BACKGROUND: Phthalates are endocrine-disrupting chemicals that can dysregulate hormonal systems supporting female sexual function (eg, estrogen interference). Female sexual function is important for positive sexual expression, fertility, and well-being but remains understudied in the context of environmental toxicants to which females are ubiquitously exposed. Identifying environmental determinants of female sexual dysfunction can inform exposure-reduction strategies and clinical practice to improve sexual health. AIM: We investigated associations between phthalate exposure and sexual function in a cohort of North American females. METHODS: We leveraged cross-sectional data from a subset of 21-45-year-old females trying to conceive enrolled in Pregnancy Study Online (n = 347) to assess associations between phthalate and phthalate alternative exposure and sexual function, measured on a modified version of the Female Sexual Function Index-6 (FSFI-6). We summed FSFI-6 responses (range = 2-30); lower scores reflected poorer function. We measured urinary concentrations of 18 phthalate and alternative metabolites using online solid phase extraction coupled with high-performance liquid chromatography isotope dilution tandem mass spectrometry. Given that the biomarkers were nonlinearly associated with FSFI-6 scores, we categorized creatinine-corrected biomarker concentrations in tertiles. We used multivariable linear regression to estimate mean differences (beta) with 95% confidence intervals (CIs) in FSFI-6 scores per tertile increase in biomarker concentrations, adjusting for hypothesized confounders. In secondary analyses, we considered individual FSFI-6 items (range = 1-5) as outcome variables. OUTCOMES: Female sexual function measured on the FSFI-6. RESULTS: Most biomarkers were not associated with FSFI-6 scores. Mono-n-butyl phthalate concentrations were weakly and non-monotonically associated with lower summed FSFI-6 scores (beta = -0.8, 95% CI = -1.8, 0.2) and orgasm scores (beta = -0.3, 95% CI = -0.7, 0.1) at the second (vs first) tertile, reflecting poorer sexual function. Mono-2-ethyl-5-carboxypentyl terephthalate concentrations were weakly associated with poorer scores for orgasm, while other biomarkers (notably, mono-carboxyisononyl phthalate) were associated with higher summed FSFI-6 and FSFI-6 item scores. CLINICAL IMPLICATIONS: Exposure to phthalates should be considered in clinical settings, particularly for females experiencing issues with sexual function. STRENGTHS AND LIMITATIONS: This study represents one of the first to assess associations of phthalate exposure and female sexual function, and we investigated associations in an established cohort with a validated measure of sexual function. We were limited by our sample size and cross-sectional study design. CONCLUSION: Although associations for most phthalate biomarkers were null, some were weakly associated with female sexual function, suggesting exposure to certain chemicals may affect female sexual function with implications for clinical practice and exposure reduction strategies.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent, widespread environmental contaminants and some are endocrine-disrupting. Studies of gynecologic cancers are limited; we evaluated ovarian cancer, a rare, often fatal malignancy. METHODS: This nested case-control study included 318 ovarian cancer cases and 472 individually matched female controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which recruited participants aged 55-74 years from 10 U.S. study centers (1993-2001). We ascertained cases through 2016 and quantitated eight PFAS in prediagnostic serum samples. We estimated ORs and 95% CIs for continuous (log2-transformed) and categorized PFAS concentrations via conditional logistic regression models implicitly adjusting for matching factors (age, center, randomization year, year of blood draw, race and ethnicity) and adjusted for smoking, body mass index, family history of cancer, menopausal hormone therapy and oral contraceptive use, parity, and number of freeze-thaws. RESULTS: We found a positive association with ovarian cancer for a doubling in 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA) concentrations (ORperlog2=1.24, CI = 1.03-1.49) and 62% greater risk among those in the highest quartile (ORQ4vsQ1=1.62, CI = 1.03-2.54; p-trend = 0.02). Perfluorooctane sulfonic acid (PFOS) was associated with increased risk (ORperlog2=1.47, CI = 1.05-2.06) with no quartile trend (p-trend = 0.79). Associations with perfluorononanoic (ORperlog2=1.36, CI = 0.95-1.95) and perfluorodecanoic acid (ORperlog2=1.35, CI = 0.94-1.95) were suggested, with non-monotonic quartile trends (p-trend = 0.12-0.21). MeFOSAA associations were strongest in women aged 55-59 (ORperlog2=1.60, CI = 1.13-2.27), more moderate in those 60-64 (ORperlog2=1.31, CI = 0.90-1.90) and null among women 65 + (ORperlog2=1.02, CI = 0.73-1.43; p-heterogeneity = 0.22). Associations persisted in cases diagnosed ≥8 years after blood collection. CONCLUSIONS: These findings offer novel evidence for PFAS as ovarian cancer risk factors, particularly PFOS and MeFOSAA, a PFOS precursor.

Exposure to phthalates is common and difficult to avoid. However, intake of long-chain n-3 polyunsaturated fatty acids (n3PUFAs) may ameliorate negative effects on ovarian reserve by exposure to phthalates as both are involved in key processes of ovarian function. Among 139 women attending a fertility center in the Environment and Reproductive Health (EARTH) Study (2004-2017), we evaluated whether associations between urinary phthalate biomarkers and antral follicle count (AFC) were modified by tertiles of serum α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We used Poisson regression (for individual phthalate biomarkers) and quantile Q-computation (for mixtures) models adjusted for age, body mass index, prior smoking, number of urine samples and urinary specific gravity. We found that serum EPA + DHA levels modified the negative association of urinary phthalate biomarkers mixture with mean AFC (P for interaction = 0.23); sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP) had the strongest effect modification (P interaction = 0.01). Specifically, phthalate biomarkers mixture and ∑DEHP were inversely related with AFC only among women in the low (P trend = 0.03 and < 0.001, respectively) and middle (P trend = 0.07 and 0.002) tertiles of serum EPA + DHA, but not among women in the high tertile (P trend = 0.56 and 0.93). No effect modifications were found by serum ALA. These findings suggest certain serum n3PUFAs may attenuate effects of phthalate exposure on ovarian reserve marker. Such interaction points toward select n3PUFAs as key modifiers of phthalate toxicity on ovarian health with potential implications for other women's reproductive health endpoints.

BACKGROUND: Evidence on the association between maternal phenol exposure and inflammation during pregnancy is limited and inconsistent. OBJECTIVE: To evaluate associations between urinary phenol biomarkers and serum inflammatory cytokines across pregnancy, and to examine whether associations vary by trimesters. METHODS: We included 175 pregnant women from the Massachusetts General Hospital Fertility Center and participating in the Environment and Reproductive Health (EARTH) Study (2005-2017), with available data on urinary concentrations of eight phenol biomarkers and serum inflammatory biomarkers, high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). Linear regression models were employed to assess the association between individual phenol biomarker concentrations and log-transformed inflammatory cytokine levels, while Bayesian Kernel Machine Regression (BKMR) models were utilized to evaluate phenol biomarker mixtures. Analyses were further stratified by the trimester of sample collection. RESULTS: Overall, detectable urinary ethylparaben was positively associated with serum hsCRP (β: 0.464; 95 % CI: 0.012, 0.917). In trimester-specific analyses, urinary butylparaben was positively associated with hsCRP (β: 0.533; 95 % CI: 0.006, 1.059) in the first trimester, but negatively associated with IL-6 (β: -0.613; 95 % CI: -1.062, -0.164) in the second trimester. Urinary bisphenol A was inversely associated with hsCRP (β: -0.428; 95 % CI: -0.731, -0.125) in the third trimester. CONCLUSIONS: Our findings suggest that exposure to certain phenols may disrupt inflammatory profiles in pregnancy, with effects varying by trimesters. These novel associations underscore the importance of exposure timing when assessing environmental risk factors for maternal and offspring health outcomes.

BACKGROUND: Folate plays a critical role during pregnancy, preventing neural tube defects and possibly adverse neurodevelopment. Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that may decrease folate levels. Although some studies have found associations between PFAS and folate, we are unaware of studies conducted in pregnant women. To address this knowledge gap, we evaluated associations between PFAS and whole blood folate (WBF) in pregnant women. METHODS: We used data from 288 pregnant women in the Health Outcomes and Measures of the Environment (HOME) Study, a pregnancy and birth cohort in the Cincinnati Ohio area. We measured eight serum PFAS and WBF concentrations at 16 weeks' gestation. We used linear regression to estimate the effect of each PFAS on WBF, and quantile-based g-computation and Bayesian kernel machine regression (BKMR) to investigate the joint effect of PFAS on WBF, adjusting for parity, prenatal vitamin intake, maternal race/ethnicity, household income, maternal age, and second trimester smoking status in all models. In addition, we investigated interactions between PFAS using BKMR. RESULTS: We did not observe inverse associations of individual PFAS or their mixture with WBF, nor interactions between PFAS in the BKMR model in pregnant women. CONCLUSION: Future studies could consider WBF measures in late pregnancy to evaluate other periods of susceptibility. Furthermore, as people are exposed to multiple PFAS, future studies should continue to consider joint PFAS exposure.

A nationwide cross-sectional study led by the Agency for Toxic Substances and Disease Registry in collaboration with research and community partners, was designed to investigate health outcomes linked to per- and polyfluoroalkyl substances (PFAS) exposure among residents of communities with contaminated drinking water. The objective was to describe the study design, methods, participant demographics, and PFAS serum concentrations. From 2019 to 2023, adult (18+) and child (ages 4-17) participants were recruited from communities with past or ongoing PFAS contamination of drinking water across eight sites in California, Colorado, Massachusetts, Michigan, New Hampshire, New York, New Jersey, and Pennsylvania. Data on demographics, lifestyle factors, and residential, occupational, and medical history were collected via questionnaires. Extensive clinical tests assessed cardiometabolic, liver, thyroid, kidney, glycemic, and immune parameters. Neurobehavioral tests were administered to children (ages 5-17). PFAS quantified in serum included MeFOSAA, PFHxS, PFOS, PFOA, PFNA, PFDA, and PFUnDA. Serum, whole blood, and urine samples were banked for future analyses. The study enrolled 5826 adults (geometric mean age: 53.6 years; 60.2 % female; 77.2 % non-Hispanic White) and 710 children (geometric mean age: 10.7 years; 48.5 % female; 69 % non-Hispanic White). Compared with NHANES data (2017-2020), adults showed elevated geometric mean concentrations of PFHxS and PFOA; only PFHxS was elevated in children. These serum concentrations reflect a wide range of PFAS exposures in communities affected by contamination from firefighting activities and industrial emissions, and other sources. This large study is a valuable resource for exploring associations between PFAS exposure and health effects in adults and children.

BACKGROUND: Few studies have evaluated the associations between phthalate exposures and maternal inflammation. OBJECTIVES: To examine cross-sectional associations of urinary phthalate metabolites, individually and as a mixture, with serum inflammatory biomarkers during pregnancy. METHODS: A total of 175 pregnant women enrolled in the Environment and Reproductive Health (EARTH) Study between 2005 and 2017 were included. Concentrations of 11 urinary phthalate metabolites and two serum inflammatory biomarkers, including C-reactive protein (CRP) and interleukin-6 (IL-6), were measured. Urinary concentrations of phthalate metabolites were adjusted for specific gravity (SG) before analysis. Linear regression and Bayesian Kernel Machine Regression models were used to examine the associations for individual phthalates and their mixture, respectively. Stratified analyses by pre-pregnancy body mass index (BMI) were also conducted. RESULTS: No association for urinary phthalate metabolites, individually or as a mixture, was observed with serum CRP overall among pregnant women. Urinary mono-3-carboxypropyl phthalate and monocarboxyisooctyl phthalate were positively associated with serum IL-6 (β [95 % CI] per 1-SD increase in log-transformed, SG-adjusted concentrations: 0.09 [0.01, 0.16] and 0.09 [0.02, 0.17], respectively). Besides, urinary mono-isobutyl phthalate was positively associated with serum IL-6 among women with a pre-pregnancy BMI ≥25 kg/m(2) (β [95 % CI] per 1-SD increase: 0.15 [0.00, 0.30]), but not with lower BMI (-0.03 [-0.12, 0.07]). A suggestive positive association between phthalate mixture and serum IL-6 was observed in the high pre-pregnancy BMI group. CONCLUSIONS: Our findings suggest that women with a higher pre-pregnancy BMI may be more vulnerable to the effects of certain phthalates on maternal inflammation reflected by IL-6.

The occupation of firefighting is classified as a Group 1 carcinogen. Increased cancer risk among firefighters may be partly attributable to increased occupational exposure to a range of chemicals, including per- and polyfluoroalkyl substances (PFAS). Some PFAS are known and suspect human carcinogens. Investigating epigenetic response to these PFAS exposures in firefighters may help to identify biological pathways of specific cancers, and previously unidentified health outcomes that are associated with PFAS. We therefore investigated the associations of serum PFAS concentrations with miRNA expression in firefighters. Serum samples collected from 303 firefighters from 6 sites across the USA were analyzed for 9 PFAS along with miRNA expression. Covariate-adjusted linear regression was used to estimate associations between log PFAS and miRNA expression, with false discovery rate (FDR) set to 0.05 for significance, and an exploratory cutoff of FDR q<0.20. Gene set enrichment analysis (GSEA) was performed using miRTarBase's miRWalk pathways. Age, race-ethnicity, BMI, fire department, and sex were controlled for in all models. At FDR<0.05, the linear isomer of perfluorooctane sulfonic acid (PFOS) was inversely associated with miR-128-1-5p expression (Beta = -0.146, 95% CI -0.216, -0.076). At a relaxed FDR of 0.20, we observed inverse associations for the sum of branched isomers of PFOS (Sm-PFOS) with 5 miRNAs (let-7d-5p, let-7a-5p, miR-423-5p, let-7b-5p, miR-629-5p). Several pathways were enriched for multiple PFAS, including those correlated with certain cancers, blood diseases, thyroid disorders, autoimmune disorders, and neurological outcomes. Some PFAS in firefighters were found to be associated with alteration of miRNA consistent with increased risk for a range of chronic diseases.

Exposure to endocrine-disrupting chemicals such as phthalates may increase risk of hypertensive disorders of pregnancy (HDP). Prior studies lack investigation of chemical mixtures, phthalate replacements, or key periods of susceptibility including early pregnancy. In the present study, we used a longitudinal approach to evaluate gestational exposure to phthalates and replacements, as both single-pollutants and mixtures, in association with blood pressure and diagnosis of preeclampsia or any HDP. The Human Placenta and Phthalates prospective pregnancy cohort includes 291 participants recruited from two U.S. clinics. Urinary metabolites of ten phthalates and replacements were quantified at up to 8 time points per individual and averaged to create early (12-15 weeks) and overall (12-38 weeks) pregnancy exposure biomarkers. We collected data on gestational blood pressure (mean = 6.2 measures per participant) and diagnosis of preeclampsia (n = 26 cases) or any HDP (n = 44 cases). Linear mixed effects models estimated associations between exposure biomarkers and repeated blood pressure measures. We estimated exposure biomarker associations with preeclampsia and HDP using Cox proportional hazards or logistic regression models, respectively. Quantile g-computation was used to estimate joint effects of a phthalate or replacement mixture with each outcome. Early pregnancy exposure biomarkers demonstrated greater associations with adverse outcomes compared to overall pregnancy. A one-interquartile range increase in early pregnancy di-isononyl phthalate metabolites (ƩDiNP) was associated with a 1.13 mmHg (95 % confidence interval [CI]: 0.25, 2.37) and 0.90 mmHg (CI: 0.16, 1.65) increase in systolic and diastolic blood pressure, respectively. We also found positive but nonsignificant associations of early pregnancy mono-3-carboxypropyl phthalate, di-2-ethylhexyl terephthalate metabolites, and the high molecular weight phthalate mixture with blood pressure. Early pregnancy ƩDiNP was furthermore associated with increased odds of HDP (odds ratio: 1.37, CI: 1.03, 1.82), but not preeclampsia. In sum, early gestational exposure to DiNP and other high molecular weight phthalates may contribute to HDP.

BACKGROUND: Phthalate exposures are ubiquitous and have been associated with pregnancy complications. Interaction between serum long-chain n-3 polyunsaturated fatty acids (n3PUFA) and phthalate biomarkers is biologically plausible because both can bind to human peroxisome proliferator-activated receptors (PPARs) which are involved in placenta development. However, evidence of this interaction in humans is lacking. OBJECTIVE: To evaluate whether serum n3PUFA modifies the associations of biomarkers of phthalate exposure on pregnancy outcomes. METHODS: Among 351 women undergoing in vitro fertilization in the Environment and Reproductive Health study (2004-2017), we evaluated the effect modification of eicosapentaenoic acid (EPA) and serum docosahexaenoic acid (DHA) on the association of pregnancy outcomes with the mixture of urinary concentrations of phthalate biomarkers by quantile g-computation. All models were adjusted for age, body mass index, prior smoking, infertility diagnosis, treatment year, and urinary specific gravity. RESULTS: Concentrations of the phthalate biomarkers mixture were associated with higher adjusted probabilities of pregnancy loss and lower estimated probabilities of live birth among women with serum EPA+DHA in the lowest tertile (< 2.66% of total fatty acids), but not among women with middle-to-high serum EPA+DHA (p interactions = 0.06 and 0.15, respectively). Among women in the lowest tertile of serum EPA+DHA, the adjusted probability [95% confidence interval (CI)] of pregnancy loss for women in the lowest and highest quartile of phthalates mixtures was 5% (2%, 16%) and 44% (23%, 85%), respectively (p trend = 0.01). The corresponding estimates were 14% (5%, 41%) and 11% (3%, 42%) among women with serum EPA+DHA in the highest tertile (⩾ 3.78% of total fatty acids) (p trend = 0.81). Similar trends were observed for live birth but not for implantation and clinical pregnancy. CONCLUSIONS: This study suggests adverse effects of phthalate exposure on pregnancy loss and live birth may be attenuated by intakes of n3PUFA. These results, if replicated, could inform clinical practice reducing the burden of infertility by phthalate exposure among the general population and improving pregnancy outcomes among subfertile couples.. https://doi.org/10.1289/EHP15942.

OBJECTIVE: To examine the joint associations of plasma concentrations of prenatal per- and polyfluoroalkyl substances (PFAS) mixtures with birth size and postnatal anthropometry measures. MATERIAL AND METHODS: The current study included 641 mother-child dyads from the New Hampshire Birth Cohort Study. PFAS concentrations were quantified in maternal plasma samples collected during pregnancy (median: 28 weeks of gestation). Information on infant weight and length were abstracted from medical records and converted to sex- and age-standardized weight-for-length z-score according to the World Health Organization standard curves. Bayesian kernel machine regression (BKMR) was used to investigate the joint associations of multiple PFAS concentrations during pregnancy with weight-for-length z score at birth, 6-months, and 12-months. To account for longitudinal outcomes, we also fit linear mixed effect models between PFAS exposure burden score, a novel method to quantify total exposure burden to PFAS mixtures, and changes in weight-for-length from birth to 12 months of age. A multiplicative interaction term ("PFAS burden score × time [birth as a reference, 6 months, and 12 months of age]") was included to evaluate a potential time-varying relationship. All models were adjusted for maternal age, education, marital status, parity, smoking, seafood consumption, pre-pregnancy body mass index, and gestational week of blood draw. RESULTS: In BKMR models, all 95 % credible intervals included the null value. In linear mixed effects models, PFAS exposure burden score was associated with a lower weight-for-length z-score (β = -0.20; 95 % confidence interval = -0.35, -0.04). The multiplicative interaction term was significant at both 6 and 12 months of age (P < 0.01 for both time points), particularly among female infants, suggesting a shift toward positive associations between the prenatal PFAS mixtures and weight-for-length z-score during infancy. CONCLUSIONS: Prenatal PFAS mixtures may affect fetal and infant anthropometry measures differently by life stage and biological sex.

Parabens are widely used preservatives with endocrine-disrupting properties, but their role in glucose metabolism during pregnancy is unclear. This study examines prospective associations between urinary concentrations of four parabens in early and mid-pregnancy and gestational diabetes (GDM). A matched case-control study nested within a diverse longitudinal pregnancy cohort (PETALS) with universal GDM screening matched GDM cases to two controls (111 cases; 222 controls). Urine samples collected 2015-2017 in early (14 ± 2.3 weeks) and mid-pregnancy (20 ± 2.4 weeks) were analyzed for paraben concentrations with mass spectrometry. Area-under-the-time-concentration-curve (AUC) assessed cumulative exposure. Conditional logistic regression models evaluated associations between paraben concentrations and GDM, adjusting for covariates. We a priori examined effect modification by Asian/Pacific Islander (A/PI) race/ethnicity due to the case-control matching and GDM prevalence highest among A/PI. Participants were 31 ± 5 years old and 40 % A/PI, 33 % Hispanic, 14 % White and 9 % Black. Methylparaben and propylparaben had >94 % detection, while ethylparaben and butylparaben ranged from 22 %-51 %. Paraben exposure was not associated with GDM overall. Among A/PI, higher methylparaben concentrations exhibited higher odds of GDM: early-pregnancy OR 1.14 per IQR (95 % CI: 0.89,1.45) and AUC 1.07 (0.89,1.30) compared to non-A/PI (early-pregnancy 0.81 [0.62,1.06] and AUC 0.70 [0.44,1.12]; P(interaction) = 0.01 and 0.03, respectively). A/PI mid-pregnancy ethylparaben exposure (detectable vs non-detectable) was linked to higher GDM odds (2.00 [0.84,4.76] vs. non-A/PI 0.47 [0.17,1.27]; P(interaction) = 0.04) as was mid-pregnancy propylparaben exposure (Tertile 2 vs. 1: 3.67 [1.21,11.1] vs. non-A/PI 0.70 [0.22, 2.25]; P(interaction) = 0.04). Although overall paraben exposure was not associated with GDM, interactions by A/PI race/ethnicity suggested potential increased odds of GDM related to propylparaben, methylparaben, and ethylparaben exposure. Future studies should explore paraben exposure in diverse populations.

BACKGROUND: Phthalate exposure during pregnancy has been associated with preterm birth, but mechanisms of action may depend on the timing of exposure. OBJECTIVE: Investigate critical periods of susceptibility during pregnancy for associations between urinary phthalate metabolite concentrations and preterm birth. METHODS: Individual-level data were pooled from 16 US cohorts (N = 6045, n = 539 preterm births). We examined trimester-averaged urinary phthalate metabolite concentrations. Most phthalate metabolites had 2248, 3703, and 3172 observations in the first, second, and third trimesters, respectively. Our primary analysis used logistic regression models with generalized estimating equations (GEE) under a multiple informant approach to estimate trimester-specific odds ratios (ORs) of preterm birth and significant (p < 0.20) heterogeneity in effect estimates by trimester. Adjusted models included interactions between each covariate and trimester. RESULTS: Differences in trimester-specific associations between phthalate metabolites and preterm birth were most evident for di-2-ethylhexyl phthalate (DEHP) metabolites. For example, an interquartile range increase in mono (2-ethylhexyl) phthalate (MEHP) during the first and second trimesters was associated with ORs of 1.15 (95 % confidence interval [CI]: 0.99, 1.33) and 1.11 (95 % CI: 0.97, 1.28) for preterm birth, respectively, but this association was null in the third trimester (OR = 0.91 [95 % CI: 0.76, 1.09]) (p-heterogeneity = 0.03). CONCLUSION: The association of preterm birth with gestational biomarkers of DEHP exposure, but not other phthalate metabolites, differed by the timing of exposure. First and second trimester exposures demonstrated the greatest associations. Our study also highlights methodological considerations for critical periods of susceptibility analyses in pooled studies.

OBJECTIVE: We investigated associations between per- and polyfluoroalkyl substances (PFAS) and changes in diabetes indicators from pregnancy to 12 years after delivery among women with a history of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Eighty Hispanic women with GDM history were followed from the third trimester of pregnancy to 12 years after delivery. Oral and intravenous glucose tolerance tests were conducted during follow-up. Plasma PFAS concentrations were measured at the third trimester of pregnancy and first postpartum visit. A linear mixed-effects model was used to analyze associations between PFAS and trajectories of diabetes indicators, adjusted for age, breastfeeding status, daily total calorie intake, and body fat percentage. RESULTS: Increased 2-(N-methyl-perfluorooctane sulfonamido) acetate level was associated with faster increase in concentrations of fasting glucose (P = 0.003). Increased perfluorononanoate (PFNA) and linear perfluorooctanoate (n-PFOA) concentrations were associated with faster increase in fasting insulin concentrations (P = 0.04 for PFNA; P = 0.02 for n-PFOA) and faster decrease in acute insulin response to glucose (P = 0.04 for PFNA; P = 0.02 for n-PFOA). CONCLUSIONS: PFAS exposure is associated with glucose intolerance, insulin resistance, and β-cell dysfunction, thus increasing type 2 diabetes risk.

OBJECTIVE: The objective of this study was to evaluate associations of early-pregnancy plasma per- and polyfluoroalkyl substances (PFAS) with maternal post-pregnancy weight trajectory parameters. METHODS: We studied 1106 Project Viva participants with measures of early-pregnancy plasma concentrations of eight PFAS. We measured weight at in-person visits at 6 months and 3, 7, and 12 years after pregnancy and collected self-reported weight via annual questionnaires up to 17 years after pregnancy. Weight trajectory parameters were estimated via the Superimposition by Translation and Rotation model. We assessed individual and joint effects of PFAS with trajectory parameters using linear regression and Bayesian kernel machine regression (BKMR). RESULTS: Perfluorooctane sulfonate (PFOS) concentrations were positively associated with weight trajectory magnitude in both linear regression (0.8 kg [95% CI: 0.1 to 1.4] per doubling of PFOS) and BKMR analyses (2.6 kg [95% CI: 1.4 to 3.8] per increase from 25th to 75th percentile of PFOS concentrations). Conversely, in BKMR analyses, perfluorononanoate was negatively associated with trajectory magnitude (-2.0 kg [95% CI: -2.9 to -1.1]). In stratified linear regression, older-aged participants had more pronounced positive associations of PFOS, perfluorooctanoate, and 2-(N-ethyl-perfluorooctane sulfonamido) acetate with weight trajectory velocity. No associations were observed with the overall PFAS mixture. CONCLUSIONS: Select PFAS, assessed in pregnancy, may affect maternal weight trajectories spanning 17 years after pregnancy, especially for older-aged individuals.

Per- and polyfluoroalkyl substances (PFAS) have been associated with increased risk of hypertensive disorders of pregnancy, but whether PFAS influence blood pressure (BP) trajectories among normotensive pregnant women is unknown. We examined associations between PFAS mixtures and BP trajectories during pregnancy among normotensive women. PFAS concentrations, including perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), and perfluorodecanoate (PFDA), were measured in plasma collected at ∼28 gestational weeks among pregnant women enrolled in the New Hampshire Birth Cohort Study (2009-2018). Systolic BP (SBP) and diastolic BP (DBP) were abstracted from pregnancy medical records. We identified BP trajectories using latent class trajectory modeling and evaluated associations between PFAS mixtures and BP trajectories using probit Bayesian kernel machine regression and multinomial quantile g-computation. We used linear mixed models to examine individual PFAS and BP changes during the third trimester. Models were adjusted for sociodemographic, lifestyle, and reproductive factors, and gestational week of blood sample collection. During late pregnancy, plasma PFOS was associated with greater increases in SBP and PFHxS was associated with greater increases in DBP. Over the third trimester, each doubling in plasma PFOS was associated with 0.07 mmHg (95% CI: -0.01, 0.14) increase per week in SBP, and each doubling in plasma PFHxS was associated with 0.07 mmHg (95% CI: 0.02, 0.12) increase per week in DBP. Our study provides additional evidence suggesting that PFAS may adversely influence blood pressure even among normotensive women.

BACKGROUND: Gestational exposure to non-persistent endocrine-disrupting chemicals (EDCs) may be associated with adverse pregnancy outcomes. While many EDCs affect the endocrine system, their effects on endocrine-related metabolic pathways remain unclear. This study aims to explore the global metabolome changes associated with EDC biomarkers at delivery. METHODS: This study included 75 pregnant individuals who delivered at the University of Cincinnati Hospital from 2014 to 2017. We measured maternal urinary biomarkers of paraben/phenol (12), phthalate (13), and phthalate replacements (4) from the samples collected during the delivery visit. Global serum metabolome profiles were analyzed from maternal blood (n = 72) and newborn (n = 63) cord blood samples collected at delivery. Fifteen of the 29 urinary biomarkers were excluded due to low detection frequency or potential exposures during hospital stay. We assessed metabolome-wide associations between 14 maternal urinary biomarkers and maternal/newborn metabolome profiles. Additionally, performed enrichment analysis to identify potential alterations in metabolic pathways. RESULTS: We observed metabolome-wide associations between maternal urinary concentrations of phthalate metabolites (mono-isobutyl phthalate), phthalate replacements (mono-2-ethyl-5-carboxypentyl terephthalate, mono-2-ethyl-5-hydroxyhexyl terephthalate) and phenols (bisphenol-A, bisphenol-S) and maternal serum metabolome, using q-value < 0.2 as a threshold. Additionally, associations of phthalate metabolites (mono-n-butyl phthalate, monobenzyl phthalate) and phenols (2,5-dichlorophenol, BPA) with the newborn metabolome were noted. Enrichment analyses revealed associations (p-gamma < 0.05) with amino acid, carbohydrate, lipid, glycan, vitamin, and other cofactor metabolism pathways. CONCLUSION: Maternal paraben, phenol, phthalate, and phthalate replacement biomarker concentrations at delivery were associated with maternal and newborn serum global metabolome.

Per- and polyfluoroalkyl substances (PFAS), also known as "forever chemicals" because of their persistence in the environment, have been used in many commercial applications since the 1940s. Of late, the detection of PFAS in drinking water throughout the United States has raised public and scientific concerns. To understand PFAS exposure trends in the general U.S. population, we analyzed select PFAS serum concentration data from participants ≥12 years old of nine National Health and Nutrition Examination Survey (NHANES) cycles. Our goals were to a) evaluate concentration changes of four legacy PFAS-perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) from 1999-2000 to 2017-March 2020, b) discuss serum concentrations and assess demographic predictors of two PFAS measured for the first time in 2017-2018, perfluoro-1-heptanesulfonic acid (PFHpS) and 9-chlorohexadecafluoro-3-oxanonane-1-sulfonic acid (9CLPF) , and c) compare concentration profiles of legacy PFAS in NHANES to profiles in exposed communities. We report a decrease in geometric mean concentrations of the four legacy PFAS (16%-87%, depending on the PFAS) from 1999-2000, although in 2017-March 2020, more than 96% of people aged 12-19 years, some of whom were born after PFAS production changes started in the early 2000s, had measurable concentrations of these PFAS. An estimated 78% of the U.S. general population had detectable concentrations of PFHpS, and 8% had detectable concentrations of 9CLPF (>44% of whom self-identified as Asian). Comparing profiles in NHANES and people living in communities with PFAS contamination can help identify exposure sources and evaluate and monitor exposures in select areas or among specific population groups. Collectively, our findings highlight the usefulness of NHANES data to help researchers, public health officials, and policy makers prioritize investigations, monitor exposure changes, and evaluate effectiveness of efforts to limit exposures.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) may impact ovarian folliculogenesis and steroidogenesis, but whether prenatal exposure may impact offspring reproductive health is unknown. This study examines the extent to which maternal PFAS plasma concentrations during pregnancy are associated with polycystic ovary syndrome (PCOS) and related characteristics in female offspring. METHODS: We studied 322 mother-daughter pairs in Project Viva, a Boston-area longitudinal pre-birth cohort enrolled 1999-2002. We examined associations of maternal prenatal (median: 9.6 weeks gestation) plasma concentrations of six PFAS (log2 transformed) with PCOS and related characteristics among daughters during mid-to-late adolescence. We estimated the associations of single PFAS and PFAS as a mixture with each outcome, using logistic regression and quantile g-computation, respectively, adjusting for parity, and maternal sociodemographic and other lifestyle/health factors. RESULTS: Among the 322 mother-daughter pairs, the majority of mothers identified as non-Hispanic White and had a college degree, and 13% of daughters had either self-reported PCOS or probable PCOS based on irregular menstrual cycles and clinical or biochemical markers of hyperandrogenism. Among all daughters, there were 27% with irregular menstrual cycles, 34% with hirsutism, and 6% with moderate-to-severe acne. When fully adjusted for confounders, per doubling of maternal 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA) concentration was associated with higher odds of self-reported PCOS [OR (95% CI) = 2.66 (1.18, 5.99)], and per doubling of maternal perfluorononanoate (PFNA) concentration was associated with higher odds of moderate-to-severe acne [OR (95% CI) = 2.33 (1.09, 4.99)] in daughters with or without irregular menstrual cycles. We found no associations of the mixture of six PFAS with PCOS or related traits. CONCLUSION: Our findings suggest a positive association between maternal concentrations of EtFOSAA and PCOS in their daughters during mid-to-late adolescence, although future studies with larger sample size and extended follow-up across the reproductive life-course are needed.

BACKGROUND: PFAS may impair bone health, but effects of PFAS exposure assessed during pregnancy and the perimenopause-life stages marked by rapidly changing bone metabolism-on later life bone health are unknown. METHODS: We studied 531 women in the Boston-area Project Viva cohort. We used multivariable linear, generalized additive, and mixture models to examine associations of plasma PFAS concentrations during early pregnancy [median (IQR) maternal age 32.9 (6.2) years] and midlife [age 51.2 (6.3)] with lumbar spine, total hip, and femoral neck areal bone mineral density (aBMD) and bone turnover biomarkersassessed in midlife. We examined effect modification by diet and physical activity measured at the time of PFAS exposure assessment and by menopausal status in midlife. RESULTS: Participants had higher PFAS concentrations during pregnancy [1999-2000; e.g., PFOA median (IQR) 5.4 (3.8) ng/mL] than in midlife [2017-2021; e.g. , PFOA: 1.5 (1.2) ng/mL]. Women with higher PFOA, PFOS and PFNA during pregnancy had higher midlife aBMD, especially of the spine [e.g., 0.28 (95% CI: 0.07, 0.48) higher spine aBMD T-score, per doubling of PFOA], with stronger associations observed among those with higher diet quality. In contrast, higher concentrations of all PFAS measured in midlife were associated with lower concurrent aBMD at all sites [e.g., -0.21 (-0.35, -0.07) lower spine aBMD T-score, per doubling of PFOA]; associations were stronger among those who were postmenopausal. The associations of several PFAS with bone resorption (loss) were also stronger among postmenopausal versus premenopausal women. DISCUSSION: Plasma PFAS measured during pregnancy versus in midlife had different associations with midlife aBMD. We found an adverse association of PFAS measured in midlife with midlife aBMD, particularly among postmenopausal women. Future studies with longer follow-up are needed to elucidate the effect of PFAS on bone health during the peri- and postmenopausal years.

BACKGROUND AND AIMS: Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on steatotic liver disease limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver outcomes, and effect modification by folic acid (FA) supplementation in mother-child pairs. METHODS: We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with measured 43 MDCs during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide [OP] metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. Outcomes included elevated liver enzymes in children and established clinical scores for steatosis and fibrosis in mothers (i.e. , AST: ALT, FLI, HSI, FIB-4). Bayesian Weighted Quantile Sum regression assessed MDC-mixture associations with liver outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. RESULTS: In children, many MDC-mixtures were associated with liver injury. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95%CI: 1.67%, 19.4%) and AST by 5.27% (95% CI: 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions<0.05). In mothers, only the LMWP-mixture was associated with odds for steatosis [OR=1.53 (95%CI: 1.01, 2.28) for HSI>36, and OR=1.62 (95%CI: 1.05, 2.49) for AST:ALT<1]. In mothers and children, most associations were attenuated (null) at FA supplementation≥600mcg/day (p-interactions<0.05). CONCLUSIONS: Pregnancy MDC exposures may increase risk for liver injury and steatosis, particularly in children. Adequate FA supplementation and maternal cobalt levels may attenuate these associations. IMPACT AND IMPLICATIONS: The effects of environmental chemical exposures on steatotic liver diseases are not well understood. In a parallel investigation of mothers and children, we found that pregnancy exposures to metabolism-disrupting chemicals may increase the risk for liver injury and steatosis, especially in the child, and that these associations could be attenuated by higher folic acid and/or cobalt levels. These findings can inform policies to decrease environmental chemical pollution and contribute to the design of clinical interventions addressing the MASLD epidemic.

Persistent endocrine-disrupting chemicals (EDCs) can dysregulate the stress response. We evaluated associations between persistent EDCs and perceived stress among participants in the Study of Environment, Lifestyle, and Fibroids (n = 1394), a prospective cohort study of Black women. Participants completed the Perceived Stress Scale 4 (PSS-4) at baseline and every 20 months through 60 months (score range: 0-16); higher scores indicate higher stress. Endocrine-disrupting chemicals, including per- and polyfluoroalkyl substances, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides, were quantified in plasma samples at baseline. We fit bayesian kernel machine regression and linear mixed-effects models to estimate associations of EDCs (as a mixture and individually) with PSS-4 scores at baseline and at each follow-up visit, respectively. Increasing percentiles of the mixture were not strongly associated with PSS-4 scores at baseline, and no interactions were observed among EDCs. Several individual EDCs (eg, perfluorodecanoic acid, PCB 118, PBDE 99) were associated with higher PSS-4 scores at baseline or follow-up, and other EDCs (eg PCB 138/158) were associated with lower PSS-4 scores at baseline or follow-up. The directionality of associations for individual EDCs was inconsistent across follow-up visits. In conclusion, specific EDCs may be associated with perceived stress in Black women. This article is part of a Special Collection on Environmental Epidemiology.

BACKGROUND: Female sexual function is important for sexual well-being, general health, fertility, and relationship satisfaction. Distressing impairments in sexual function, clinically recognized as female sexual dysfunction (FSD), can manifest as issues with interest/desire, arousal, orgasm, and pain during vaginal penetration. Some evidence suggests that exposure to endocrine-disrupting chemicals may adversely affect female sexual function, but associations for per- and polyfluoroalkyl substances (PFAS) have not been previously evaluated. OBJECTIVE: We investigated associations between serum PFAS concentrations and female sexual function among U.S. pregnancy planners. METHODS: We used cross-sectional data from participants from Pregnancy Study Online (PRESTO), a prospective preconception cohort study. Participants reported sexual function and distress at baseline on two validated measures: a modified version of the Female Sexual Function Index-6 (FSFI-6) and the Female Sexual Distress Scale (FSDS). We quantified PFAS serum concentrations in samples collected in the preconception period (i.e., at baseline) using solid phase extraction-high performance liquid chromatography-isotope-dilution-mass spectrometry. Participants reported sociodemographic information on structured baseline questionnaires. We included 78 participants with complete PFAS and sexual function data and fit multivariable linear regression models to estimate mean differences in FSFI-6 scores (β) or percent differences (%) in FSDS scores per interquartile range (IQR) increase in PFAS concentrations, adjusting for age, annual household income, years of education, parity, and body mass index. We further investigated effect measure modification by parity (parous vs. nulliparous) in stratified models. RESULTS: An IQR increase in perfluorohexanesulfonic acid was associated with a 1.0-point decrease (95% CI = -1.8, -0.1) in reported FSFI-6 scores, reflecting poorer sexual function. PFAS were consistently associated with lower FSFI-6 scores among parous participants. PFAS were also associated, though imprecisely, with greater sexual distress. CONCLUSION: Some PFAS were associated with poorer sexual function among U.S. pregnancy planners, but future studies are needed to clarify the extent to which PFAS influences female sexual health.

In 2022, the International Society of Exposure Science (ISES) International Human Biomonitoring (i-HBM) Working Group launched a free, online repository of biomonitoring guidance values referred to as the Human Biomonitoring Health-Based Guidance Value (HB2GV) Dashboard. The goal of the Dashboard is to assist global human biomonitoring data users (e.g., risk assessors, risk managers) and human biomonitoring programs with a readily available compilation of guidance values for the general population. The Dashboard contains approximately 600 HB2GVs for over 150 chemicals or their metabolites. Although there are many different types of HB2GVs, most are Biomonitoring Equivalents (BEs), Human Biomonitoring (HBM-I and HBM-II) values, or Human Biomonitoring Guidance Values (HBM-GVs). For users new to human biomonitoring, understanding how the different types of HB2GVs are derived and how to interpret those values in the context of human biomonitoring data can be difficult. Therefore, there is a need to inform users of the differences among available guidance values and to help users identify the HB2GV that could be most suitable for their purposes. Here, we summarize the derivation of HB2GVs for a case study chemical, di-(2-ethylhexyl) phthalate (DEHP). We selected DEHP as there are 36 unique HB2GVs available from three of the most common types of guidance values (i.e., BE, HBM-I value, HBM-GV). We also compare the available HB2GVs with a focus on the differences among their derivation methods, relative quality and confidence, and interpretation. This case study provides guidance on the use of existing HB2GVs for health-based interpretation of human biomonitoring data that may be applied to other chemicals. As with any other type of guidance or regulatory value (e.g., RfDs, MRLs), thoughtful selection and use are strongly encouraged. Appropriately interpreting HBM data with the aid of guidance values can result in improved decision making which, ultimately, could lead to better protection of public health.

There is limited research on associations of per- and polyfluoroalkyl substances (PFAS) with areal bone mineral density (aBMD) through adolescence and whether bone-strengthening factors ameliorate effects. In the Project Viva cohort (N = 484; 50% female), we used sex-stratified linear regression and quantile g-computation mixture models to examine associations of mid-childhood (median: 7.8 years; 2007-2010) plasma PFAS concentrations with a dual-energy X-ray absorptiometry total-body aBMD Z-score in early and late adolescence (median: 12.9 and 17.6 years, respectively). We explored stratum-specific estimates by parent/self-reported physical activity and dairy intake. Using linear mixed models, we evaluated associations with aBMD accrual from mid-childhood through late adolescence. Females with higher perfluorooctanoate (PFOA) and perfluorodecanoate (PFDA) had lower early adolescent aBMD Z-score [e.g., β(95%CI)] per doubling PFOA: -0.19(-0.41, 0.03)]. Youth with higher PFOA and PFDA had lower late adolescent aBMD Z-score, but CIs were wide [e.g., PFOA: females, -0.12(-0.40, 0.16); males, -0.10(-0.42, 0.21)]. Mixture models generally corroborated single PFAS results, and in linear mixed models, females with higher PFAS concentrations, and males with higher PFOA, had slower aBMD accrual. Less active males with higher PFOA, PFDA, and the PFAS mixture had lower late adolescent aBMD Z-score. Some PFAS appeared more negatively associated with the aBMD Z-score among those who consumed less dairy, but there was not consistent evidence of effect modification. Exposure to select PFAS may affect bone accrual through adolescence, with possible resilience conferred by greater physical activity and dairy intake.

BACKGROUND: Environmental chemical exposures in utero may play a role in autism development. While preconception risk factors for autism are increasingly being investigated, little is known about the influence of chemical exposures during the preconception period, particularly for paternal exposures. METHODS: In 195 children from the Preconception Environmental exposures And Childhood health Effects (PEACE) cohort born to parents recruited from a fertility clinic in Boston, Massachusetts between 2004 and 2017, we quantified concentrations of 11 phthalate metabolites and bisphenol A (BPA) in urine samples collected from mothers and fathers before conception and mothers throughout pregnancy. When children were 6-15 years old, parents completed the Social Responsiveness Scale (SRS) questionnaire assessing autistic behaviors. We used linear mixed effect models to estimate covariate-adjusted associations of phthalate biomarker and BPA concentrations, separately for maternal preconception (n = 179), paternal preconception (n = 121), and maternal pregnancy (n = 177), with SRS T-scores, based on age and gender, in offspring. We used quantile g-computation models for mixture analyses and evaluated modification by selected dietary factors. RESULTS: The mean SRS T-score was 47.7 (±7.4), lower than the normative mean of 50. In adjusted models for individual biomarkers or mixtures, few associations were observed and estimates were generally negative (e.g., lower SRS T-scores) and imprecise. We observed associations of higher mono-isobutyl phthalate (MiBP) concentrations measured in maternal preconception and paternal preconception periods with lower SRS T-scores (β(maternal_precon) = -1.6, 95% CI -2.7; -0.4; β(paternal_precon) = -2.9, 95% CI -4.6; -1.2) for each log(e) increase. In a subset of participants with maternal preconception nutrition information, we generally observed stronger inverse associations with higher folate and iron intake, particularly for folate intake and MiBP concentrations. CONCLUSIONS: Urinary phthalate biomarker and BPA concentrations during preconception (maternal and paternal) and pregnancy (maternal) were not associated with adverse autistic behaviors in these children. Larger studies are needed to elucidate the observed associations, while considering interactions between maternal nutrition and chemical exposures.

BACKGROUND: Experimental studies have shown associations between gestational phthalate exposure and behavioral problems among offspring; however, epidemiological evidence is still mixed. This study aims to investigate whether gestational phthalate exposure is associated with behavioral problems in preschool-aged children. METHODS: Participants include 178 mother-child pairs from MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a cohort with high familial likelihood of autism spectrum disorder (ASD). We quantified 14 phthalate metabolites in multiple maternal urine samples collected during the 2nd and 3rd trimesters. Preschool behavior problems were assessed using the Child Behavioral Checklist (CBCL), a standardized instrument for evaluating behavior problems of children aged 1.5-5 years. To examine associations of CBCL scores with both individual phthalate biomarker concentrations and their mixture, we used negative binomial regression and weighted quantile sum regression. RESULTS: Overall, maternal phthalate biomarker concentrations were not associated with child behavior problems. Monoisobutyl phthalate (MiBP) concentrations were inversely associated with child anxious/depressed symptoms and somatic complaints. Mono-hydroxy-isobutyl phthalate (MHiBP) and monobenzyl phthalate (MBzP) were also inversely associated with somatic complaints. When assessing trimester-specific associations, more behavior problems were associated with the 2nd trimester biomarker concentrations: mono(3-carboxypropyl) phthalate (MCPP) and monocarboxyisononyl phthalate (MCNP) were positively associated with somatic complaints. All associations became non-significant after false discovery rate correction. No association between a mixture of phthalates and CBCL scores was found. CONCLUSIONS: Our study observed no clear evidence of gestational phthalate exposure on child behavior problems. However, our findings based on the biomonitoring assessment of multiple samples per participant could improve our understanding of gestational phthalate exposure in association with behavior problems in preschool-aged children.

BACKGROUND: Evidence from toxicological studies indicate organophosphate esters (OPEs) are neurotoxic, but few epidemiological studies investigated associations between gestational OPEs and executive function. OBJECTIVE: To examine the associations between gestational concentrations of OPE urinary metabolites and executive function at 12 years METHODS: We used data from 223 mother-adolescent dyads from the Health Outcomes of Measures of the Environment (HOME) Study. Women provided spot urine samples at 16 weeks gestation, 26 weeks gestation, and at delivery for quantification of bis(1,3-dichloro-2-propyl) phosphate, bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP). Executive function was assessed at age 12 years using the parent- and self-report Behavior Rating Inventory of Executive Function (BRIEF2). Covariate-adjusted associations between specific gravity-corrected OPEs and BRIEF2 scores were estimated using multiple informant models. Bayesian Kernel Machine Regression (BKMR) was used to assess the impact of all OPEs simultaneously. RESULTS: Parent- and self-report BRIEF2 indices and composite scores were weakly to moderately correlated (r(s)=0.32-0.41). A natural-log unit increase in BCEP at 26 weeks was associated with approximately a 1-point increase on the self-report Cognitive Regulation Index [CRI] (95% CI 0.4, 2.3), the Emotion Regulation Index [ERI] (95% CI 0.3, 2.2), and the Global Executive Composite [GEC] (95% CI 0.4, 2.2), indicating poorer performance. Higher DPHP at 16 weeks was associated with lower parent-report GEC score (β=-1.1, 95% CI -2.3, -0.003). BKMR identified BCEP and DNBP at 26 weeks as important contributors to CRI and ERI, respectively. CONCLUSION: OPE metabolites during gestational development, particularly BCEP, may influence adolescent executive function. However, since the FDR p-values failed to reach statistical significance, additional studies would benefit from using larger cohorts.

BACKGROUND AND OBJECTIVES: Diet plays critical roles in modulating maternal metabolic health in pregnancy, but is also a source of metabolic-disrupting phthalates and their replacements. We aimed to evaluate whether the effects of better diet quality on favorable maternal metabolic outcomes could be partially explained by lower exposure to phthalates/replacements. METHODS: At 13 weeks gestation, 295 Illinois women (enrolled 2015-2018) completed a three-month food frequency questionnaire that we used to calculate the Alternative Healthy Eating Index (AHEI)-2010 diet quality index. We quantified 19 metabolites, reflecting exposure to 10 phthalates/replacements, in a pool of five first-morning urine samples collected monthly across pregnancy. We measured 15 metabolic biomarkers in fasting plasma samples collected at 17 weeks gestation, which we reduced to five uncorrelated principal components (PCs), representing adiposity, lipids, cholesterol, inflammation, and growth. We used linear regression to estimate associations of diet quality with [1] phthalates/replacements and [2] metabolic PCs, as well as [3] associations of phthalates/replacements with metabolic PCs. We estimated the proportion of associations between diet quality and metabolic outcomes explained by phthalates/replacements using a causal mediation framework. RESULTS: Overall, every 10-point improvement in AHEI-2010 score was associated with -0.15 (95% CI: -0.27, -0.04) lower adiposity scores, reflecting lower glucose, insulin, C-peptide, leptin, C-reactive protein, but higher adiponectin biomarker levels. Every 10-point increase in diet quality was also associated with 18% (95%CI: 7%, 28%) lower sum of di-2-ethylhexyl terephthalate urinary metabolites (∑DEHTP). Correspondingly, each 18% increase in ∑DEHTP was associated with 0.03 point (95% CI: 0.01, 0.05) higher adiposity PC scores. In mediation analyses, 21% of the inverse relationship between diet quality and adiposity PC scores was explained by lower ∑DEHTP. CONCLUSIONS: The favorable impact of diet quality on maternal adiposity biomarkers may be partially attributed to lower metabolite concentrations of DEHTP, a plasticizer allowed to be used in food packaging materials.