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BACKGROUND: Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women. OBJECTIVE: We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity. METHODS: This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005-2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (f[T.sub.4], T[T.sub.4]) and triiodothyronine (f[T.sub.3], T[T.sub.3]), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores. RESULTS: We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of f[T.sub.4], T[T.sub.4], f[T.sub.3], and T[T.sub.3] [absolute difference: -0.62; 95% confidence interval (CI): -0.12, -0.01; p = 0.04; absolute difference: -8.31; 95% CI: -13.8, -2.85; p = 0.003; absolute difference: -0.37; 95% CI: 0.54, -0.19; p CONCLUSIONS: Mixtures of urinary DEHP metabolites were inversely associated with serum biomarkers of thyroid function but not with autoimmunity, which were within normal ranges for healthy adult women. https://doi.org/10.1289/EHP6740, Introduction Phthalates are a class of endocrine-disrupting chemicals (EDCs) used in consumer and personal care products, leading to widespread general population exposure through ingestion, inhalation, and dermal absorption (CDC 2019; [...]

Background: Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have been conducted to evaluate effects on fertility and pregnancy outcomes. Objectives: We evaluated associations between urinary concentrations of PFR metabolites and outcomes of in vitro fertilization (IVF) treatment among couples recruited from an academic fertility clinic. Methods: This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman. Results: Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of [SIGMA]PFR were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%). Conclusions: Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021, Introduction One in six couples worldwide is affected by infertility, which is defined as the inability to get pregnant after 1 y or more of unprotected intercourse (Chandra et al. [...]

BACKGROUND: Exposure to dioxins has been associated with delayed pubertal onset in both epidemiologic and animal studies. Whether genetic polymorphisms may modify this association is currently unknown. Identifying such genes [...]

BACKGROUND: Exposures to endocrine-disrupting chemicals during critical phases of testicular development may be related to poorer semen parameters. However, few studies have assessed the association between childhood organochlorine (OC) exposure and adult semen parameters. OBJECTIVE: We examined whether peripubertal serum OC concentrations are associated with semen parameters among young Russian men. METHODS: From 2003 through 2005, 516 boys were enrolled at age 8-9 years and followed for up to 10 years. Serum OCs were measured in the enrollment samples using high-resolution mass spectrometry. At 18-19 years, 133 young men provided 1 or 2 semen samples (256 samples) collected approximately 1 week apart, which were analyzed for volume, sperm concentration, and motility. Unadjusted and adjusted linear mixed models were used to examine the associations of quartiles of lipid-standardized concentrations of dioxins [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated dibenzo-p-dioxins (PCDDs)], furans, polychlorinated biphenyls (PCBs), and corresponding toxic equivalents (TEQs) with semen parameters. RESULTS: The median (range) for TCDD was 2.9 (0.4-12.1) pg/g lipid and PCDD TEQ was 8.7 (1.0-36.0) pg TEQ/g lipid. Higher quartiles of TCDD and PCDD TEQs were associated with lower sperm concentration, total sperm count, and total motile sperm count (p-trends ≤ 0.05). The highest quartile of peripubertal serum TCDD concentrations was associated with a decrease (95% CI) of 40% (18, 66%), 29% (3, 64%), and 30% (2, 70%) in sperm concentration, total sperm count, and total motile sperm count, respectively, compared with the lowest quartile. Similar associations were observed for serum PCDD TEQs with semen parameters. Serum PCBs, furans, and total TEQs were not associated with semen parameters. CONCLUSION: Higher peripubertal serum TCDD concentrations and PCDD TEQs were associated with poorer semen parameters. http://dx.doi.org/10.1289/EHP25, Introduction Over the past several decades, numerous studies have explored whether semen parameters have declined (Carlsen et al. 1992; Swan et al. 2000), and whether there are geographical differences in [...]

BACKGROUND: Dioxins, furans, and polychlorinated biphenyls (PCBs), dioxin-like and non-dioxin-like, have been linked to alterations in puberty. OBJECTIVES: We examined the association of peripubertal serum levels of these compounds [and their toxic equivalents (TEQs)] with pubertal onset and maturity among Russian boys enrolled at ages 8-9 years and followed prospectively through ages 17-18 years. METHODS: At enrollment, 473 boys had serum dioxin-like compounds and PCBs measured. At the baseline visit and annually until age 17-18 years, a physician performed pubertal staging [genitalia (G), pubarche (P), and testicular volume (TV)]. Three hundred fifteen subjects completed the follow-up visit at 17-18 years of age. Pubertal onset was defined as TV > 3 mL, G2, or P2. Sexual maturity was defined as TV ≥ 20 mL, G5, or P5. Multivariable interval-censored models were used to evaluate associations of lipid-standardized concentrations with pubertal timing. RESULTS: Medians (interquartile ranges) of the sum of dioxin-like compounds, TEQs, and nondioxin-like PCBs were 362 pg/g lipid (279-495), 21.1 pg TEQ/g lipid (14.4-33.2), and 250 ng/g lipid (164-395), respectively. In adjusted models, the highest compared to lowest TEQ quartile was associated with later pubertal onset [TV = 11.6 months (95% CI: 3.8, 19.4); G2 = 10.1 months (95% CI: 1.4, 18.8)] and sexual maturity [TV = 11.6 months (95% CI: 5.7, 17.6); G5 = 9.7 months (95% CI: 3.1, 16.2)]. However, the highest compared to the lowest quartile of non-dioxin-like PCBs, when co-adjusted by TEQs, was associated with earlier pubertal onset [TV = -8.3 months (95% CI:-16.2, -0.3)] and sexual maturity [TV = -6.3 months (95% CI:-12.2, -0.3); G5 = -7.2 months (95% CI:-13.8, -0.6)]; the non-dioxin-like PCB associations were only significant when adjusted for TEQs. TEQs and PCBs were not significantly associated with pubic hair development. CONCLUSIONS: Our results suggest that TEQs may delay, while non-dioxin-like PCBs advance, the timing of male puberty. http://dx.doi.org/10.1289/EHP154, Introduction Considerable evidence supports a decline in age of pubertal onset among girls in recent decades (Aksglaede et al. 2009; Herman-Giddens et al. 1997; Sorensen et al. 2012), whereas studies [...]

BACKGROUND: Few human studies have evaluated the impact of childhood exposure to organochlorine pesticides (OCP) on pubertal development. OBJECTIVE: We evaluated associations of serum OCP concentrations [hexachlorobenzene (HCB), β-hexachlorocyclohexane (βHCH), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE)] with age at attainment of sexual maturity among boys. METHODS: From 2003 through 2005, 350 8- to 9-year-old boys from Chapaevsk, Russia, with measured OCPs were enrolled and followed annually for 8 years. We used multivariable interval-censored models to evaluate associations of OCPs (quartiles) with three physician-assessed measures of sexual maturity: Tanner stage 5 for genitalia growth, Tanner stage 5 for pubic hair growth, or testicular volume (TV) ≥ 20 mL in either testis. RESULTS: In adjusted models, boys with higher HCB concentrations achieved sexual maturity reflected by TV ≥ 20 mL a mean of 3.1 months (95% CI: -1.7, 7.8), 5.3 months (95% CI: 0.6, 10.1), and 5.0 months (95% CI: 0.2, 9.8) later for quartiles Q2, Q3, and Q4, respectively, compared with Q1 (p trend = 0.04). Tanner stage 5 for genitalia growth was attained a mean of 2.2 months (95% CI: -3.1, 7.5), 5.7 months (95% CI: 0.4, 11.0), and 3.7 months (95% CI: -1.7, 9.1) later for quartiles Q2, Q3, and Q4, respectively, of βHCH compared with Q1 (p trend = 0.09). Tanner stage 5 for pubic hair growth occurred 6-9 months later on average for boys in the highest versus lowest quartile for HCB (p trend < 0.001), βHCH (trend p = 0.01), and p,p'-DDE (p trend = 0.04). No associations were observed between p,p'-DDE and Tanner stage 5 for genitalia growth or TV ≥ 20 mL. CONCLUSIONS AND RELEVANCE: Higher prepubertal serum HCB and βHCH concentrations were associated with a later age at attainment of sexual maturity. Only the highest quartile of serum p,p'-DDE was associated with later pubic hair maturation. http://dx.doi.org/10.1289/ehp.1409022, Introduction Organochlorine pesticides (OCPs) such as hexachlorobenzene (HCB), β-hexachlorocyclohexane (βHCH), and 1,1,1,-trichloro-2,2,bis(p-chlorophenyl)ethane (DDT) were used as insecticides and fungicides for decades until the 1980s (Barber et al. 2005; Jaga and [...]

BACKGROUND: Human exposure to phenols, including bisphenol A and parabens, is widespread. Evidence suggests that paternal exposure to environmental chemicals may adversely affect reproductive outcomes. OBJECTIVES: We evaluated associations of paternal phenol urinary concentrations with fertilization rate, embryo quality, implantation, and live birth. METHODS: Male-female couples who underwent in vitro fertilization (IVF) and/or intrauterine insemination (IUI) cycles in a prospective study of environmental determinants of fertility and pregnancy outcomes were included. The geometric mean of males' specific gravity-adjusted urinary phenol concentrations measured before females' cycle was quantified. Associations between male urinary phenol concentrations and fertilization rate, embryo quality, implantation, and live birth were investigated using generalized linear mixed models to account for multiple cycles per couple. RESULTS: Couples (n = 218) underwent 195 IUI and 211 IVF cycles. Paternal phenol concentrations were not associated with fertilization or live birth following IVF. In adjusted models, compared with the lowest quartile of methyl paraben, paternal concentrations in the second quartile were associated with decreased odds of live birth following IUI (adjusted odds ratio = 0.19; 95% CI: 0.04, 0.82). CONCLUSIONS: To our knowledge, these are some of the first data on the association of paternal urinary phenol concentrations with reproduction and pregnancy outcomes. Although these results do not preclude possible adverse effects of paternal paraben exposures on such outcomes, given the modest sample size, further understanding could result from confirmation using a larger and more diverse population. http://dx.doi.org/10.1289/ehp.1408605, Introduction Humans experience ubiquitous exposure to phenols, including bisphenol A (BPA) and parabens. The National Report on Human Exposure to Environmental Chemicals [Centers for Disease Control and Prevention (CDC) 2013], [...]

BACKGROUND: Few studies have evaluated predictors of childhood exposure to organochlorine pesticides (OCPs), a class of lipophilic persistent chemicals. OBJECTIVES: Our goal was to identify predictors of serum OCP concentrations-- hexachlorobenzene (HCB), [beta]-hexachlorocyclohexane ([beta]-HCH), and p,p- dichlorodiphenyldichloroethylene (p,p'-DDE)--among boys in Chapaevsk, Russia. METHODS: Between 2003 and 2005, 499 boys 8-9 years of age were recruited in a prospective cohort. The initial study visit included a physical examination; blood collection; health, lifestyle, and food-frequency questionnaires; and determination of residential distance from a local factory complex that produced HCB and [beta]-HCH. Fasting serum samples were analyzed for OCPs at the U.S. Centers for Disease Control and Prevention. General linear regression models were used to identify predictors of the boys' serum HCB, [beta]-HCH, and p,p'-DDE concentrations. RESULTS: Among 355 boys with OCP measurements, median serum HCB, [beta]-HCH, and p,p'-DDE concentrations were 158, 167, and 284 ng/g lipid, respectively. Lower body mass index, longer breastfeeding duration, and local dairy consumption were associated with higher concentrations of OCPs. Boys who lived < 2 km from the factory complex had 64% (95% CI: 37, 96) and 57% (95% CI: 32, 87) higher mean HCB and [beta]-HCH concentrations, respectively, than boys who lived > 5 km away. Living > 3 years in Chapaevsk predicted higher [beta]-HCH concentrations, and having parents who lacked a high school education predicted higher p,p'-DDE concentrations. CONCLUSIONS: Among this cohort of prepubertal Russian boys, predictors of serum OCPs included consumption of local dairy products, longer local residence, and residential proximity to the local factory complex., Introduction Persistent, lipid-soluble organochlorine pesticides (OCPs) such as hexachlorobenzene (HCB), P-hexachlorocyclohexane ([beta]-HCH), dichlorodiphenyltrichlorethane (DDT), and its primary metabolite p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE) are ubiquitous in the environment. Although these insecticides and fungicides [...]

BACKGROUND: Parabens are preservatives commonly used in personal care products, pharmaceuticals, and foods. There is documented widespread human exposure to parabens, and some experimental data suggest that they act as estrogenic endocrine disruptors. As far as we are aware, no epidemiologic studies have assessed female reproductive health effects in relation to paraben exposure. OBJECTIVE: We examined the association of urinary paraben concentrations with markers of ovarian reserve in a prospective cohort study of women seeking fertility treatment at Massachusetts General Hospital, Boston, Massachusetts. METHODS: Measures of ovarian reserve were day-3 follicle-stimulating hormone (FSH), antral follicle count (AFC), and ovarian volume. Paraben concentrations [methylparaben (MP), propylparaben (PP), and butylparaben (BP)] were measured in spot urine samples collected prior to the assessment of outcome measures. We used linear and Poisson regression models to estimate associations of urinary paraben concentrations (in tertiles) with ovarian reserve measures. RESULTS: Of the women enrolled in 2004-2010, 192 had at least one ovarian reserve outcome measured (mean age [+ or -] SD, 36.1 [+ or -] 4.5 years; range, 21.0-46.7 years). MP and PP were detected in > 99% of urine samples and BP in > 75%. We found a suggestive trend of lower AFC with increasing urinary PP tertiles [mean percent change (95% CI) for tertiles 2 and 3 compared with tertile 1, respectively, were -5.0% (-23.7, 18.4) and -16.3% (-30.8, 1.3); trend p-value ([p.sub.trend]) = 0.07] as well as higher day-3 FSH with higher urinary PP tertiles [mean change (95% CI) for tertiles 2 and 3 compared with tertile 1 were 1.16 IU/L (-0.26, 2.57) and 1.02 IU/L (- 0.40, 2.43); [p.sub.trend] = 0.16]. We found no consistent evidence of associations between urinary MP or BP and day-3 FSH or AFC, or between urinary MP, PP, or BP and ovarian volume. CONCLUSIONS: PP may be associated with diminished ovarian reserve. However, our results require confirmation in further studies., Introduction Parabens are a family of chemicals commonly used as antimicrobial preservatives in personal care products, pharmaceuticals, and foods (Andersen 2008; National Toxicology Program 2005; Orth 1980). Exposure to parabens [...]

BACKGROUND: Childhood lead exposure has been associated with growth delay. However, the association between blood lead levels (BLLs) and insulin-like growth factor 1 (IGF-1) has not been characterized in a large cohort with low-level lead exposure. METHODS: We recruited 394 boys 8-9 years of age from an industrial Russian town in 2003-2005 and followed them annually thereafter. We used linear regression models to estimate the association of baseline BLLs with serum IGF-1 concentration at two follow-up visits (ages 10-11 and 12-13 years), adjusting for demographic and socioeconomic covariates. RESULTS: At study entry, median BLL was 3 µg/dL (range, < 0.5-31 µg/dL), most boys (86%) were prepubertal, and mean ± SD height and BMI z-scores were 0.14 ± 1.0 and -0.2 ± 1.3, respectively. After adjustment for covariates, the mean follow-up IGF-1 concentration was 29.2 ng/mL lower (95% CI: -43.8, -14.5) for boys with high versus low BLL (≥ 5 µg/dL or < 5 µg/dL); this difference persisted after further adjustment for pubertal status. The association of BLL with IGF-1 was stronger for mid-pubertal than prepubertal boys (p = 0.04). Relative to boys with BLLs < 2 µg/dL, adjusted mean IGF-1 concentrations decreased by 12.8 ng/mL (95% CI: -29.9, 4.4) for boys with BLLs of 3-4 µg/dL; 34.5 ng/mL (95% CI: -53.1, -16.0) for BLLs 5-9 µg/dL; and 60.4 ng/mL (95% CI: -90.9, -29.9) for BLLs ≥ 10 µg/dL. CONCLUSIONS: In peripubertal boys with low-level lead exposure, higher BLLs were associated with lower serum IGF-1. Inhibition of the hypothalamic--pituitary--growth axis may be one possible pathway by which lead exposure leads to growth delay. KEY WORDS: cohort studies, growth, insulin-like growth factor 1, lead; puberty. http://dx.doi.org/10.1289/ehp.1206105., The Centers for Disease Control and Prevention (CDC) recently revised the reference value for childhood lead exposure downward from 10 to 5 µg/dL (Betts 2012). This has occurred in response [...]

BACKGROUND: Evidence from both animal and human studies suggests that exposure to phthalates may be associated with adverse female reproductive outcomes. Objective: We evaluated the associations between urinary concentrations of phthalate metabolites and outcomes of assisted reproductive technologies (ART). METHODS: This analysis included 256 women enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2004-2012) who provided one to two urine samples per cycle before oocyte retrieval. We measured 11 urinary phthalate metabolites [mono(2ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), monoethyl phthalate (MEP), monocarboxyisooctyl phthalate (MCOP), monocarboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate (MCPP)]. We used generalized linear mixed models to evaluate the association of urinary phthalate metabolites with in vitro fertilization (IVF) outcomes, accounting for multiple IVF cycles per woman. RESULTS: In multivariate models, women in the highest as compared with lowest quartile of MEHP, MEHHP, MEOHP, MECPP, SDEHP (MEHP + MEHHP + MEOHP + MECPP), and MCNP had lower oocyte yield. Similarly, the number of mature (MII) oocytes retrieved was lower in the highest versus lowest quartile for these same phthalate metabolites. The adjusted differences (95% CI) in proportion of cycles resulting in clinical pregnancy and live birth between women in the fourth versus first quartile of SDEHP were -0.19 (-0.29, -0.08) and -0.19 (-0.28, -0.08), respectively, and there was also a lower proportion of cycles resulting in clinical pregnancy and live birth for individual DEHP metabolites. CONCLUSIONS: Urinary concentrations of DEHP metabolites were inversely associated with oocyte yield, clinical pregnancy, and live birth following ART. Citation: Hauser R, Gaskins AJ, Souter I, Smith KW, Dodge LE, Ehrlich S, Meeker JD, Calafat AM, Williams PL, for the EARTH Study Team. 2016. Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: results from the EARTH study. Environ Health Perspect 124:831-839; http://dx.doi. org/10.1289/ehp.1509760 [ABSTRACT FROM AUTHOR]