, and mid- upper arm and thigh length). Plasma EDC concentrations were quantified using high resolution gas chromatography-high resolution mass spectrometry and liquid chromatography-tandem mass spectrometry. EDCs were log-transformed and rescaled by their deviations (SD) when modeled relative to neonatal endpoints using linear regression adjusting for age, education, pre-pregnancy body mass index (BMI), serum cotinine, serum lipids for lipophilic chemicals, and a race/ethnicity interaction term; p-values had false discovery rate correction (<0.05). RESULTS:, SD = 3). Maternal EDC concentrations varied by self-identified race/ethnicity and neonatal outcomes, though no specific EDC was consistently associated with neonatal anthropometric outcomes across racial/ethnic groups. For the overall cohort, perfluorooctanoic acid was negatively associated with birth length per SD increase in concentration (β = -0.23 cm; 95% CI -0.35, -0.10), while perfluorohexanesulfonic acid was negatively associated with umbilical circumference (β = -0.26 cm; 95% CI -0.40, -0.13), perfluorodecanoic acid with arm length (-0.09 cm; 95% CI -0.14, -0.04), and PCBs congeners 118/106 (-0.12 cm; 95% CI -0.20, -0.04) and 146/161 (-0.14 cm; 95% CI -0.23, -0.05) with thigh length, as were 7 other poly-and-perfluorinated alkyl substances (PFASs). CONCLUSIONS:Among healthy pregnant women with low risk antenatal profiles and relatively low EDC concentrations, reductions in umbilical circumference and bone lengths may be a sensitive marker of intrauterine EDC exposure, particularly for PFAS.

Pantyhose, a skin-tight item of clothing made of synthetic fibers and worn by women in many countries, is a source of exposure to several endocrine-disrupting chemicals. Little is known regarding the occurrence of and dermal exposure to chemicals present in pantyhose. In this study, concentrations and profiles of 23 endocrine-disrupting chemicals, including bisphenols, benzophenones, chlorophenols, parabens, and triclocarban (TCC), were determined in 74 pantyhose samples collected from 6 countries. Pantyhose samples were analyzed by two extraction methods: complete dissolution and ultrasonic extraction. Dissolution of the fabric in 1,1,1,3,3,3-hexafluoro-2-propanol/chloroform yielded concentrations of several target chemicals that were up to 286 times higher than in the ultrasonic extraction. Bisphenol S (BPS) and bisphenol A (BPA) were found in 100% and 96% of the samples at median concentrations of 1430 and 14.3 ng/g, respectively. Several brands of pantyhose contained BPS, bisphenol F (BPF), benzophenone-1 (BP-1), ethyl-paraben (EtP), and TCC at concentrations of milligrams per gram. Benzophenone-3 (BP-3), 4-hydroxy benzoic acid (4-HB), and methyl- (MeP) and propyl-parabens (PrP) were found in ≥85% of the samples at median concentrations on the order of several tens to hundreds of nanograms per gram of fabric. Pantyhose made in Japan and China with 21-50% Spandex contained the highest concentrations of BPS (2.2 mg/g), BP-1 (2.4 mg/g), and EtP (88 μg/g). Calculated dermal exposure doses to BPS, BP-1, and EtP by women via pantyhose were as high as 45 900, 50 600, and 1800 picograms per kilogram of body weight per day, respectively.

Background/UNASSIGNED:Increasing evidence suggests that exposure to synthetic chemicals such as bisphenols and phthalates can influence fecundability. The current study describes associations of first trimester urinary concentrations of bisphenol A (BPA), BPA analogues and phthalate metabolites with time to pregnancy (TTP). Methods/UNASSIGNED:Among 877 participants in the population-based Generation R pregnancy cohort, we measured first trimester urinary concentrations of bisphenols and phthalates (median gestational age 12.9 weeks [inter-quartile range 12.1-14.4 weeks]). We used fitted covariate-adjusted Cox proportional hazard models to examine associations of bisphenol and phthalate concentrations with TTP. Participants who conceived using infertility treatment were censored at 12 months. Biologically plausible effect measure modification by folic acid supplement use was tested. Results/UNASSIGNED:In the main models, bisphenol and phthalate compounds were not associated with fecundability. In stratified models, total bisphenols and phthalic acid were associated with longer TTP among women who did not use folic acid supplements preconceptionally (respective fecundability ratios per each natural log increase were 0.90 [95% Confidence Interval (CI) 0.81, 1.00] and 0.88 [95% CI 0.79, 0.99]). Using an interaction term for the exposure and folic acid supplement use showed additional effect measure modification by folic acid supplement use for high molecular weight phthalate metabolites. Conclusions/UNASSIGNED:We found no associations of bisphenols and phthalates with fecundability. Preconception folic acid supplementation seems to modify effects of bisphenols and phthalates on fecundability. Folic acid supplements may protect against reduced fecundability among women exposed to these chemicals. Further studies are needed to replicate these findings and investigate potential mechanisms.

Parabens are used as preservatives in many consumer products, and human exposure to these chemicals has been a public concern. In this study, mollusks ( n = 186), collected from the Chinese Bohai Sea during 2006-2015, were analyzed for six parabens and their five metabolites. The total concentration of parabens was in the range of 2.66-299 ng/g dw (geometric mean: 24.1). Methyl paraben and 4-hydroxybenzoic acid were the predominant parent and metabolic parabens, respectively found in mollusks. Mollusk species, Mactra veneriformis, Mytilus edulis, and Cyclina sinensis contained elevated concentrations of both parent and metabolic parabens. A gradual increase in paraben concentrations was found in mollusks collected between 2006 and 2012. Principal component analysis suggested the existence of a common source for these chemicals in mollusks. Consumption of mollusks can contribute to human exposures and we estimated daily intakes of parabens through the consumption of mollusks. This is the first study to report temporal trends and accumulation of parabens and their metabolites in a variety of invertebrate species from coastal marine environments.