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.

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.

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.

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.

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.

Previous studies reported that exposures to per- and polyfluoroalkyl substances (PFAS), largely in higher exposed populations, were associated with elevated risk of polycystic ovary syndrome (PCOS). However, studies evaluating PCOS risk in populations with lower background exposures to PFAS are limited. This study aimed to examine the associations between serum PFAS concentrations and PCOS risk among women attending a U.S. academic fertility clinic during 2005-2019. A total of 502 females who sought fertility evaluation and assisted reproduction treatments were included. Nine PFAS were quantified in non-fasting serum samples collected at study entry. Diagnosis of PCOS was based on the Rotterdam criteria. We used logistic regression to examine the odds ratio (OR) of PCOS in relation to individual PFAS concentrations (continuous and by tertiles) and quantile g-computation (QGC) and Bayesian Kernel Machine Regression (BKMR) to examine the joint associations of PFAS mixture with PCOS. Most participants were White and had a graduate degree or higher. Per doubling of serum perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) concentrations were associated with higher odds of PCOS [OR (95%CI): 1.70 (1.06, 2.81) and 1.45 (1.02, 2.08) for PFOS and PFHxS respectively]. There was a dose-response relationship of PFOS with PCOS risk (p of trend by PFOS tertiles = 0.07). Both QGC and BKMR identified PFOS as the most important contributor among the mixture to PCOS risk. No clear joint effects were found for other PFAS or PFAS mixtures on PCOS risk. Our findings are consistent with existing evidence in populations with higher background PFAS concentrations and highlight the adverse effects of PFAS exposure on reproductive health. Findings can inform public health measures and clinical care to protect populations vulnerable to PCOS, in part, due to environmental exposures.

STUDY QUESTION: What is the longitudinal association between gestational phthalate exposure and in vivo placental outcomes? SUMMARY ANSWER: Phthalates were adversely associated with placental microvasculature, stiffness, and presence of calcification, with different metabolites associated with different outcomes. WHAT IS KNOWN ALREADY: Phthalate exposure is ubiquitous and implicated as a contributor to adverse pregnancy outcomes, possibly through impacts on the placenta. STUDY DESIGN, SIZE, DURATION: A total of 303 women were recruited in early pregnancy and prospectively followed for up to eight visits across gestation in the Human Placenta and Phthalates study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At each visit, women provided urine samples and underwent placental ultrasounds. Urine was analyzed for 18 metabolites of phthalates and replacements. We took the geometric mean of repeated measurements to reflect pregnancy-averaged phthalate or replacement exposure for each participant (n = 303). Placental microvasculature, stiffness, and microcalcification presence were quantified from ultrasounds at each visit. Higher scores reflected worse placental function for all measures. Generalized linear mixed models were created to estimate the association between pregnancy-averaged exposure biomarker concentrations and repeated outcome measurements for microvasculature and stiffness. Gestational age at the time of calcification detection was modeled using Cox proportional hazards models. MAIN RESULTS AND THE ROLE OF CHANCE: Monocarboxyisononyl phthalate and summed di(2-ethylhexyl) phthalate metabolites were associated with impaired microvasculature development, such that an interquartile range increase in concentration was associated with 0.11 standard deviation increase in the microvasculature ratio, indicating poorer vascularization (95% CI: 0.00, 0.22); 0.11 [95% CI: -0.01, 0.22], respectively. Monoethyl phthalate was associated with increased placental stiffness (0.09 [95% CI: -0.01, 0.19]) while summed di-iso-butyl phthalate metabolites and monobenzyl phthalate were associated with increased hazard of calcification detection (hazard ratios: 1.18 [95% CI: 0.98, 1.42]; 1.13 [95% CI: 0.96, 1.34]). LIMITATIONS, REASONS FOR CAUTION: Outcomes used in this study are novel and further investigation is needed to provide clinical context and relevance. WIDER IMPLICATIONS OF THE FINDINGS: We found evidence of associations between select phthalate biomarkers and various aspects of in vivo placental health, although we did not observe consistency across placental outcomes. These findings could illustrate heterogeneous effects of phthalate exposure on placental function. STUDY FUNDING/COMPETING INTEREST(S): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES103344), and NIEHS T32ES007018. The authors declare that they have no competing interests to disclose. 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. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services. TRIAL REGISTRATION NUMBER: N/A.

BACKGROUND: Exposure to environmental chemicals such as phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs) during pregnancy can increase the risk of adverse newborn outcomes. We explored the associations between maternal exposure to select environmental chemicals and DNA methylation in cord blood mononuclear cells (CBMC) and placental tissue (maternal and fetal sides) to identify potential mechanisms underlying these associations. METHOD: This study included 75 pregnant individuals who planned to give birth at the University of Cincinnati Hospital between 2014 and 2017. Maternal urine samples during the delivery visit were collected and analyzed for 37 biomarkers of phenols (12), phthalates (13), phthalate replacements (4), and PAHs (8). Cord blood and placenta tissue (maternal and fetal sides) were also collected to measure the DNA methylation intensities using the Infinium HumanMethylation450K BeadChip. We used linear regression, adjusting for potential confounders, to assess CpG-specific methylation changes in CBMC (n = 54) and placenta [fetal (n = 67) and maternal (n = 68) sides] associated with gestational chemical exposures (29 of 37 biomarkers measured in this study). To account for multiple testing, we used a false discovery rate q-values < 0.05 and presented results by limiting results with a genomic inflation factor of 1±0.5. Additionally, gene set enrichment analysis was conducted using the Kyoto Encyclopedia of Genes and Genomics pathways. RESULTS: Among the 29 chemical biomarkers assessed for differential methylation, maternal concentrations of PAH metabolites (1-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 1-hydroxypyrene), monocarboxyisononyl phthalate, mono-3-carboxypropyl phthalate, and bisphenol A were associated with altered methylation in placenta (maternal or fetal side). Among exposure biomarkers associated with epigenetic changes, 1-hydroxynaphthalene, and mono-3-carboxypropyl phthalate were consistently associated with differential CpG methylation in the placenta. Gene enrichment analysis indicated that maternal 1-hydroxynaphthalene was associated with lipid metabolism and cellular processes of the placenta. Additionally, mono-3-carboxypropyl phthalate was associated with organismal systems and genetic information processing of the placenta. CONCLUSION: Among the 29 chemical biomarkers assessed during delivery, 1-hydroxynaphthalene and mono-3-carboxypropyl phthalate were associated with DNA methylation in the placenta. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43682-024-00027-7.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are endocrine-disrupting chemicals used in commercial and consumer products. OBJECTIVE: We evaluated PFAS exposure in relation to incidence and growth of uterine leiomyomata (UL), hormone-dependent neoplasms that are associated with severe gynecologic morbidity. METHODS: We studied 1158 participants in the Study of Environment, Lifestyle, and Fibroids, a Detroit-based prospective cohort study of Black females aged 23-35 years at enrollment (2010-2012). At enrollment and four subsequent visits during 10 years of follow-up, participants attended in-person clinic visits, completed questionnaires, provided non-fasting blood samples, and underwent ultrasound for UL detection. We quantified 7 PFAS in baseline plasma samples using mass spectrometry. We used Cox regression and probit Bayesian kernel machine regression to estimate individual and joint effects of PFAS on UL incidence. We fit linear mixed models to estimate effects of individual PFAS on UL growth. We stratified by parity, an important route of PFAS elimination and determinant of UL. RESULTS: In individual PFAS analyses, we observed inverse associations for perfluorodecanoate (PFDA; ≥0.3 vs. <0.2 ng/ml: hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.54-1.00) and perfluoroundecanoate (detected vs. non-detected: HR = 0.78; 95% CI: 0.61-1.01) and a weak positive association for perfluorohexane sulfonate (≥1 vs. <0.6 ng/ml: HR = 1.17; 95% CI: 0.85-1.61), while perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate (PFNA), and 2-N-methyl-perfluorooctane sulfonamido acetate (MeFOSAA) showed little association with UL incidence. The PFAS mixture was inversely associated with UL incidence, a finding driven by MeFOSAA and PFDA; however, PFNA was positively associated with UL incidence. The inverse association for PFDA and positive association for PFNA were stronger among nulliparous participants. Most PFAS showed slight inverse associations with UL growth. IMPACT STATEMENT: In this prospective ultrasound study of 1158 Black females aged 23-35 years at enrollment, we conducted a mixtures analysis to account for co-pollutant confounding and interaction. MeFOSAA and PFDA concentrations were inversely associated with UL incidence, while PFNA concentrations were positively associated with UL incidence. Concentrations of most PFAS were associated with decreased UL growth. This study contributes data to the sparse literature on PFAS exposure and UL development.

BACKGROUND: Emerging studies suggest that endocrine disrupting chemicals (EDCs) in personal care and other consumer products are linked with various adverse health effects, including respiratory and reproductive effects. Despite Black persons using more personal care products than other demographic groups and having a high asthma burden, little is known regarding their consumer product use patterns and associated EDC exposures. OBJECTIVE: To examine the association between recent exposure to select EDCs with specific consumer products and behaviors in a cohort of 110 predominantly Black children with asthma, ages 8-17 years, living in Baltimore City, Maryland. METHODS: We quantified concentrations of bisphenol A (BPA), bisphenol S (BPS), bisphenol F, two dichlorophenols, four parabens, triclosan, benzophenone-3, and triclocarban in spot urine samples. Questionnaires were used to capture recent (last 24-h) consumer product use and behaviors. Associations between EDCs and consumer product uses/behaviors were assessed using multivariable linear regression, adjusting for age, gender, race/ethnicity, and caregiver income level. Effect estimates were expressed as geometric mean ratios of biomarker concentrations of product-users vs non-users. RESULTS: Increased concentrations to select EDCs were associated with recent use of air freshener (ratios; BPA: 1.9, 95%CI 1.4-2; BPS 1.7, 95%CI 1-2.97; propyl paraben: 3.0, 95%CI 1.6-5.6), scented candles (methyl paraben: 2.6, 95%CI 1.1-6.1), and scented carpet powder (2,5-dichlorophenol: 2.8, 95%CI 1.2-6.3). Additionally, consuming canned food was associated with some increased biomarker concentrations (ratios: BPA: 1.7, 95%CI 1.2-2.4; BPS: 2.1, 95% CI: 1.2-3.6). SIGNIFICANCE: These findings add to the body of evidence suggesting that recent use of select consumer products in Black children contributes to exposure of chemicals of concern and could potentially inform exposure mitigation interventions. Findings have broad potential health implications for pediatric populations and Black children who may face exposure and health disparities. IMPACT: Little is known about how children's personal care product use and consumer behaviors affect their exposures to endocrine disrupting chemicals (EDCs). This is particularly true for Black children who often experience a disparate exposure burden to many EDCs. This is a significant knowledge gap among children that are uniquely vulnerable to EDCs as they undergo critical windows of growth and development. Our findings show associations between consumer products and EDC exposures in predominantly Black children in low-income settings. Identifying EDC exposure determinants has broad health implications as many of these chemicals have been associated with adverse health risks.

Per- and polyfluoroalkyl substances (PFAS) are related to various adverse health outcomes, and food is a common source of PFAS exposure. Dietary sources of PFAS have not been adequately explored among U.S. pregnant individuals. We examined associations of dietary factors during pregnancy with PFAS concentrations in maternal plasma and human milk in the New Hampshire Birth Cohort Study. PFAS concentrations, including perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), and perfluorodecanoate (PFDA), were measured in maternal plasma collected at ~28 gestational weeks and human milk collected at ~6 postpartum weeks. Sociodemographic, lifestyle and reproductive factors were collected from prenatal questionnaires and diet from food frequency questionnaires at ~28 gestational weeks. We used adaptive elastic net (AENET) to identify important dietary variables for PFAS concentrations. We used multivariable linear regression to assess associations of dietary variables selected by AENET models with PFAS concentrations. Models were adjusted for sociodemographic, lifestyle, and reproductive factors, as well as gestational week of blood sample collection (plasma PFAS), postpartum week of milk sample collection (milk PFAS), and enrollment year. A higher intake of fish/seafood, eggs, coffee, or white rice during pregnancy was associated with higher plasma or milk PFAS concentrations. For example, every 1 standard deviation (SD) servings/day increase in egg intake during pregnancy was associated with 4.4 % (95 % CI: 0.6, 8.4), 3.3 % (0.1, 6.7), and 10.3 % (5.6, 15.2) higher plasma PFOS, PFOA, and PFDA concentrations respectively. Similarly, every 1 SD servings/day increase in white rice intake during pregnancy was associated with 7.5 % (95 % CI: -0.2, 15.8) and 12.4 % (4.8, 20.5) greater milk PFOS and PFOA concentrations, respectively. Our study suggests that certain dietary factors during pregnancy may contribute to higher PFAS concentrations in maternal plasma and human milk, which could inform interventions to reduce PFAS exposure for both birthing people and offspring.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are endocrine-disrupting chemicals with neurotoxic properties. PFAS have been associated with depressive symptoms in women in some studies, but little research has evaluated the effects of PFAS mixtures. Further, no study has investigated interactions of PFAS-depression associations by perceived stress, which has been shown to modify PFAS effects on other health outcomes. OBJECTIVE: In a prospective cohort study of reproductive-aged Black women, we investigated associations between PFAS and depressive symptoms and the extent to which perceived stress modified these associations. METHODS: We analyzed data from 1499 participants (23-35 years) from the Study of Environment, Lifestyle, and Fibroids. We quantified concentrations of nine PFAS in baseline plasma samples using online solid-phase extraction-liquid chromatography-isotope dilution tandem mass spectrometry. Participants reported perceived stress via the Perceived Stress Scale (PSS-4; range = 0-16) at baseline and depressive symptoms via the Center for Epidemiologic Studies Depression Scale (CESD; range = 0-44) at the 20-month follow-up visit. We used Bayesian Kernel Machine Regression to estimate associations between PFAS concentrations, individually and as a mixture, and depressive symptoms, and to assess effect modification by PSS-4 scores, adjusting for confounders. RESULTS: Baseline perfluorodecanoic acid concentrations were associated with greater depressive symptoms at the 20-month follow-up, but associations for other PFAS were null. The PFAS were not associated with depressive symptoms when evaluated as a mixture. The association between the 90th percentile (vs. 50th percentile) of the PFAS mixture with CES-D scores was null at the 10th (β = 0.03; 95 % CI = 0.20, 0.25), 50th (β = 0.02; 95 % CI = -0.16, 0.19), and 90th (β = 0.01; 95 % CI = 0.18, 0.20) percentiles of PSS-4 scores, suggesting perceived stress did not modify PFAS mixture. CONCLUSION: In this prospective cohort study, PFAS concentrations-assessed individually or as a mixture-were not appreciably associated with depressive symptoms, and there was no evidence of effect modification by perceived stress.

BACKGROUND: Prior studies suggest that prenatal per- and polyfluoroalkyl substances (PFAS) exposures are associated with shorter breastfeeding duration. Studies assessing PFAS mixtures and populations in North America are sparse. METHODS: We quantified PFAS concentrations in maternal plasma collected during pregnancy in the New Hampshire Birth Cohort Study (2010-2017). Participants completed standardized breastfeeding surveys at regular intervals until weaning (n = 813). We estimated associations between mixtures of 5 PFAS and risk of stopping exclusive breastfeeding before 6 months or any breastfeeding before 12 months using probit Bayesian kernel machine regression. For individual PFAS, we calculated the relative risk and hazard ratio (HR) of stopping breastfeeding using modified Poisson regression and accelerated failure time models respectively. RESULTS: PFAS mixtures were associated with stopping exclusive breastfeeding before 6 months, primarily driven by perfluorooctanoate (PFOA). We observed statistically significant trends in the association of perfluorohexane sulfonate (PFHxS), PFOA, and perfluorononanoate (PFNA) (p-trends≤0.02) with stopping exclusive breastfeeding. Participants in the highest PFOA quartile had a 28% higher risk of stopping exclusive breastfeeding before 6 months compared to those in the lowest quartile (95% Confidence Interval: 1.04, 1.56). Similar trends were observed for PFHxS and PFNA with exclusive breastfeeding (p-trends≤0.05). PFAS were not associated with stopping any breastfeeding before 12 months. CONCLUSIONS: In this cohort, we observed that participants with greater overall plasma PFAS concentrations had greater risk of stopping exclusive breastfeeding before 6 months and associations were driven largely by PFOA. These findings further support the growing literature indicating that PFAS may be associated with shorter duration of breastfeeding.

Previous studies have examined the predictors of PFAS concentrations among pregnant women and children. However, no study has explored the predictors of preconception PFAS concentrations among couples in the United States. This study included 572 females and 279 males (249 couples) who attended a U.S. fertility clinic between 2005 and 2019. Questionnaire information on demographics, reproductive history, and lifestyles and serum samples quantified for PFAS concentrations were collected at study enrollment. We examined the PFAS distribution and correlation within couples. We used Ridge regressions to predict the serum concentration of each PFAS in females and males using data of (1) socio-demographic and reproductive history, (2) diet, (3) behavioral factors, and (4) all factors included in (1) to (3) after accounting for temporal exposure trends. We used general linear models for univariate association of each factor with the PFAS concentration. We found moderate to high correlations for PFAS concentrations within couples. Among all examined factors, diet explained more of the variation in PFAS concentrations (1-48%), while behavioral factors explained the least (0-4%). Individuals reporting White race, with a higher body mass index, and nulliparous women had higher PFAS concentrations than others. Fish and shellfish consumption was positively associated with PFAS concentrations among both females and males, while intake of beans (females), peas (male), kale (females), and tortilla (both) was inversely associated with PFAS concentrations. Our findings provide important data for identifying sources of couples' PFAS exposure and informing interventions to reduce PFAS exposure in the preconception period.

Per- and polyfluoroalkyl substances (PFAS) exposure was associated with changes in thyroid function in pregnant mothers and the general population. Limited such evidence exists in other susceptible populations such as females with fertility problems. This cross-sectional study included 287 females seeking medically assisted reproduction at a fertility clinic in Massachusetts, United States, between 2005 and 2019. Six long-alkyl chain PFAS, thyroid hormones, and autoimmune antibodies were quantified in baseline serum samples. We used generalized linear models and quantile g-computation to evaluate associations of individual PFAS and their total mixture with thyroid biomarkers. Most females were White individuals (82.7%), had graduate degrees (57.8%), and nearly half had unexplained subfertility (45.9%). Serum concentrations of all examined PFAS and their mixture were significantly associated with 2.6%-5.6% lower total triiodothyronine (TT3) concentrations. Serum concentrations of perfluorononanoate (PFNA), perfluorodecanoate (PFDA), and perfluoroundecanoate (PFUnDA), and of the total mixture were associated with higher ratios of free thyroxine (FT4) to free triiodothyronine (FT3). No associations were found for PFAS and TSH or autoimmune antibodies. Our findings support the thyroid-disrupting effect of long alkyl-chain PFAS among a vulnerable population of subfertile females.

Prenatal per and polyfluoroalkyl substances (PFAS) exposure is associated with adverse birth outcomes. There is an absence of evidence on the relationship between maternal and paternal preconception PFAS exposure and birth outcomes. This study included 312 mothers and 145 fathers with a singleton live birth from a preconception cohort of subfertile couples seeking fertility treatment at a U.S. clinic. PFAS were quantified in serum samples collected before conception. Gestational age (GA) and birthweight (BW) were abstracted from delivery records. We also assessed low birthweight (BW < 2500 g) and preterm birth (GA < 37 completed weeks). We utilized multivariable linear regression, logistic regression, and quantile-based g computation to examine maternal or paternal serum concentrations of individual PFAS and mixture with birth outcomes. Maternal serum concentrations of perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate (PFHxS), and the total PFAS mixture were inversely associated with birthweight. Maternal PFOS concentration was associated with a higher risk of low birthweight. Conversely, paternal PFOS and PFHxS concentrations were imprecisely associated with higher birthweight. No associations were found for gestational age or preterm birth. The findings have important implications for preconception care. Future research with larger sample sizes would assist in validating these findings.

BACKGROUND: Humans are exposed to phthalates, a class of non-persistent chemicals, through multiple products, including personal care and cosmetics. Associations between specific phthalates and product use have been inconsistent. However, determining these connections could provide avenues for exposure reduction. OBJECTIVE: Examine the association between patterns of personal care product use and associations with phthalate and replacement biomarkers. METHODS: In the Human Placenta and Phthalates Study, 303 women were enrolled in early pregnancy and followed for up to 8 visits across gestation. At each visit, women completed a questionnaire about product use in the prior 24 hours and contributed urine samples, subsequently analyzed for 18 phthalate and replacement metabolites. At early, mid-, and late pregnancy, questionnaire responses were condensed and repeated metabolite concentrations were averaged. Latent class analysis (LCA) was used to determine groups of women with similar use patterns, and weighted associations between group membership and biomarker concentrations were assessed. RESULTS: LCA sorted women into groups which largely corresponded to: (1) low fragranced product use (16-23% of women); (2) fragranced product and low body wash use (22-26%); 3) fragranced product and low bar soap use (26-51%); and (4) low product use (7-34%). Monoethyl phthalate (MEP) urinary concentrations were 7-10% lower and concentrations of summed di(2-ethylhexyl) terephthalate metabolites were 15-21% lower among women in the "low fragranced product use" group compared to the population mean. Few other consistent associations between group and biomarker concentrations were noted. IMPACT STATEMENT: Personal care products and cosmetics are a known exposure source for phthalates and potentially represent one of the most accessible intervention targets for exposure reduction. However, in this analysis accounting for concurrent use and fragranced status of products, we did not find any use patterns that corresponded to universally lower levels.

OBJECTIVE: Firefighters are occupationally exposed to per- and polyfluoroalkyl substances (PFAS). This study objective was to compare serum PFAS concentrations in incumbent and recruit firefighters and evaluate temporal trends among recruits. METHODS: Serum PFAS concentrations were measured in 99 incumbent and 55 recruit firefighters at enrollment in 2015-2016, with follow-up 20-37 months later for recruits. Linear and logistic regression and linear mixed-effects models were used for analyses. Fireground exposure impact on PFAS concentrations was investigated using adjusted linear and logistic regression models. RESULTS: Incumbents had lower n-PFOA and PFNA than recruits and most PFAS significantly decreased over time among male recruits. No significant links were found between cumulative fireground exposures and PFAS concentrations. CONCLUSIONS: Serum PFAS concentrations were not increased in incumbent firefighters compared with recruits and were not associated with cumulative fireground exposures.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent synthetic chemicals found in consumer products, firefighting foam, and contaminated food and water.1 Routes of exposure include ingestion, inhalation, and dermal absorption.1 Several PFAS have long biological half-lives and can bioaccumulate in living organisms.2 Although the prevalence of commonly manufactured PFAS in the United States has decreased since 2000 following phase-outs and chemical substitutions, their detection in humans remains high.1 | | PFAS can cross the blood–follicle barrier and have been detected in follicular fluid.3 Greater serum PFAS concentrations have been associated with irregular menses, longer menstrual cycles, lower estradiol and progesterone concentrations, and premature ovarian insufficiency.3 Greater concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorodecanoic acid (PFDA), and perfluorononanoic acid (PFNA) have been associated with reduced fertility,4 though results vary by study design and parity. For example, most retrospective studies showed inverse associations between PFOA and fertility, whereas most prospective studies did not4; some showed inverse associations among nulliparous participants only.4

BACKGROUND: Studying carcinogens in tobacco and non-tobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer. METHODS: Golestan Cohort Study (GCS) has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma (ESCC). For this nested study, the cases comprised of all incident cases by Jan 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and tobacco-specific nitrosamines (TSNAs). We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for associations between the 90th versus the 10th percentiles of the biomarker concentrations and incident ESCC. RESULTS: Among individuals who did not currently use tobacco (148 cases/163 controls), two acrolein metabolites, two acrylonitrile metabolites, one propylene oxide metabolite and one 1,3-butadiene metabolite were significantly associated with incident ESCC (adjusted ORs between 1.8 and 4.3). Among tobacco users (57 cases/63 controls), metabolites of two other VOCs (styrene and xylene) were associated with ESCC (ORs= 6.2 and 9.0). In tobacco users, two TSNAs (NNN and N'-Nitrosoanatabine) were also associated with ESCC. Suggestive associations were seen with some PAHs (especially 2-hydroxynaphthalene) in non-users of tobacco products and other TSNAs in tobacco users. CONCLUSION: These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications.

INTRODUCTION: High mammographic density is among the strongest and most established predictors for breast cancer risk. Puberty, the period during which breasts undergo exponential mammary growth, is considered one of the critical stages of breast development for environmental exposures. Benzylbutyl phthalate (BBP) and perfluorooctanoic acid (PFOA) are pervasive endocrine disrupting chemicals that may increase hormone-sensitive cancers. Evaluating the potential impact of BBP and PFOA exposure on pubertal breast density is important to our understanding of early-life environmental influences on breast cancer etiology. OBJECTIVE: To prospectively assess the effect of biomarker concentrations of monobenzyl phthalate (MBzP) and PFOA at specific pubertal window of susceptibility (WOS) on adolescent breast density. METHOD: This study included 376 Chilean girls from the Growth and Obesity Cohort Study with data collection at four timepoints: Tanner breast stages 1 (B1) and 4 (B4), 1- year post- menarche (1YPM) and 2-years post-menarche (2YPM). Dual-energy X-ray absorptiometry was used to assess the absolute fibroglandular volume (FGV) and percent breast density (%FGV) at 2YPM. We used concentrations of PFOA in serum and MBzP in urine as an index of exposure to PFOA and BBP, respectively. Parametric G-formula was used to estimate the time-specific effects of MBzP and PFOA on breast density. The models included body fat percentage as a time-varying confounder and age, birthweight, age at menarche, and maternal education as fixed covariates. RESULTS: A doubling of serum PFOA concentration at B4 resulted in a non-significant increase in absolute FGV (β:11.25, 95% confidence interval (CI): -0.28, 23.49)), while a doubling of PFOA concentration at 1YPM resulted in a decrease in % FGV (β:-4.61, 95% CI: -7.45, -1.78). We observed no associations between urine MBzP and breast density measures. CONCLUSION: In this cohort of Latina girls, PFOA serum concentrations corresponded to a decrease in % FGV. No effect was observed between MBzP and breast density measures across pubertal WOS.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent organic pollutants detectable in the serum of most U.S. adults. We previously reported a positive association between serum perfluorooctanoate (PFOA) concentrations and risk of renal cell carcinoma (RCC) within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, comprising predominantly White individuals enrolled in 1993-2001. To extend our investigations to a larger and more racially and ethnically diverse population, we conducted a nested case-control study of serum PFAS concentrations and RCC within the Multiethnic Cohort Study. We measured pre-diagnostic serum concentrations of nine PFAS among 428 RCC cases and 428 individually matched controls. We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for risk of RCC in relation to each PFAS using conditional logistic regression, adjusting for RCC risk factors and other PFAS. PFOA was not associated with RCC risk overall [doubling in serum concentration, OR(continuous) = 0.89 (95 %CI = 0.67, 1.18)]. However, we observed suggestive positive associations among White participants [2.12 (0.87, 5.18)] and among participants who had blood drawn before 2002 [1.49 (0.77, 2.87)]. Furthermore, higher perfluorononanoate (PFNA) concentration was associated with increased risk of RCC overall [fourth vs. first quartile, OR = 1.84 (0.97, 3.50), P(trend) = 0.04; OR(continuous) = 1.29 (0.97, 1.71)], with the strongest association observed among African American participants [OR(continuous) = 3.69 (1.33, 10.25)], followed by Native Hawaiian [2.24 (0.70, 7.19)] and White [1.98 (0.92, 4.25)] participants. Most other PFAS were not associated with RCC. While PFOA was not associated with RCC risk overall in this racially and ethnically diverse population, the positive associations observed among White participants and those with sera collected before 2002 are consistent with previous PLCO findings. Our study also provided new evidence of a positive association between PFNA and RCC risk that was strongest in African American participants. These findings highlight the need for additional epidemiologic research investigating PFAS exposures and RCC in large racially and ethnically diverse populations.

Human exposure to phthalates is widespread, but assessment of variability across pregnancy has been hampered by short half-lives of phthalate biomarkers and a few repeated measures in prior studies. We aimed to characterize the variability and longitudinal profiles of phthalate and replacement biomarkers across pregnancy. Within the Human Placenta and Phthalates Study, 303 pregnant women provided urine samples at up to 8 visits across gestation. Concentrations of 14 metabolites of phthalates and 4 metabolites of replacements were quantified in each sample, and subject-specific averages within each trimester were calculated. We examined variability in individual biomarker concentrations across the 8 visits, within trimesters, and across trimester-specific averages using intraclass correlation coefficients (ICCs). To explore longitudinal exposure biomarker profiles, we applied group-based trajectory modeling to trimester-specific averages over pregnancy. Pooling multiple visits into trimester-specific averages improved the ICCs for all biomarkers. Most biomarkers generally showed stable concentrations across gestation, i.e., high-, medium-, and low-concentration profiles, with small proportions of participants falling into the "high"-exposure groups. Variability over pregnancy is likely attributable to random fluctuations around a baseline exposure rather than true changes in concentrations over time.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a component of firefighting foams used at military installations. Although high PFAS exposures have been related to cancer risks among civilian populations, the effects for military personnel are unclear. OBJECTIVES: We investigated associations between serum PFAS concentrations and testicular germ cell tumors (TGCT) among U.S. Air Force servicemen. METHODS: This nested case-control study involved active-duty Air Force servicemen with sera from the Department of Defense Serum Repository. We selected 530 cases and 530 controls individually matched on birth date, race and ethnicity, year entered the service, and year of sample collection, with prediagnostic serum samples collected between 1988 and 2017. A second prediagnostic sample, collected a median of 4 y after the first, was selected for 187 case-control pairs. Seven PFAS were quantified using isotope-dilution tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals (CIs) from conditional logistic regression adjusting for military grade, number of deployments, and, in some models, other PFAS, estimated associations between PFAS concentrations (categorized using quartiles among controls) and TGCT. RESULTS: Elevated concentrations of some PFAS were observed for military employment in firefighting [perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid] and service at a base with high PFAS concentrations in drinking water (PFHxS). Elevated PFOS concentrations in the second sample were positively associated with TGCT [OR for fourth vs. first quartile (ORQ4) = 2.6, 95% CI: 1.1, 6.4; ptrend = 0.02], including after adjustment for other PFAS (ORQ4 = 4.6, 95% CI: 1.4, 15.1; ptrend = 0.009). Associations with PFOS in the first/only samples were weak and not statistically significant. Elevated concentrations of perfluorononanoic acid were inversely associated with TGCT, whereas results were null for other PFAS. DISCUSSION: We identified service-related predictors of PFAS concentrations and increased TGCT relative risks with elevated PFOS concentrations among Air Force servicemen. These findings warrant further investigation in other populations and military service branches. 10.1289/EHP12603.

BACKGROUND: Free thyroxine (FT4) measurement is one of the most requested tests in patient care for diagnosing and treating thyroid-related illnesses. Equilibrium dialysis (ED) is considered the "gold standard" for FT4 measurement; however, several factors have a profound effect on the reliability of FT4 assays and require special consideration. METHODS: In the current study, we focused on evaluating critical factors that could contribute to reporting errors, such as adsorption of thyroxine (T4) to labware surfaces, stability of serum samples, stock solutions, and calibrator storage conditions, as well as the solvents used to prepare T4 solutions. RESULTS: The adsorption of T4 in ethanolic solutions and dialysates to labware surfaces can be reduced with the careful selection of pipette tips, test tubes, and 96-well plates. Adding pH modifiers to neat T4 solutions can improve its stability. FT4 in serum samples remains stable after exposure to four freeze-thaw cycles, 5 °C for 18-20 h, or -70 °C for a minimum of three years. CONCLUSION: The presented study has demonstrated that the loss of analyte due to pre-analytical and analytical factors during operation of the FT4 reference measurement procedure (RMP) can be minimized by careful selection of all labware for sample preparation. It was found that the accuracy and imprecision of FT4 assays can be influenced by different types of dialysis devices, but acceptable alternatives to ED membranes were identified. This study demonstrates approaches to establish a FT4 method that is independent from specific suppliers and addresses critical pre-analytical and analytical factors important for FT4 measurements.

Per- and polyfluoroalkyl substances (PFAS), widely used in industrial and consumer products, are suspected metabolic disruptors. We examined the association between a PFAS mixture during pregnancy and postpartum weight retention in 482 participants from the New Hampshire Birth Cohort Study. PFAS concentrations, including perfluorohexane sulfonate, perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), and perfluorodecanoate, were quantified in maternal plasma collected at ~28 gestational weeks. Postpartum weight change was calculated as the difference between self-reported weight from a postpartum survey administered in 2020 and pre-pregnancy weight abstracted from medical records. Associations between PFAS and postpartum weight change were examined using Bayesian kernel machine regression and multivariable linear regression, adjusting for demographic, reproductive, dietary, and physical activity factors; gestational week of blood sample collection; and enrollment year. PFOS, PFOA, and PFNA were positively associated with postpartum weight retention, and associations were stronger among participants with a higher pre-pregnancy body mass index. A doubling of PFOS, PFOA, and PFNA concentrations was associated with a 1.76 kg (95%CI: 0.31, 3.22), 1.39 kg (-0.27, 3.04), and 1.04 kg (-0.19, 2.28) greater postpartum weight retention, respectively, among participants who had obesity/overweight prior to pregnancy. Prenatal PFAS exposure may be associated with increased postpartum weight retention.

BACKGROUND: Pregnant persons are exposed ubiquitously to phthalates and increasingly to chemicals introduced to replace phthalates. In early pregnancy, exposure to these chemicals may disrupt fetal formation and development, manifesting adverse fetal growth. Previous studies examining the consequences of early pregnancy exposure relied on single spot urine measures and did not investigate replacement chemicals. OBJECTIVE: Characterize associations between urinary phthalate and replacement biomarkers in early pregnancy and fetal growth outcomes. METHODS: Analyses were conducted among 254 pregnancies in the Human Placenta and Phthalates Study, a prospective cohort with recruitment 2017-2020. Exposures were geometric mean concentrations of phthalate and replacement biomarkers quantified in two spot urine samples collected around 12- and 14-weeks of gestation. Outcomes were fetal ultrasound biometry (head and abdominal circumferences, femur length, estimated fetal weight) collected in each trimester and converted to z-scores. Adjusted linear mixed effects (single-pollutant) and quantile g-computation (mixture) models with participant-specific random effects estimated the difference, on average, in longitudinal fetal growth for a one-interquartile range (IQR) increase in individual (single-pollutant) or all (mixture) early pregnancy phthalate and replacement biomarkers. RESULTS: Mono carboxyisononyl phthalate and the sums of metabolites of di-n-butyl, di-iso-butyl, and di-2-ethylhexyl phthalate were inversely associated with fetal head and abdominal circumference z-scores. A one-IQR increase in the phthalate and replacement biomarker mixture was inversely associated with fetal head circumference (β: -0.36 [95% confidence interval: -0.56, -0.15]) and abdominal circumference (-0.31 [-0.49, -0.12]) z-scores. This association was mainly driven by phthalate biomarkers. CONCLUSIONS: Urine concentrations of phthalate biomarkers, but not replacement biomarkers, in early pregnancy were associated with reductions in fetal growth. Though the clinical implications of these differences are unclear, reduced fetal growth contributes to excess morbidity and mortality across the lifecourse. Given widespread global exposure to phthalates, findings suggest a substantial population health burden resulting from early pregnancy phthalate exposure.