CONTEXT: Evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases the risk of developing cardiometabolic disease risk factors. Limited research has evaluated associations between PFAS, assessed during pregnancy, a sensitive window for maternal endocrine effects, and long-term maternal adiposity. OBJECTIVE: Estimate associations of early pregnancy measures of individual PFAS, and PFAS mixtures, with maternal adiposity in midlife. METHODS: We studied 547 Project Viva participants with measures of early pregnancy (mean gestation 10.0 weeks; mean age 32.5 years) plasma concentrations of 6 PFAS and midlife adiposity outcomes (mean follow-up 17.7 years; mean age 50.7 years), including weight, waist circumference (WC), trunk fat mass (TFM), and total body fat mass (TBFM). We used linear regression and Bayesian Kernel Machine Regression (BKMR). RESULTS: Linear regression estimated higher midlife weight per doubling of perfluorooctane sulfonate (PFOS) (3.8 kg [95% CI: 1.6, 5.9]) and 2-(N-ethyl-perfluorooctane sulfonamido) acetate (2.3 kg [95% CI: 0.9, 3.7]). BKMR analyses of single PFAS plasma concentrations (comparing the 25th percentile concentration to the 75th percentile) showed a positive association between PFOS and midlife adiposity (weight: 7.7 kg [95% CI: 4.0, 11.5]; TFM: 1.2 kg [95% CI: 0.0, 2.3]; TBFM: 3.0 kg [95% CI: 0.8, 5.2]), but inverse associations with perfluorononanoate (weight: -6.0 kg [95% CI: -8.5, -3.5]; WC: -1.8 cm [95% CI: -3.2, -0.3]; TFM: -0.8 kg [95% CI: -1.5, -0.1]; TBFM: -1.4 kg [95% CI: -2.7, -0.3]) and perfluorohexane sulfonate (TFM: -0.8 kg [95% CI: -1.5, -0.1]; TBFM: -1.4 kg [95% CI: -2.6, -0.2]). No associations were observed with the overall PFAS mixture. CONCLUSION: Select PFAS, assessed in pregnancy, may differentially affect maternal midlife adiposity, influencing later-life maternal cardiometabolic health.

BACKGROUND: Evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases risk of high blood pressure (BP) during pregnancy. Prior studies did not examine associations with BP trajectory parameters (i.e., overall magnitude and velocity) during pregnancy, which is linked to adverse pregnancy outcomes. OBJECTIVES: To estimate associations of multiple plasma PFAS in early pregnancy with BP trajectory parameters across the second and third trimesters. To assess potential effect modification by maternal age and parity. METHODS: In 1297 individuals, we quantified six PFAS in plasma collected during early pregnancy (median gestational age: 9.4 weeks). We abstracted from medical records systolic BP (SBP) and diastolic BP (DBP) measurements, recorded from 12 weeks gestation until delivery. BP trajectory parameters were estimated via Super Imposition by Translation and Rotation modeling. Subsequently, Bayesian Kernel Machine Regression (BKMR) was employed to estimate individual and joint associations of PFAS concentrations with trajectory parameters - adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index, income, parity, smoking status, and seafood intake. We evaluated effect modification by age at enrollment and parity. RESULTS: We collected a median of 13 BP measurements per participant. In BKMR, higher concentration of perfluorooctane sulfonate (PFOS) was independently associated with higher magnitude of overall SBP and DBP trajectories (i.e., upward shift of trajectories) and faster SBP trajectory velocity, holding all other PFAS at their medians. In stratified BKMR analyses, participants with ≥ 1 live birth had more pronounced positive associations between PFOS and SBP velocity, DBP magnitude, and DBP velocity - compared to nulliparous participants. We did not observe significant associations between concentrations of the overall PFAS mixture and either magnitude or velocity of the BP trajectories. CONCLUSION: Early pregnancy plasma PFOS concentrations were associated with altered BP trajectory in pregnancy, which may impact future cardiovascular health of the mother.

We examined whether mixtures of urinary concentrations of bisphenol A (BPA), parabens and phthalate metabolites were associated with serum lipid levels among 175 pregnant women who enrolled in the Environment and Reproductive Health (EARTH) Study (2005-2017), including triglycerides, total cholesterol, high-density lipoprotein (HDL), non-HDL, and low-density lipoprotein (LDL). We applied Bayesian Kernel Machine Regression (BKMR) and quantile g-computation while adjusting for confounders. In the BKMR models, we found no associations between chemical mixture and lipid levels, e.g., total cholesterol [mean difference (95% CRI, credible interval) = 0.02 (-0.31, 0.34)] and LDL [mean difference (95% CRI) = 0.10 (-0.22, 0.43)], when comparing concentrations at the 75th to the 25th percentile. When stratified by BMI, we found suggestive positive relationships between urinary propylparaben and total cholesterol and LDL among women with high BMI [mean difference (95% CRI) = 0.25 (-0.26, 0.75) and 0.35 (-0.25, 0.95)], but not with low BMI [mean difference (95% CRI) = 0.00 (-0.06, 0.07) and 0.00 (-0.07, 0.07)]. No association was found by quantile g-computation. This exploratory study suggests mixtures of phenol and phthalate metabolites were not associated with serum lipid levels during pregnancy, while there were some suggestive associations for certain BMI subgroups. Larger longitudinal studies with multiple assessments of both exposure and outcome are needed to corroborate these novel findings.

Although prior studies have found associations of the ovarian reserve with urinary concentrations of some individual phenols and phthalate metabolites, little is known about the potential associations of these chemicals as a mixture with the ovarian reserve. We investigated whether mixtures of four urinary phenols (bisphenol A, butylparaben, methylparaben, propylparaben) and eight metabolites of five phthalate diesters including di(2-ethylhexyl) phthalate were associated with markers of the ovarian reserve among 271 women attending a fertility center who enrolled in the Environment and Reproductive Health study (2004-2017). The analysis was restricted to one outcome per study participant using the earliest outcome after the last exposure assessment. Ovarian reserve markers included lower antral follicle count (AFC) defined as AFC < 7, circulating serum levels of day 3 follicle stimulating hormone (FSH) assessed by immunoassays, and diminished ovarian reserve (DOR) defined as either AFC < 7, FSH > 10 UI/L or primary infertility diagnosis of DOR. We applied Bayesian Kernel Machine Regression (BKMR) and quantile g-computation to estimate the joint associations and assess the interactions between chemical exposure biomarkers on the markers of the ovarian reserve while adjusting for confounders. Among all 271 women, 738 urine samples were collected. In quantile g-computation models, a quartile increase in the exposure biomarkers mixture was not significantly associated with lower AFC (OR = 1.10, 95 % CI = 0.52, 2.30), day 3 FSH levels (Beta = 0.30, 95 % CI = -0.32, 0.93) or DOR (OR = 1.02, 95 % CI = 0.52, 2.05). Similarly, BKMR did not show any evidence of associations between the mixture and any of the studied outcomes, or interactions between chemicals. Despite the lack of associations, these results need to be explored among women in other study cohorts.

Endocrine disrupting chemicals (EDCs) can adversely affect human health and are ubiquitously found in everyday products. We examined temporal trends in urinary concentrations of EDCs and their replacements. Urinary concentrations of 11 environmental phenols, 15 phthalate metabolites, phthalate replacements such as two di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) metabolites, and triclocarban were quantified using isotope-dilution tandem mass spectrometry. This prospective ecological study included 996 male and 819 female patients who were predominantly White/Caucasian (83 %) with an average age of 35 years and a BMI of 25.5 kg/m(2) seeking fertility treatment in Boston, MA, USA. Patients provided a total of 6483 urine samples (median = 2, range = 1-30 samples per patient) between 2000 and 2017. Over the study period, we observed significant decreases (% per year) in urinary concentrations of traditional phenols, parabens, and phthalates such as bisphenol A (β: -6.3, 95 % CI: -7.2, -5.4), benzophenone-3 (β: -6.5, 95 % CI: -1.1, -18.9), parabens ((β range:-5.4 to -14.2), triclosan (β: -18.8, 95 % CI: -24, -13.6), dichlorophenols (2.4-dichlorophenol β: -6.6, 95 % CI: -8.8, -4.3); 2,5-dichlorophenol β: -13.6, 95 % CI: -17, -10.3), di(2-ethylhexyl) phthalate metabolites (β range: -11.9 to -22.0), and other phthalate metabolites including mono-ethyl, mono-n-butyl, and mono-methyl phthalate (β range: -0.3 to -11.5). In contrast, we found significant increases in urinary concentrations of environmental phenol replacements including bisphenol S (β: 3.9, 95 % CI: 2.7, 7.6) and bisphenol F (β: 6, 95 % CI: 1.8, 10.3), DINCH metabolites (cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester [MHiNCH] β: 20, 95 % CI: 17.8, 22.2; monocarboxyisooctyl phthalate [MCOCH] β: 16.2, 95 % CI: 14, 18.4), and newer phthalate replacements such as mono-3-carboxypropyl phthalate, monobenzyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate and di-isobutyl phthalate metabolites (β range = 5.3 to 45.1), over time. Urinary MHBP concentrations remained stable over the study period. While the majority of biomarkers measured declined over time, concentrations of several increased, particularly replacement chemicals that are studied.

The associations between urinary phenol concentrations and markers of thyroid function and autoimmunity among potentially susceptible subgroups, such as subfertile women, have been understudied, especially when considering chemical mixtures. We evaluated cross-sectional associations of urinary phenol concentrations, individually and as a mixture, with serum markers of thyroid function and autoimmunity. We included 339 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2009-2015). We quantified four phenols in urine using isotope dilution high-performance liquid chromatography-tandem mass spectrometry, and biomarkers of thyroid function (thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4), and triiodothyronine (fT3, TT3)), and autoimmunity (thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies (Ab)) in serum using electrochemoluminescence assays. We fit linear and additive models to investigate the association between urinary phenols-both individually and as a mixture-and serum thyroid function and autoimmunity, adjusted for confounders. As a sensitivity analysis, we also applied Bayesian Kernel Machine Regression (BKMR) to investigate non-linear and non-additive interactions. Urinary bisphenol A was associated with thyroid function, in particular, fT(3) (mean difference for a 1 log unit increase in concentration: -0.088; 95% CI [-0.151, -0.025]) and TT(3) (-0.066; 95% CI [-0.112, -0.020]). Urinary methylparaben and triclosan were also associated with several thyroid hormones. The overall mixture was negatively associated with serum fT(3) concentrations (mean difference comparing all four mixture components at their 75th vs. 25th percentiles: -0.19, 95% CI [-0.35, -0.03]). We found no evidence of non-linearity or interactions. These results add to the current literature on phenol exposures and thyroid function in women, suggesting that some phenols may alter the thyroid system.

We examined whether urinary concentrations of phthalate and phthalate replacement metabolites were associated with lipid biomarker levels among pregnant women. This cross-sectional study included 175 women who enrolled in the Environment and Reproductive Health (EARTH) Study (2005-2017). We used linear regression models to assess the relationship between urinary phthalates and lipid biomarkers [triglycerides, total cholesterol, high density lipoprotein (HDL), non-HDL, and low-density lipoprotein (LDL) cholesterol] levels while adjusting for confounders. Pregnant women in the highest quartile of urinary mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) had, overall, 14% [31 (95% CI = 6.56) mg/dL], 21% [33 (95% CI = 9.57) mg/dL] and 25% [30 (95% CI = 8.53) mg/dL] higher serum total, non-HDL and LDL cholesterol, respectively, compared to women in the lowest quartile of MECPP. Similar positive associations were found for urinary concentrations of other metabolites of di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. Pregnant women with urinary mono-n-butyl phthalate (MBP) in the highest quartile had higher triglycerides and non-HDL cholesterol compared to women with MBP in the lowest quartile. Women with detectable concentrations of two phthalate replacement metabolites had lower HDL cholesterol compared to women with non-detectable concentrations. Gestational urinary concentrations of certain phthalate and phthalate replacement metabolites were associated with lipid levels among these women.

The epidemiologic literature on associations between urinary phenol concentrations and lipid profiles during pregnancy is limited. We examined whether urinary concentrations of phenol and phenol replacement biomarkers were associated with serum lipid levels among pregnant women. This cross-sectional study included 175 women attending the Massachusetts General Hospital Fertility Center who enrolled in the Environment and Reproductive Health (EARTH) Study between 2005 and 2017 and had data available on urinary phenol biomarkers and serum lipids during pregnancy. We used linear regression models to assess the relationship between groups of urinary phenol and phenol replacement biomarkers and serum lipid levels [total cholesterol, high density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL) cholesterol, and triglycerides], while adjusting for age at sample collection, pre-pregnancy BMI, education, race, infertility diagnosis, cycle type, number of fetuses, trimester and specific gravity. In adjusted models, pregnant women with urinary propylparaben concentrations in the highest tertile had 10% [22 (95% CI = 5, 40) mg/dL], 12% [19 (95% CI = 2, 36) mg/dL] and 16% [19 (95% CI = 3, 35) mg/dL] higher mean total, non-HDL and LDL cholesterol, respectively, compared to women with concentrations in the lowest tertile. Similar elevations were observed for urinary bisphenol A concentrations. Urinary bisphenol S, benzophenone-3, triclosan, methylparaben, ethylparaben, and butylparaben were unrelated to serum lipids. Among pregnant women, urinary concentrations of bisphenol A and propylparaben were associated with higher serum levels of total, non-HDL and LDL cholesterol.

OBJECTIVES: To quantify adequacy of personal protective equipment (PPE) for U.S. healthcare personnel (HCP) at the outset of the COVID-19 pandemic and its association with infection risk. METHODS: March-May 2020 survey of the national Nurses' Health Studies and the Growing Up Today study regarding self-reported PPE access, use and reuse. COVID-19 endpoints included SARS-CoV-2 tests and COVID-19 status predicted from symptoms. RESULTS: Nearly 22% of 22,232 frontline HCP interacting with COVID-19 patients reported sometimes or always lacking PPE. Fifty percent of HCP reported not needing respirators, including 13% of those working in COVID-19 units. Lack of PPE was cross-sectionally associated with two-fold or greater odds of COVID-19 among those who interacted with infected patients. CONCLUSION: These data show the need to improve the U.S. infection prevention culture of safety when confronting a novel pathogen.

OBJECTIVES: To examine the association of occupational exposure to high-level disinfectants (HLDs) with risk of miscarriage among nurses. METHODS: Our study included women who enrolled in the Nurses' Health Study 3 (2010-2020) and had at least one pregnancy during follow-up. Occupational exposure to HLDs was self-reported at baseline. Every 6 months, a follow-up questionnaire was sent to participants asking for detailed information on pregnancies. We used a discrete-time Cox model to calculate the HRs and 95% CIs of miscarriage according to exposure to HLDs. RESULTS: Our study included 2579 nurses with a median of 5.6 years of follow-up (range: 1-9 years), and we documented 768 (19%) cases of miscarriage among 3974 pregnancies. Compared with women with no HLD exposure, the HRs of miscarriage were 1.08 (95% CI: 0.87 to 1.34) for past users and 0.84 (95% CI: 0.68 to 1.04) for HLD users. Compared with women with no HLD exposure, duration, frequency, and type of HLD and use of exposure controls were not associated with risk of miscarriage. When restricting to pregnancies that occurred within 12 months of HLD use, occupational exposure to unspecified types of HLD was significantly associated with higher risk of miscarriage (HR=1.78; 95% CI: 1.08 to 2.93). CONCLUSIONS: We observed no associations between occupational use of HLDs and miscarriage, except when we restricted to pregnancies occurring within 12 months of assessed baseline exposure. Given the observational design and limited sample size, results should be interpreted cautiously.

BACKGROUND: Diet is thought to account for most adult human exposure to per- and polyfluoroalkyl substances (PFAS). Children are particularly vulnerable to adverse health effects of PFAS and may have different eating habits than adults. However, studies of dietary patterns and PFAS in children are limited. METHODS: We studied 548 Boston-area children with food frequency questionnaire data (89 food items) in early childhood (median age 3.3 years) and plasma concentrations of 6 PFAS quantified in mid-childhood (median age 7.7 years). We used univariate linear regression to examine associations between each food item and PFAS, accounting for multiple comparisons. We next used reduced rank regression (RRR) to estimate overall percent variation in PFAS explained by diet and identify dietary patterns most correlated with PFAS. All models were adjusted for race/ethnicity, maternal education, and household income. RESULTS: In univariate analyses, 2-(N-methyl-perfluorooctane sulfonamide) acetate (MeFOSAA) plasma concentrations were 17.8% (95% CI: 7.2, 29.5) and 17.0% (95% CI: 6.4, 28.7) higher per SD increment in intake of ice cream and soda, respectively. RRR identified 6 dietary patterns that together explained 18% variation in the plasma concentrations of the 6 PFAS, of which 50% was explained by a dietary pattern consisting of primarily packaged foods (including ice cream and soda) and fish. Children with higher intake of the packaged foods and fish dietary pattern had higher plasma concentrations of all PFAS, particularly MeFOSAA and PFOS. CONCLUSIONS: Our analysis examined food intake in association with several PFAS in children and identified dietary determinants that may be sources of PFAS exposure or reflect correlated lifestyle or toxicokinetic factors. Further investigation may help inform measures to modify childhood PFAS exposure.

OBJECTIVES: Occupational use of disinfectants among healthcare workers has been associated with asthma. However, most studies are cross-sectional, and longitudinal studies are not entirely consistent. To limit the healthy worker effect, it is important to conduct studies among early- to mid-career workers. We investigated the prospective association between use of disinfectants and asthma incidence in a large cohort of early- to mid-career female nurses. METHODS: The Nurses' Health Study 3 is an ongoing, prospective, internet-based cohort of female nurses in the USA and Canada (2010-present). Analyses included 17 280 participants without a history of asthma at study entry (mean age: 34 years) and who had completed ≥1 follow-up questionnaire (sent every 6 months). Occupational use of high-level disinfectants (HLDs) was evaluated by questionnaire. We examined the association between HLD use and asthma development, adjusted for age, race, ethnicity, smoking status and body mass index. RESULTS: During 67 392 person-years of follow-up, 391 nurses reported incident clinician-diagnosed asthma. Compared with nurses who reported ≤5 years of HLD use (89%), those with >5 years of HLD use (11%) had increased risk of incident asthma (adjusted HR (95% CI), 1.39 (1.04 to 1.86)). The risk of incident asthma was elevated but not statistically significant in those reporting >5 years of HLD use and current use of ≥2 products (1.72 (0.88 to 3.34)); asthma risk was significantly elevated in women with >5 years of HLD use but no current use (1.46 (1.00 to 2.12)). CONCLUSIONS: Occupational use of HLDs was prospectively associated with increased asthma incidence in early- to mid-career nurses.

BACKGROUND: Few epidemiologic studies have evaluated the impact of paternal environmental exposures, particularly as mixtures, on couples' pregnancy outcomes. OBJECTIVE: We investigated whether mixtures of paternal urinary bisphenol A (BPA), paraben, and phthalates were associated with pregnancy outcomes among couples attending a fertility center. METHODS: We included 210 couples undergoing 300 in vitro fertilization (IVF) between 2004 and 2017 in this prospective analysis. We quantified paternal urinary biomarker concentrations in one sample per cycle using isotope-dilution tandem mass spectrometry. We used principal component analysis (PCA) to identify correlations of biomarker concentrations and multivariable Cox proportional hazards models for discrete survival time to estimate the hazard ratios (HRs) and 95% CIs for the associations between PCA-derived factor scores and probability of failing to achieve a live birth. Interactions were also included in the models to examine strength of associations over three vulnerable periods [embryo transfer to implantation, implantation to clinical pregnancy, and clinical pregnancy to live birth]. Models were adjusted for paternal and maternal ages and body mass indexes, urinary dilution (specific gravity) and year of collection, infertility diagnosis, and other PCA factor scores. Sensitivity analyses with further adjustment for maternal PCA factor scores were performed. RESULTS: We identified three factors, representing di-2-ethylhexyl phthalate (DEHP) metabolites, BPA and non-DEHP metabolites, and parabens, accounting for 56%, 15% and 10%, respectively, of the total variance explained. An interquartile range (25th and 75th percentiles) increase in the DEHP-related factor score was associated with elevated probability of failing prior to live birth (HR = 1.41, 95% CI: 1.08, 1.81) and the association was stronger between implantation and clinical pregnancy as well as between clinical pregnancy and live birth compared to before implantation. The overall HRs of failure for the BPA/non-DEHP-related and paraben-related factor scores were HR = 1.24 (95% CI: 0.97, 1.59) and HR = 0.99 (95% CI: 0.80, 1.24). We found similar HRs when additionally adjusting for maternal PCA factor scores. CONCLUSION: Paternal mixtures of urinary concentrations of DEHP metabolites were related to higher infertility treatment failure.

OBJECTIVE: To examine the association between handling of antineoplastic drugs (AD), use of exposure controls, and risk of miscarriage. METHODS: Women in the Nurses' Health Study 3 self-reported AD administration and use of engineering controls (EC) and personal protective equipment (PPE) at baseline. Nurses who reported pregnancies after baseline were included in this analysis. We estimated the Hazard Ratio (HR) of miscarriage in relation to baseline AD handling using multivariable Cox proportional regression modified for discrete time data. RESULTS: 2,440 nurses reported 3,327 pregnancies within a median of 3 years after baseline (range:1-8 years), of which 550 (17%) ended as miscarriages. Mean (standard deviation) age at baseline was 29.7 years (4.3). At baseline, 12% of the nurses self-reported currently handling AD and 28% previously handling. Compared to nurses who never handled AD, nurses who handled AD at baseline had a HR of miscarriage of 1.26 (95% CI: 0.97, 1.64) after adjusting for age, body mass index, and smoking. This association was stronger for losses after 12 weeks gestation (HR=2.39 [95% CI: 1.13, 5.07]), and among nurses who did not always use EC and PPE. Nurses who did not always use gloves had a HR of 1.51 (95% CI:0.91, 2.51) compared to 1.19 (95% CI:0.89, 1.60) for those always using gloves; nurses who did not always use gowns had a HR of 1.32 (95% CI:0.95, 1.83) compared to 1.19 (95% CI:0.81, 1.75) for nurses always using gowns. AD handling prior to baseline was unrelated to risk of miscarriage. CONCLUSION(S): We observed a suggestive positive association between AD handling and miscarriage, particularly among nurses who did not consistently use PPE and EC. These associations appeared to be more evident among second trimester losses.

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 (fT4, TT4) and triiodothyronine (fT3, TT3), 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 fT4, TT4, fT3, and TT3 [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<0.0001; and absolute difference: -0.21; 95% CI: -0.32, -0.10; p=0.003, respectively]. Using BKMR, we observed that mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was the primary contributor to these negative associations. DEHP and non-DEHP factor scores were not associated with serum TSH, TgAb, or TPOAb. 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.

BACKGROUND: Bisphenol S (BPS) was introduced in the market as a potentially safer alternative to bisphenol A (BPA). However, there are limited studies on health effects of BPS and no epidemiologic studies on its relationship with male reproductive health outcomes, specifically semen quality. OBJECTIVE: To investigate predictors of urinary BPS concentrations and its association with semen parameters among men attending a fertility center. METHODS: This cross-sectional analysis included 158 men of couples seeking fertility treatment (2011-2017) contributing 338 paired semen and urine samples. At the time of sample collection, men completed a questionnaire on self-reported use of household products and food intake within the previous 24h. Urinary concentrations of BPA, BPS and bisphenol F were quantified using isotope-dilution tandem mass spectrometry. Semen samples were analyzed following WHO guidelines. Multivariable mixed models were used to investigate predictors of urinary BPS concentrations and to evaluate associations between urinary BPS concentrations and semen parameters, using random intercept to account for correlation in outcomes across multiple observations per man and adjusting for abstinence time, specific gravity, age, body mass index (BMI), year of sample collection and BPA concentrations. Analyses were also stratified by BMI (>/=25 vs <25kg/m(2)). RESULTS: Median (IQR) urinary BPS concentration was 0.30 (0.20, 0.90) mug/L, and 76% of samples had detectable (>0.1mug/L) concentrations. Self-reported fabric softener and paint/solvent use as well as intake of beef and cheese within 24h before urine collection were positively associated with BPS concentrations. Men with higher BPS concentrations also had significantly higher BMI. Lower semen parameters were found among men with detectable BPS concentrations, compared to men with non-detectable BPS [2.66 vs. 2.91mL for volume (p=0.03), 30.7 vs. 38.3 mil/mL for concentration (p=0.03), 76.8 vs. 90.0 mil for total count (p=0.09), 43.7 vs. 47.0% for motility (p=0.06), and 5.42 vs. 6.77% for morphologically normal sperm (p=0.24)]. Some associations of BPS with lower semen parameters were only found among men with a BMI>/=25kg/m(2). CONCLUSIONS: We identified dietary and lifestyle factors associated with BPS exposure, suggesting potential avenues for reducing exposures. We also observed negative associations between BPS and semen parameters, especially among overweight and obese men.

BACKGROUND: We examined the association between the administration of antineoplastic drugs (AD) and fecundity among female nurses. METHODS: AD administration and use of exposure controls (EC) such as gloves, gowns, and needleless systems were self-reported at baseline among 2649 participants of the Nurses' Health Study 3, who were actively attempting pregnancy. Every 6 months thereafter, the nurses reported the current duration of their pregnancy attempt. Multivariable accelerated failure time models were used to estimate time ratios (TR) and 95% confidence intervals (CI) adjusted for age, race, body mass index, smoking, marital status, hours of work, and other occupational risk factors. RESULTS: Mean (standard deviation) age and BMI at baseline were 30.7 years (4.7) and 26.0 kg/m(2) (6.4). Forty-one percent of nurses reported ever administering AD; 30% only in the past and 11% currently. The former administration of AD (TR = 1.02, 95% CI, 0.93-1.12) was unrelated to the ongoing duration of pregnancy attempt. Among nurses currently administering AD, those who had administered AD for 6 years and above had a 27% (95% CI, 6%-53%) longer duration of pregnancy attempt than nurses who never handled ADs in unadjusted analyses. This difference disappeared in multivariable analyses (TR = 1.01, 95% CI, 0.85-1.21). 93% (n = 270) of the nurses currently administering ADs reported consistent use of EC. These nurses had a similar median duration of pregnancy attempt to those who never handled AD (TR = 1.00, 95% CI, 0.87-1.15). CONCLUSIONS: Administration of ADs did not appear to have an impact on fecundity in a cohort of nurses planning for pregnancy with a high prevalence of consistent ECs. Our results may not be generalizable to women who are less compliant with PPE use or with less availability to ECs. Therefore, it is possible that we did not observe an association between occupational exposure to AD and reduced fecundity because of lower exposure due to the more prevalent use of effective ECs.

Benzophenone-3 is used in a variety of cosmetic products as a sunscreen, and has shown weak estrogenic and antiandrogenic activity in animal and in vitro studies. Few studies have evaluated whether benzophenone-3 is associated with reproductive outcomes among women. We studied 304 women undergoing infertility treatment (2007-2017) in the prospective Environment and Reproductive Health cohort study and who underwent 449 treatment cycles (n=788 urines). Generalized linear mixed models were used with random intercepts to account for multiple cycles, and adjusting for confounders including physical activity. Analyses were also stratified by self-reported moderate/heavy outdoor work. The cycle-specific median (IQR) urinary benzophenone-3 concentration was 147 (58, 462) mcg/L, and 98% samples had detectable concentrations. Self-reported sunscreen use, physical activity, and time spent on moderate/heavy outdoor work were positively associated with urinary benzophenone-3. Adjusted probabilities of implantation, clinical pregnancy and live birth were higher in increasing quartiles of benzophenone-3, but these associations were restricted to women who reported spending time outdoors performing moderate/heavy work. Specifically, among these women, those in the highest quartile of benzophenone-3 concentrations had 51% higher implantation (p,trend=0.02), 68% higher clinical pregnancy (p,trend=0.01) and 75% higher live birth (p,trend=0.02) adjusted probabilities than women in the lowest quartile. Benzophenone-3 was unrelated to these outcomes among women who did not report doing moderate/heavy work outdoors. These results confirm that sunscreen use is a source of benzophenone-3 exposure, and show positive associations between benzophenone-3 and pregnancy outcomes, especially among women who reported engaging in outdoor work. Since these associations may be subject to important residual confounding by lifestyle factors, further research is needed to confirm these novel results in other populations, and to investigate whether other factors may be affecting the relation of benzophenone-3 with fertility and other health outcomes.

Findings from this cross-sectional study indicate a need for expanded training in safe handling practices. Background: Many antineoplastic (chemotherapeutic) drugs are known or probable human carcinogens, and many have been shown to be reproductive toxicants in cancer patients. Evidence from occupational exposure studies suggests that health care workers who have long-term, low-level occupational exposure to antineoplastic drugs have an increased risk of adverse reproductive outcomes. It's recommended that, at minimum, nurses who handle or administer such drugs should wear double gloves and a nonabsorbent gown to protect themselves. But it's unclear to what extent nurses do. PURPOSE: This study assessed glove and gown use by female pregnant and nonpregnant nurses who administer antineoplastic drugs in the United States and Canada. METHODS: We used data collected from more than 40,000 nurses participating in the Nurses' Health Study 3. The use of gloves and gowns and administration of antineoplastic drugs within the past month (among nonpregnant nurses) or within the first 20 weeks of pregnancy (among pregnant nurses) were self-reported via questionnaire. RESULTS: Administration of antineoplastic drugs at any time during their career was reported by 36% of nonpregnant nurses, including 27% who reported administering these drugs within the past month. Seven percent of pregnant nurses reported administering antineoplastic drugs during the first 20 weeks of pregnancy. Twelve percent of nonpregnant nurses and 9% of pregnant nurses indicated that they never wore gloves when administering antineoplastic drugs, and 42% of nonpregnant nurses and 38% of pregnant nurses reported never using a gown. The percentage of nonpregnant nurses who reported not wearing gloves varied by type of administration: 32% of those who administered antineoplastic drugs only as crushed pills never wore gloves, compared with 5% of those who administered such drugs only via infusion. CONCLUSIONS: Despite longstanding recommendations for the safe handling of antineoplastic and other hazardous drugs, many nurses-including those who are pregnant-reported not wearing protective gloves and gowns, which are considered the minimum protective equipment when administering such drugs. These findings underscore the need for further education and training to ensure that both employers and nurses understand the risks involved and know which precautionary measures will minimize such exposures.

Background: The Environment and Reproductive Health (EARTH) Study is an ongoing prospective preconception cohort designed to investigate the impact of environmental, nutritional, and lifestyle factors among both women and men on fertility and pregnancy outcomes. Methods: The EARTH Study recruits women 18 to 45 years and men 18 to 55 years seeking fertility evaluation and treatment at the Massachusetts General Hospital (MGH) Fertility Center, Boston, USA. Women and men are eligible to join either independently or as a couple. Participants are followed from study entry throughout each fertility treatment cycle, once per trimester of pregnancy (for those achieving pregnancy), and up to labor and delivery, or until they discontinue treatment or withdraw from the study. The study collects biological samples, self-reported questionnaire data (including a food frequency questionnaire) and clinically abstracted information. Results: As of June 2017, the study cohort included 799 women and 487 men (447 couples; 40 men joined without female partners). Women were on average 34.7 years old at time of enrolment and predominantly Caucasian (81%), educated (49% have a graduate degree), and nulliparous (83%). Men were on average 36.6 years at baseline and mostly Caucasian (86%) and never-smokers (67%). Conclusions: The EARTH Study is one of the few cohorts designed to examine multiple potentially critical windows of vulnerability, including the paternal and maternal preconception windows and the periconception and prenatal windows in pregnancy. It is also one of the few human studies that has assessed potential interactions between environmental exposures and dietary factors.

We developed a pesticide residue burden score (PRBS) based on a food frequency questionnaire and surveillance data on food pesticide residues to characterize dietary exposure over the past year. In the present study, we evaluated the association of the PRBS with urinary concentrations of pesticide biomarkers. Fruit and vegetable (FV) intake was classified as having high (PRBS≥4) or low (PRBS<4) pesticide residues for 90 men from the EARTH study. Two urine samples per man were analyzed for seven biomarkers of organophosphate and pyrethroid insecticides, and the herbicide 2,4-dichlorophenoxyacetic acid. We used generalized estimating equations to analyze the association of the PRBS with urinary concentrations of pesticide biomarkers. Urinary concentrations of pesticide biomarkers were positively related to high pesticide FV intake but inversely related to low pesticide FV intake. The molar sum of urinary concentrations of pesticide biomarkers was 21% (95% confidence interval (CI): 2%, 44%) higher for each one serving/day increase in high pesticide FV intake, and 10% (95% CI: 1%, 18%) lower for each one serving/day increase in low pesticide FV intake. Furthermore, intake of high pesticide FVs positively related to most individual urinary biomarkers. Our findings support the usefulness of the PRBS approach to characterize dietary exposure to select pesticides.Journal of Exposure Science and Environmental Epidemiology advance online publication, 20 September 2017; doi:10.1038/jes.2017.22.

Objective This study aimed to examine the relationship between occupational use of high-level disinfectants (HLD) and fecundity among female nurses. Methods Women currently employed outside the home and trying to get pregnant (N=1739) in the Nurses' Health Study 3 cohort (2010-2014) were included in this analysis. Occupational exposure to HLD used to disinfect medical instruments and use of protective equipment (PE) was self-reported on the baseline questionnaire. Every six months thereafter women reported the duration of their ongoing pregnancy attempt. Multivariable accelerated failure time models were used to estimate time ratios (TR) and 95% confidence intervals (95% CI). Results Nurses exposed to HLD prior to and at baseline had a 26% (95% CI 8-47%) and 12% (95% CI -2-28%) longer median duration of pregnancy attempt compared to nurses who were never exposed. Among nurses exposed at baseline to HLD, use of PE attenuated associations with fecundity impairments. Specifically, women using 0, 1, and ≥2 types of PE had 18% (95% CI -7-49%), 16% (95% -3-39%), and 0% (95% -22-28%) longer median durations of pregnancy attempt compared to women who were never exposed. While the use of PE varied greatly by type (9% for respiratory protection to 69% for protective gloves), use of each PE appeared to attenuate the associations of HLD exposure with reduced fecundity. Conclusion Occupational use of HLD is associated with reduced fecundity among nurses, but use of PE appears to attenuate this risk.

Experimental data in rodents suggest that the effects of bisphenol A (BPA) on oocyte development may be modified by dietary methyl donors. Whether the same interaction exists in humans is unknown. We evaluated whether intake of methyl donors modified the associations between urinary BPA concentrations and treatment outcomes among 178 women who underwent 248 IVF cycles at a fertility center in Boston between 2007 and 2012. Participants completed a validated food frequency questionnaire and provided up to two urine samples per treatment cycle. High urinary BPA concentrations were associated with a 66% lower probability of implantation (p=0.007) among women who consumed <400mug/day of food folate, but not among women consuming ≥400mug/day (21% higher probability of implantation, p=0.18) (p,interaction=0.04). A similar pattern was observed for probability of clinical pregnancy (p,interaction=0.07) and live birth (p,interaction=0.16). These results are consistent with previous animal data but further evaluation in other human populations is needed.

CONTEXT: Experimental data in rodents suggest that the adverse reproductive health effects of bisphenol A (BPA) can be modified by intake of soy phytoestrogens. Whether the same is true in humans is not known. OBJECTIVE: The purpose of this study was to evaluate whether soy consumption modifies the relation between urinary BPA levels and infertility treatment outcomes among women undergoing assisted reproduction. SETTING: The study was conducted in a fertility center in a teaching hospital. DESIGN: We evaluated 239 women enrolled between 2007 and 2012 in the Environment and Reproductive Health (EARTH) Study, a prospective cohort study, who underwent 347 in vitro fertilization (IVF) cycles. Participants completed a baseline questionnaire and provided up to 2 urine samples in each treatment cycle before oocyte retrieval. IVF outcomes were abstracted from electronic medical records. We used generalized linear mixed models with interaction terms to evaluate whether the association between urinary BPA concentrations and IVF outcomes was modified by soy intake. MAIN OUTCOME MEASURE: Live birth rates per initiated treatment cycle were measured. RESULTS: Soy food consumption modified the association of urinary BPA concentration with live birth rates (P for interaction = .01). Among women who did not consume soy foods, the adjusted live birth rates per initiated cycle in increasing quartiles of cycle-specific urinary BPA concentrations were 54%, 35%, 31%, and 17% (P for trend = .03). The corresponding live birth rates among women reporting pretreatment consumption of soy foods were 38%, 42%, 47%, and 49% (P for trend= 0.35). A similar pattern was found for implantation (P for interaction = .02) and clinical pregnancy rates (P for interaction = .03) per initiated cycle, where urinary BPA was inversely related to these outcomes among women not consuming soy foods but unrelated to them among soy consumers. CONCLUSION: Soy food intake may protect against the adverse reproductive effects of BPA. As these findings represent the first report suggesting a potential interaction between soy and BPA in humans, they should be further evaluated in other populations.

OBJECTIVES: To evaluate the association of work schedule and physical factors with fecundity. METHODS: Women currently employed outside the home and trying to get pregnant (n=1739) in the Nurses' Health Study 3 cohort (2010-2014) were included in this analysis. Work schedule and physical labour were self-reported on the baseline questionnaire, and every 6 months thereafter the women reported the duration of their ongoing pregnancy attempt. Multivariable accelerated failure time models were used to estimate time ratios (TR) and 95% CIs. RESULTS: Among the 1739 women (median age=33 years, 93% Caucasian) the estimated proportions of women not pregnant after 12 and 24 months were 16% and 5%, respectively. None of the various shift work patterns were associated with duration of pregnancy attempt (as a surrogate for fecundity). However, women working >40 h/week had a 20% (95% CI 7 to 35%) longer median duration of pregnancy attempt compared to women working 21-40 h/week (p-trend=0.005). Women whose work entailed heavy lifting or moving (ie, 25+ pounds) >15 times/day also had a longer median duration of pregnancy attempt (adjusted TR=1.49; 95% CI 1.20 to 1.85) compared to women who never lifted or moved heavy loads (p-trend=0.002). The association between heavy moving and lifting and duration of pregnancy attempt was more pronounced among overweight or obese women (body mass index, BMI<25: TR=1.17; 95% CI 0.88 to 1.56; BMI≥25: TR=2.03, 95% CI 1.48 to 2.79; p-interaction=0.007). CONCLUSIONS: Working greater than 40 h per week and greater frequency of lifting or moving a heavy load were associated with reduced fecundity in a cohort of nurses planning pregnancy.

STUDY QUESTION: Are urinary BPA concentrations associated with in vitro fertilization (IVF) outcomes among women attending an academic fertility center? SUMMARY ANSWER: Urinary BPA concentrations were not associated with adverse reproductive and pregnancy outcomes among women from a fertility clinic. WHAT IS KNOWN ALREADY: Bisphenol A (BPA), an endocrine disruptor, is detected in the urine of most Americans. Although animal studies have demonstrated that BPA reduces female fertility through effects on the ovarian follicle and uterus, data from human populations are scarce and equivocal. STUDY DESIGN, SIZE AND DURATION: This prospective cohort study between 2004 and 2012 at the Massachusetts General Hospital Fertility Center included 256 women (n = 375 IVF cycles) who provided up to two urine samples prior to oocyte retrieval (total N = 673). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Study participants were women enrolled in the Environment and Reproductive Health (EARTH) Study. Intermediate and clinical end-points of IVF treatments were abstracted from electronic medical records. We used generalized linear mixed models with random intercepts to evaluate the association between urinary BPA concentrations and IVF outcomes adjusted by age, race, body mass index, smoking status and infertility diagnosis. MAIN RESULTS AND THE ROLE OF CHANCE: The specific gravity-adjusted geometric mean of BPA was 1.87 microg/l, which is comparable to that for female participants in the National Health and Nutrition Examination Survey, 2011-2012. Urinary BPA concentrations were not associated with endometrial wall thickness, peak estradiol levels, proportion of high quality embryos or fertilization rates. Furthermore, there were no associations between urinary BPA concentrations and implantation, clinical pregnancy or live birth rates per initiated cycle or per embryo transfer. Although we did not find any associations between urinary BPA concentrations and IVF outcomes, the relation between BPA and endometrial wall thickness was modified by age. Younger women (<37 years old) had thicker endometrial thickness across increasing quartiles of urinary BPA concentrations, while older women (≥37 years old) had thinner endometrial thickness across increasing quartiles of urinary BPA concentrations. LIMITATIONS, REASONS FOR CAUTION: Limitations to this study include a possible misclassification of BPA exposure and difficulties in extrapolating the findings to the general population. WIDER IMPLICATIONS OF THE FINDINGS: Data on the relation between urinary BPA concentrations and reproductive outcomes remain scarce and additional research is needed to clarify its role in human reproduction. STUDY FUNDING/COMPETING INTERESTS: This work was supported by NIH grants R01ES022955, R01ES009718 and R01ES000002 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32DK00770316 from the National Institute of Child Health and Human Development (NICHD). None of the authors has any conflicts of interest to declare. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

OBJECTIVES: The relationship between job strain and weight gain has been unclear, especially for women. Using data from over 52 000 working women, we compare the association between change in job strain and change in BMI across different levels of baseline BMI. SUBJECTS/METHODS: We used data from participants in the Nurses' Health Study II (n=52 656, mean age=38.4), an ongoing prospective cohort study. Using linear regression, we modeled the change in BMI over 4 years as a function of the change in job strain, baseline BMI, and the interaction between the two. Change in job strain was characterized in four categories combining baseline and follow-up levels: consistently low strain [low at both points], decreased strain [high strain at baseline only], increased strain [high strain at follow-up only], and consistently high strain [high at both points]. Age, race/ethnicity, pregnancy history, job types, and health behaviors at baseline were controlled for in the model. RESULTS: In adjusted models, women who reported high job strain at least once during the four-year period had a greater increase in BMI (DeltaBMI=0.06-0.12, P<0.05) than those who never reported high job strain. The association between the change in job strain exposure and the change in BMI depended on the baseline BMI level (P=0.015 for the interaction): the greater the baseline BMI, the greater the BMI gain associated with consistently high job strain. The BMI gain associated with increased or decreased job strain was uniform across the range of baseline BMI. CONCLUSIONS: Women with higher BMI may be more vulnerable to BMI gain when exposed to constant work stress. Future research focusing on mediating mechanisms between job strain and BMI change should explore the possibility of differential responses to job strain by initial BMI.

OBJECTIVES: This study aimed to evaluate occupational exposures and menstrual cycle characteristics among nurses. METHODS: Using cross-sectional data collected in 2010-2012 from 6309 nurses aged 21-45 years, we investigated nurses' menstrual function in the Nurses' Health Study 3. We used multivariable regression modeling to analyze the associations between occupational exposures and prevalence of irregular cycles and long and short cycle lengths. RESULTS: The cohort reported cycle length as <21 (1.5%), 21-25 (15.6%), 26-31 (69.7%), and 32-50 (13.2%) days. In addition, 19% of participants reported irregular cycles. Working ≥41 hours/week was associated with a 16% [95% confidence interval (95% CI): 4-29%] higher prevalence of irregular cycles and a higher prevalence of very short (<21-day) cycles [prevalence odds ratio (OR) 1.93, 95% CI 1.24-3.01] in adjusted models. Irregular menstrual cycles were more prevalent among women working nights only (32% higher; 95% CI 15-51%) or rotating nights (27% higher, 95% CI 10-47%), and was associated with the number of night shifts per month (P for trend <0.0001). Rotating night schedule was associated with long (32-50 day) cycles (OR 1.28, 95% CI 1.03-1.61). Heavy lifting was associated with a higher prevalence of irregular cycles (34% higher), and the prevalence of cycles <21 days and 21-25 day cycles increased with increasing heavy lifting at work (P for trend <0.02 for each endpoint). CONCLUSION: Night work, long hours, and physically demanding work might relate to menstrual disturbances.