Cross-Sectional Associations between Prenatal Per- and Poly-Fluoroalkyl Substances and Bioactive Lipids in Three Environmental Influences on Child Health Outcomes (ECHO) Cohorts.

Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks' gestation) from three Environmental influences on Child Health Outcomes Program cohorts. Pairwise association estimates across cohorts were obtained through linear mixed models and meta-analysis, adjusting the former for false discovery rates. Associations between the PFAS mixture and bioactive lipids were estimated using quantile g-computation. Pairwise analyses revealed bioactive lipid levels associated with PFDeA, PFNA, PFOA, and PFUdA (p < 0.05) across three enzymatic pathways (cyclooxygenase, cytochrome p450, lipoxygenase) in at least one combined cohort analysis, and PFOA and PFUdA (q < 0.2) in one linear mixed model. The strongest signature revealed doubling in PFOA corresponding with PGD2 (cyclooxygenase pathway; +24.3%, 95% CI: 7.3-43.9%) in the combined cohort. Mixture analysis revealed nine positive associations across all pathways with the PFAS mixture, the strongest signature indicating a quartile increase in the PFAS mixture associated with PGD2 (+34%, 95% CI: 8-66%), primarily driven by PFOS. Bioactive lipids emerged as prenatal PFAS exposure biomarkers, deepening insights into PFAS' influence on pregnancy outcomes.

Associations of per- and polyfluoroalkyl substances with maternal early second trimester sex-steroid hormones.

BACKGROUND/AIMS: Pregnant women are exposed to persistent environmental contaminants, including per- and polyfluoroalkyl substances (PFAS) that disrupt thyroid function. However, it is unclear if PFAS alter maternal sex-steroid hormone levels, which support pregnancy health and fetal development. METHODS: In Illinois women with relatively high socioeconomic status (n = 460), we quantified perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid, perfluorohexanesulphonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid concentrations in fasting serum samples at median 17 weeks gestation, along with plasma progesterone, testosterone, and estradiol. We evaluated covariate-adjusted associations of ln-transformed hormones with each ln-transformed PFAS individually using linear regression and with the PFAS mixture using quantile-based g-computation (QGComp). RESULTS: Interquartile range (IQR) increases in PFOS were associated with higher progesterone (%Δ 3.0; 95%CI: -0.6, 6.6) and estradiol (%Δ: 8.1; 95%CI: 2.2, 14.4) levels. Additionally, PFHxS was positively associated with testosterone (%Δ: 10.2; 95%CI: 4.0, 16.7), whereas both PFDeA and PFUdA were inversely associated with testosterone (%Δ: -5.7; 95%CI: -10.3, -0.8, and %Δ: -4.1; 95%CI: -7.6, -0.4, respectively). The IQR-standardized PFAS mixture was not associated with progesterone (%Δ: 1.6; 95%CI: -5.8, 9.2), due equal partial positive (%Δ: 9.2; driven by PFOA) and negative (%Δ: -7.4; driven by PFOS) mixture associations. Similarly, the mixture was not associated with testosterone (%Δ: 5.3; 95%CI: -9.0, 20.1), due to similar partial positive (%Δ: 23.6; driven by PFHxS) and negative (%Δ: -17.4; driven by PFDeA) mixture associations. However, we observed a slightly stronger partial positive (%Δ: 25.6; driven by PFOS and PFUdA) than negative (%Δ: -16.3; driven by PFOA) association resulting in an overall non-significant positive trend between the mixture and estradiol (%Δ: 8.5; 95%CI: -3.7, 20.9). CONCLUSION: PFAS mixture modeled using QGComp was not associated with maternal sex-steroid hormones due to potential opposing effects of certain PFAS. Additional prospective studies could corroborate these findings.

Birth outcomes in relation to neighborhood food access and individual food insecurity during pregnancy in the Environmental Influences on Child Health Outcomes (ECHO)-wide cohort study.

BACKGROUND: Limited access to healthy foods, resulting from residence in neighborhoods with low-food access or from household food insecurity, is a public health concern. Contributions of these measures during pregnancy to birth outcomes remain understudied. OBJECTIVES: We examined associations between neighborhood food access and individual food insecurity during pregnancy with birth outcomes. METHODS: We used data from 53 cohorts participating in the nationwide Environmental Influences on Child Health Outcomes-Wide Cohort Study. Participant inclusion required a geocoded residential address or response to a food insecurity question during pregnancy and information on birth outcomes. Exposures include low-income-low-food-access (LILA, where the nearest supermarket is >0.5 miles for urban or >10 miles for rural areas) or low-income-low-vehicle-access (LILV, where few households have a vehicle and >0.5 miles from the nearest supermarket) neighborhoods and individual food insecurity. Mixed-effects models estimated associations with birth outcomes, adjusting for socioeconomic and pregnancy characteristics. RESULTS: Among 22,206 pregnant participants (mean age 30.4 y) with neighborhood food access data, 24.1% resided in LILA neighborhoods and 13.6% in LILV neighborhoods. Of 1630 pregnant participants with individual-level food insecurity data (mean age 29.7 y), 8.0% experienced food insecurity. Residence in LILA (compared with non-LILA) neighborhoods was associated with lower birth weight [ß -44.3 g; 95% confidence interval (CI): -62.9, -25.6], lower birth weight-for-gestational-age z-score (-0.09 SD units; -0.12, -0.05), higher odds of small-for-gestational-age [odds ratio (OR) 1.15; 95% CI: 1.00, 1.33], and lower odds of large-for-gestational-age (0.85; 95% CI: 0.77, 0.94). Similar findings were observed for residence in LILV neighborhoods. No associations of individual food insecurity with birth outcomes were observed. CONCLUSIONS: Residence in LILA or LILV neighborhoods during pregnancy is associated with adverse birth outcomes. These findings highlight the need for future studies examining whether investing in neighborhood resources to improve food access during pregnancy would promote equitable birth outcomes.

Associations of per- and polyfluoroalkyl substances with maternal metabolic and inflammatory biomarkers in early-to-mid-pregnancy.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) can disrupt metabolism. Early-to-mid pregnancy is characterized by amplified metabolic processes and inflammation to support maternal adaptations and fetal growth. Thus, we cross-sectionally evaluated whether PFAS are individually and jointly associated with these processes in early-to-mid pregnancy. METHODS: Pregnant Illinois women (n = 452) provided fasted blood samples at median 17 weeks gestation. We quantified serum perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid (Me-PFOSA-AcOH), perfluorohexanesulfonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid. Key outcomes were plasma glucose, insulin, C-peptide, insulin-like growth factor 1 (IGF-1), adiponectin, leptin, triglycerides, free fatty acids, total cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6. We calculated homeostatic model assessment for insulin resistance (HOMA-IR), low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL). We evaluated associations of PFAS with each metabolic/inflammatory biomarker individually using covariate-adjusted linear regression and jointly using quantile-based g-computation. RESULTS: In linear regression, all PFAS (except Me-PFOSA-AcOH) were negatively associated with insulin, HOMA-IR, and leptin, whereas all PFAS were positively associated with HDL cholesterol. We also observed negative associations of some PFAS with TNF-α and MCP-1; positive associations with adiponectin and total cholesterol also emerged. Additionally, PFOS was positively, whereas Me-PFOSA-AcOH was negatively, associated with triglycerides and VLDL. Each 25% increase in the PFAS mixture was associated with -31.3% lower insulin (95%CI: -45.8, -12.9), -31.9% lower HOMA-IR (95%CI: -46.4, -13.4), and -9.4% lower leptin (95%CI: -17.3, -0.8), but 7.4% higher HDL cholesterol (95%CI: 4.6, 10.3). For most outcomes, the major contributors to the PFAS mixture often differed compared to single-PFAS analyses. IMPLICATIONS: Individual and joint PFAS exposures were associated with markers of maternal metabolism and inflammation in pregnancy. Further investigation is needed to elucidate possible mechanisms and consequences of these findings.

Associations of urinary non-persistent endocrine disrupting chemical biomarkers with early-to-mid pregnancy plasma sex-steroid and thyroid hormones.

BACKGROUND/OBJECTIVES: Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones. METHODS: Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8-40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions. RESULTS: In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with -5.65% (95% CI: -9.79, -1.28) lower testosterone and -0.09 µIU/mL (95% CI: -0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: -0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with -1.77% (95% CI: -4.08, 0.58) lower TT4 and -0.18 µIU/mL (95% CI: -0.33, -0.03) lower TSH. We also identified select chemical interactions. CONCLUSION: Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes.

Cross-sectional associations between prenatal maternal per- and poly-fluoroalkyl substances and bioactive lipids in three Environmental influences on Child Health Outcomes (ECHO) cohorts.

Background: Per- and poly-fluoroalkyl substances (PFAS) exposure can occur through ingestion of contaminated food and water, and inhalation of indoor air contaminated with these chemicals from consumer and industrial products. Prenatal PFAS exposures may confer risk for pregnancy-related outcomes such as hypertensive and metabolic disorders, preterm birth, and impaired fetal development through intermediate metabolic and inflammation pathways. Objective: Estimate associations between maternal pregnancy PFAS exposure (individually and as a mixture) and bioactive lipids. Methods: Our study included pregnant women in the Environmental influences on Child Health Outcomes Program: Chemicals in our Bodies cohort (CiOB, n=73), Illinois Kids Developmental Study (IKIDS, n=287), and the ECHO-PROTECT cohort (n=54). We measured twelve PFAS in serum and 50 plasma bioactive lipids (parent fatty acids and eicosanoids derived from cytochrome p450, lipoxygenase, and cyclooxygenase) during pregnancy (median 17 gestational weeks). Pairwise associations across cohorts were estimated using linear mixed models and meta-analysis. Associations between the PFAS mixture and individual bioactive lipids were estimated using quantile g-computation. Results: PFDeA, PFOA, and PFUdA were associated (p<0.05) with changes in bioactive lipid levels in all three enzymatic pathways (cyclooxygenase [n=6 signatures]; cytochrome p450 [n=5 signatures]; lipoxygenase [n=7 signatures]) in at least one combined cohort analysis. The strongest signature indicated that a doubling in PFOA corresponded with a 24.3% increase (95% CI [7.3%, 43.9%]) in PGD2 (cyclooxygenase pathway) in the combined cohort. In the mixtures analysis, we observed nine positive signals across all pathways associated with the PFAS mixture. The strongest signature indicated that a quartile increase in the PFAS mixture was associated with a 34% increase in PGD2 (95% CI [8%, 66%]), with PFOS contributing most to the increase. Conclusions: Bioactive lipids were revealed as biomarkers of PFAS exposure and could provide mechanistic insights into PFAS' influence on pregnancy outcomes, informing more precise risk estimation and prevention strategies.

Interrogating Components of 2 Diet Quality Indices in Pregnancy using a Supervised Statistical Mixtures Approach.

BACKGROUND: The Healthy Eating Index (HEI)-2015 and Alternative Healthy Eating Index (AHEI)-2010 evaluate diet holistically in pregnancy. However, it remains unclear how individual index components interact to contribute to health. OBJECTIVES: To evaluate associations of HEI-2015 and AHEI-2010 components with gestational length using traditional and novel statistical methods in a prospective cohort. METHODS: Pregnant women completed a 3-mo food-frequency questionnaire (FFQ) at median 13 wk gestation to calculate the HEI-2015 or AHEI-2010. Covariate-adjusted linear regression models evaluated associations of HEI-2015 and AHEI-2010 total scores and individual components (one at a time and simultaneously adjusted) with gestational length. Covariate-adjusted weighted quantile sum regression models evaluated 1) associations of HEI-2015 or AHEI-2010 components as mixtures with gestational length and 2) contributions of components to these associations. RESULTS: Each 10-point increase in HEI-2015 and AHEI-2010 total score was associated with 0.11 (95% CI: -0.05, 0.27) and 0.14 (95% CI: 0.00, 0.28) wk longer gestation, respectively. In individual or simultaneously adjusted HEI-2015 models, higher intakes of seafood/plant proteins, total protein foods, greens/beans, and saturated fats but lower intakes of added sugars and refined grains were associated with longer gestational length. For the AHEI-2010, higher intake of nuts/legumes and lower intake of sugar-sweetened beverages (SSBs)/fruit juice were associated with longer gestational length. Jointly, 10% increases in HEI-2015 or AHEI-2010 mixtures were associated with 0.17 (95% CI: 0.001, 0.34) and 0.18 (95% CI: 0.05, 0.30) wk longer gestational length, respectively. Seafood/plant protein, total protein foods, dairy, greens/beans, and added sugars were the largest contributors to the HEI-2015 mixture. Nuts/legumes, SSBs/fruit juice, sodium, and DHA/EPA were the largest contributors to the AHEI-2010 mixture. Associations were less precise but consistent in women with spontaneous labors. CONCLUSIONS: Compared to traditional methods, associations of diet index mixtures with gestational length were more robust and identified unique contributors. Additional studies could consider interrogating these statistical approaches using other dietary indices and health outcomes.

The potential role of environmental factors in modulating mitochondrial DNA epigenetic marks.

Many studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases. Mitochondria are responsible for most cellular energy production, and unlike other cytoplasmic organelles, mitochondria contain their own genome. Most research to date, through investigating mitochondrial DNA copy number, has focused on larger structural changes or alterations to the entire mitochondrial genome and their role in human disease. Using these methods, mitochondrial dysfunction has been linked to cancers, cardiovascular disease, and metabolic health. However, like the nuclear genome, the mitochondrial genome may experience epigenetic alterations, including DNA methylation that may partially explain some of the health effects of various exposures. Recently, there has been a movement to understand human health and disease within the context of the exposome, which aims to describe and quantify the entirety of all exposures people encounter throughout their lives. These include, among others, environmental pollutants, occupational exposures, heavy metals, and lifestyle and behavioral factors. In this chapter, we summarize the current research on mitochondria and human health, provide an overview of the current knowledge on mitochondrial epigenetics, and describe the experimental and epidemiologic studies that have investigated particular exposures and their relationships with mitochondrial epigenetic modifications. We conclude the chapter with suggestions for future directions in epidemiologic and experimental research that is needed to advance the growing field of mitochondrial epigenetics.

Ovarian volume partially explains associations of phthalate biomarkers with anti-Müllerian hormone and estradiol in midlife women.

BACKGROUND/OBJECTIVES: Women are ubiquitously exposed to endocrine disruptors, including phthalates. Ovarian follicles undergoing folliculogenesis (indirectly measured by ovarian volume) produce anti-Müllerian hormone (AMH) and estradiol (E2). We evaluated associations of phthalates with ovarian volume to assess whether this explained prior positive associations of phthalates with AMH and E2. METHODS: Women ages 45-54 years (n = 614) had transvaginal ultrasounds of right/left ovaries to calculate mean ovarian volume. Women provided up-to-four urine and blood samples for quantifying AMH (first serum sample), E2 (all serum samples), and nine phthalate metabolites (from pooled urine, representing six parent phthalates). Multivariable linear or logistic regression models (for individual phthalate biomarkers), as well as weighted quantile sum (WQS) regression (for mixture analyses) evaluated associations of phthalate biomarkers with ovarian volume. Using cross-sectional mediation analysis, we assessed whether associations of phthalates with ovarian volume partially explained those of phthalates with AMH or E2. RESULTS: Most women were non-Hispanic White (68%) and pre-menopausal (67%) with higher urinary phthalate metabolite concentrations than U.S. women. In single-pollutant models, 10% increases in mono(3-carboxypropyl) phthalate (MCPP) and monobenzyl phthalate (MBzP) were associated with 0.44% (95% CI: -0.02%, 0.91%) and 0.62% (95% CI: 0.02%, 1.23%) larger ovarian volumes, respectively. As a cumulative mixture, 10% increases in the phthalate mixture were associated with 2.89% larger ovarian volume (95%CI: 0.27, 5.59) with MCPP (35%) and MBzP (41%) identified as major contributors. Higher ovarian volume due to a 10% increase in MBzP (indirect effect OR: 1.004; 95% CI: 1.00, 1.01) explained 16% of the positive association between MBzP and higher AMH, whereas higher ovarian volume due to a 10% increase in MCPP (indirect effect %Δ: 0.11; 95% CI: -0.01, 0.22) explained 23% of the positive association between MCPP and E2. CONCLUSION: In this cross-sectional study, phthalates were associated with increased ovarian volume, with implications for midlife hormone production.

Urinary phthalate metabolite concentrations and hot flash outcomes: Longitudinal associations in the Midlife Women's Health Study.

Midlife in women is an understudied time for environmental chemical exposures and menopausal outcomes. Recent cross-sectional research links phthalates with hot flashes, but little is known regarding such associations over time. Our objective was to estimate longitudinal associations between repeated measures of urinary phthalate metabolite concentrations and hot flash outcomes in midlife women. Using data from the Midlife Women's Health Study (MWHS), a prospective longitudinal study, we fit generalized linear mixed-effects models (GLMMs) and Cox proportional hazards regression models to repeated measures over a 4-year period. Recruitment occurred in Baltimore and surrounding counties, Maryland, USA between 2006 and 2015. Participants were premenopausal/perimenopausal women (n = 744) aged 45-54 years, who were not pregnant, not taking menopausal symptom medication or oral contraceptives, did not have hysterectomy/oophorectomy, and irrespective of hot flash experience. Baseline mean (SD) age was 48.4 (2.45), and 65% were premenopausal. Main outcome measures included adjusted odds ratios (ORs) for 4 self-reported hot flash outcomes (ever experienced, past 30 days experience, weekly/daily, and moderate/severe), and hazard ratios (HRs) for incident hot flashes. We observed mostly increased odds of certain hot flash outcomes with higher concentrations of metabolites of di (2-ethylhexyl) phthalate (DEHP), monoisobutyl phthalate (MiBP), and a molar summary measure of plasticizer phthalate metabolites (DEHP metabolites, mono-(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP)). Some associations between exposures and outcomes indicated decreased odds. In conclusion, phthalate metabolites were associated with certain hot flash outcomes in midlife women. Midlife may be a sensitive period for higher phthalate metabolite concentrations with respect to menopausal symptoms.

Associations of individual and cumulative urinary phthalate and replacement biomarkers with gestational weight gain through late pregnancy.

BACKGROUND/AIMS: Phthalates and their replacements are endocrine/metabolic disruptors that may impact gestational weight gain (GWG) - a pregnancy health indicator. We investigated overall and fetal sex-specific associations of individual and cumulative phthalate/replacement biomarkers with GWG. METHODS: Illinois women (n = 299) self-reported their weight pre-pregnancy and at their final obstetric appointment before delivery (median 38 weeks). We calculated pre-pregnancy body mass index and gestational age-specific GWG z-scores (GWGz). We quantified 19 phthalate/replacement metabolites (representing 10 parent compounds) in pools of up-to-five first-morning urine samples, collected approximately monthly between 8 and 40 weeks gestation. We used linear regression, quantile-based g-computation (QGComp), and weighted quantile sum regression (WQSR) to evaluate associations of ten biomarkers (individual metabolites or parent molar-sums) individually or as mixtures (in interquartile range intervals) with GWGz. We evaluated associations in all women and stratified by fetal sex. RESULTS: Individually, sums of metabolites of di(2-ethylhexyl) phthalate (Æ©DEHP), di(isononyl) cyclohexane-1,2-dicarboxylate (Æ©DiNCH), and di(2-ethylhexyl) terephthalate (Æ©DEHTP) had consistent inverse associations with GWGz, and some associations were fetal sex-specific. When evaluating phthalates/replacements as a mixture, QGComp identified Æ©DEHP, Æ©DEHTP, and mono-(3-carboxypropyl) phthalate, along with sum of di(isononyl) phthalate metabolites (Æ©DiNP) and monobenzyl phthalate as notable contributors to lower and higher GWGz, respectively, resulting in a marginal inverse joint association in all women (ß: -0.29; 95% CI: -0.70, 0.12). In women carrying females, Æ©DEHP contributed to the marginal inverse joint association (ß: -0.54; 95% CI: -1.09, 0.03). However, there was no overall association in women carrying males (ß: 0.00; 95% CI: -0.60, 0.59), which was explained by approximately equal negative (driven by Æ©DEHTP) and positive (driven by Æ©DiNP) partial associations. WQSR analyses consistently replicated these QGComp findings. CONCLUSIONS: Biomarkers of phthalates/replacements were fetal sex-specifically associated with GWGz. Because Æ©DEHTP contributed substantively to mixture associations, additional studies in pregnant women may be needed around this plasticizer replacement.

Mono-(2-ethyl-5-hydroxyhexyl) phthalate promotes uterine leiomyoma cell survival through tryptophan-kynurenine-AHR pathway activation.

Uterine leiomyoma is the most common tumor in women and causes severe morbidity in 15 to 30% of reproductive-age women. Epidemiological studies consistently indicate a correlation between leiomyoma development and exposure to endocrine-disrupting chemical phthalates, especially di-(2-ethylhexyl) phthalate (DEHP); however, the underlying mechanisms are unknown. Here, among the most commonly encountered phthalate metabolites, we found the strongest association between the urine levels of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), the principal DEHP metabolite, and the risk of uterine leiomyoma diagnosis (n = 712 patients). The treatment of primary leiomyoma and smooth muscle cells (n = 29) with various mixtures of phthalate metabolites, at concentrations equivalent to those detected in urine samples, significantly increased cell viability and decreased apoptosis. MEHHP had the strongest effects on both cell viability and apoptosis. MEHHP increased cellular tryptophan and kynurenine levels strikingly and induced the expression of the tryptophan transporters SLC7A5 and SLC7A8, as well as, tryptophan 2,3-dioxygenase (TDO2), the key enzyme catalyzing the conversion of tryptophan to kynurenine that is the endogenous ligand of aryl hydrocarbon receptor (AHR). MEHHP stimulated nuclear localization of AHR and up-regulated the expression of CYP1A1 and CYP1B1, two prototype targets of AHR. siRNA knockdown or pharmacological inhibition of SLC7A5/SLC7A8, TDO2, or AHR abolished MEHHP-mediated effects on leiomyoma cell survival. These findings indicate that MEHHP promotes leiomyoma cell survival by activating the tryptophan-kynurenine-AHR pathway. This study pinpoints MEHHP exposure as a high-risk factor for leiomyoma growth, uncovers a mechanism by which exposure to environmental phthalate impacts leiomyoma pathogenesis, and may lead to the development of novel druggable targets.

Effects of Elevated Maternal Adiposity on Offspring Reproductive Health: A Perspective From Epidemiologic Studies.

One in seven couples in developed countries suffers from infertility. Maternal overweight or obesity have detrimental and lasting effects on offspring cardiometabolic health, and although substantially more data are needed, hormonal imbalances in utero resulting from excessive maternal adiposity could also disrupt reproductive programming and affect the future reproductive health of offspring. Therefore, this mini-review evaluates the human epidemiologic evidence that maternal overweight/obesity could be associated with poor reproductive health outcomes in offspring. We searched PubMed for relevant studies using terms such as "maternal obesity" and "reproductive development." While the human epidemiologic literature is limited, studies have thus far observed that maternal obesity is associated with disrupted external genital development and several other markers of reproductive health across the lifespan. Specifically, maternal obesity is associated with higher risks of hypospadias and cryptorchidism in males and disrupted anogenital distance both in males and females. Maternal obesity has also been linked to earlier age at menarche in daughters, and precocious puberty in both sons and daughters. Finally, daughters of women with overweight or obesity have higher risks of developing polycystic ovarian syndrome, which has implications for fertility. This body of research suggests that in utero exposure to maternal obesity could disrupt reproductive system development, but substantially more evidence is needed, as almost no human epidemiologic studies have evaluated the long-term consequences of maternal obesity with regard to offspring fertility/fecundity.

Determinants of urinary phthalate biomarker concentrations in pre- and perimenopausal women with consideration of race.

BACKGROUND/OBJECTIVES: Phthalates are endocrine disruptors in consumer plastics and personal care products. Our objectives were to identify determinants of phthalate biomarkers in women during the hormonally-sensitive midlife period, and to consider differences between non-Hispanic White and Black women. METHODS: We used information from the Midlife Women's Health Study of pre- and peri-menopausal women from Baltimore, Maryland (enrolled 2006-2015). We collected sociodemographic/health information via baseline questionnaires or during clinic visits and measured nine phthalate metabolites in pools of 2-4 urines collected across one menstrual cycle. We calculated molar sums of metabolites to estimate exposure to di(2-ethylhexyl) phthalate (ΣDEHP), personal care product phthalates (ΣPCPs), and phthalates in plastics (ΣPlastics). Accounting for meaningful predictors from bivariable analyses, our multivariable linear regression models evaluated determinants of phthalate biomarkers in all women (n = 689), non-Hispanic White women only (n = 467), or non-Hispanic Black women only (n = 195). RESULTS: In multivariable analyses of all women, those who were perimenopausal, widowed/divorced, non-Hispanic Black, with higher family income, with lower BMI, or who reported more frequent nausea had higher monoethyl phthalate (MEP) and ΣPCP. Non-Hispanic White women who were perimenopausal had lower mono-(3-carboxypropyl) phthalate (MCPP) and monobutyl phthalate (MBP), those who consume alcohol had higher mono-isobutyl phthalate (MiBP), and those with higher BMI had lower MEP and higher MCPP. Alternatively, widowed/divorced Black women had higher ΣDEHP, monobenzyl phthalate (MBzP), and ΣPlastics, whereas Black women with higher income had higher MEP and ΣPCP. Black women who described themselves as having "as much" physical activity as others or who reported a skin condition had lower MBzP and MCPP, respectively. CONCLUSION: We identified important determinants of phthalate biomarkers in midlife women and observed some differences by race. Future studies could consider reasons for these differences when developing interventions to reduce phthalate disparities and related health effects.

Maternal diet quality moderates associations between parabens and birth outcomes.

BACKGROUND/OBJECTIVE: Maternal paraben exposure and diet quality are both independently associated with birth outcomes, but whether these interact is unknown. We assessed sex-specific associations of parabens with birth outcomes and differences by maternal diet quality. METHODS: Illinois pregnant women (n = 458) provided five first-morning urines collected at 8-40 weeks gestation, which we pooled for quantification of ethylparaben, methylparaben, and propylparaben concentrations. We collected/measured gestational age at delivery, birth weight, body length, and head circumference within 24 h of birth, and calculated sex-specific birth weight-for-gestational-age z-scores and weight/length ratio. Women completed three-month food frequency questionnaires in early and mid-to-late pregnancy, which we used to calculate the Alternative Healthy Eating Index (AHEI)-2010. Linear regression models evaluated sex-specific associations of parabens with birth outcomes, and differences in associations by average pregnancy AHEI-2010. RESULTS: In this predominately non-Hispanic white, college-educated sample, maternal urinary paraben concentrations were only modestly inversely associated with head circumference and gestational length. However, methylparaben and propylparaben were inversely associated with birth weight, birth weight z-scores, body length, and weight/length ratio in female, but not male newborns. For example, each 2-fold increase in methylparaben concentrations was associated with -46.61 g (95% CI: -74.70, -18.51) lower birth weight, -0.09 (95% CI: -0.15, -0.03) lower birth weight z-scores, -0.21 cm (95% CI: -0.34, -0.07) shorter body length, and -0.64 g/cm (95% CI: -1.10, -0.19) smaller weight/length ratio in females. These inverse associations were more prominent in females of mothers with poorer diets (AHEI-2010 < median), but attenuated in those with healthier diets (AHEI-2010 ≥ median). In newborn males of mothers with healthier diets, moderate inverse associations emerged for propylparaben with gestational length and head circumference. CONCLUSIONS: Maternal diet may moderate associations of parabens with birth size in a sex-specific manner. Additional studies may consider understanding the inflammatory and metabolic mechanisms underlying these findings.

Associations of maternal anthropometrics with newborn anogenital distance and the 2:4 digit ratio.

STUDY QUESTION: Are maternal anthropometrics associated with anogenital distance (AGD) and 2:4 digit ratio (2:4D) in newborns? SUMMARY ANSWER: Select maternal anthropometrics indicative of obesity or increased adiposity are associated with elongated AGD in daughters. WHAT IS KNOWN ALREADY: Excessive maternal weight or adiposity before or in early pregnancy may impact child reproductive, and other hormonally mediated, development. AGD and 2:4D are proposed markers of in utero reproductive development. STUDY DESIGN, SIZE, DURATION: This study includes 450 mother/newborn dyads participating in the Illinois Kids Development Study (I-KIDS), a prospective pregnancy cohort from Champaign-Urbana, IL, USA. Participants included in the current study enrolled between 2013 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Most mothers in this study were college-educated (82%) and non-Hispanic White (80%), and 55% were under- or normal weight before pregnancy. Pregnant women aged 18-40 years reported pre-pregnancy weight and height to calculate pre-pregnancy BMI. At 8-15 weeks gestation, we measured waist and hip circumference, and evaluated weight, % body fat, visceral fat level, % muscle and BMI using bioelectrical impedance analysis. Within 24 h of birth, we measured newborn 2nd and 4th left/right digits to calculate the 2:4D. In daughters, we measured AGDAF (anus to fourchette) and AGDAC (anus to clitoris). In sons, we measured AGDAS (anus to scrotum) and AGDAP (anus to base of the penis). MAIN RESULTS AND THE ROLE OF CHANCE: Select maternal anthropometrics were positively associated with AGD in newborn daughters, but not sons. For example, AGDAC was 0.73 mm (95% CI: 0.15, 1.32) longer for every interquartile range (IQR) increase in pre-pregnancy BMI and 0.88 mm (95% CI: 0.18, 1.58) longer for every IQR increase in hip circumference, whereas AGDAF was 0.51 mm (95% CI: 0.03, 1.00) and 0.56 mm (95% CI: 0.03, 1.09) longer for every IQR increase in hip and waist circumference, respectively. Quartile analyses generally supported linear associations, but additional strong associations emerged in Q4 (versus Q1) of maternal % body fat and visceral fat levels with AGDAC. In quartile analyses, we observed only a few modest associations of maternal anthropometrics with 2:4D, which differed by hand (left versus right) and newborn sex. Although there is always the possibility of spurious findings, the associations for both measures of female AGD were consistent across multiple maternal anthropometric measures, which strengthens our conclusions. LIMITATIONS, REASONS FOR CAUTION: Our study sample was racially and ethnically homogenous, educated and relatively healthy, so our study may not be generalizable to other populations. Additionally, we may not have been powered to identify some sex-specific associations, especially for 2:4D. WIDER IMPLICATIONS OF THE FINDINGS: Increased maternal weight and adiposity before and in early pregnancy may lengthen the female AGD, which warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This publication was made possible by the National Institute for Environmental Health Sciences (NIH/NIEHS) grants ES024795 and ES022848, the National Institute of Child Health and Human Development grant R03HD100775, the U.S. Environmental Protection Agency grant RD83543401 and National Institute of Health Office of the Director grant OD023272. Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the US EPA or NIH. Furthermore, the US EPA does not endorse the purchase of any commercial products or services mentioned in the publication. This project was also supported by the USDA National Institute of Food and Agriculture and Michigan AgBioResearch. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Parabens and Menopause-Related Health Outcomes in Midlife Women: A Pilot Study.

Background: Parabens are antimicrobial agents prevalently found in daily-use products that can interfere with the endocrine and reproductive systems. In this study, we examined the cross-sectional associations of parabens with hot flashes, hormone concentrations, and ovarian volume in a subsample of 101 nonsmoking, non-Hispanic 45- to 54-year-old women from the Midlife Women's Health Study. Materials and Methods: Women self-reported their hot flash history and underwent a transvaginal ultrasound to measure ovarian volume. Participants provided blood for quantification of serum hormones (by enzyme-linked immunosorbent assay or radioimmunoassay) and urine samples for measurements of urinary paraben biomarker levels (by high-performance liquid chromatography negative-ion electrospray ionization-tandem mass spectrometry). Linear or logistic regression models evaluated associations of specific gravity-adjusted paraben biomarker concentrations with hot flashes, hormone concentrations, and ovarian volume. Results: We observed marginal associations of propylparaben, methylparaben, and ∑parabens biomarkers (molar sum of four parabens) with hot flashes and follicle-stimulating hormone (FSH) concentrations, and of these paraben biomarkers and ethylparaben with ovarian volume. For example, women tended to have 32% (95% confidence intervals [CI]: 0.9 to 1.81), 40% (95% CI: 1.0 to 1.95), and 40% (95% CI: 0.98 to 2.01) higher odds of having recent, monthly, and mild hot flashes, respectively, for every two-fold increase in ∑parabens. Similarly, women tended to have 14.54% (95% CI: -0.10 to 31.32) higher FSH concentrations, but 5.67% (95% CI: -12.54 to 1.75) reduced ovarian volume for every two-fold increase in ∑parabens Conclusions: Overall, our preliminary findings suggest that urinary paraben biomarkers may be associated with menopause-related outcomes in midlife women. Additional studies in larger and diverse populations are needed to expand on these findings.

Identification of profiles and determinants of maternal pregnancy urinary biomarkers of phthalates and replacements in the Illinois Kids Development Study.

BACKGROUND/OBJECTIVES: Pregnant women are exposed to multiple phthalates and their replacements, which are endocrine disrupting chemicals associated with adverse maternal and child health outcomes. Identifying maternal characteristics associated with phthalate/replacement exposure during pregnancy is important. METHODS: We evaluated 13 maternal sociodemographic and lifestyle factors, enrollment year, and conception season as determinants of exposure biomarkers of phthalates and their replacements in 482 pregnant women from the Illinois Kids Development Study (I-KIDS, enrolled 2013-2018). We quantified 19 phthalate/replacement metabolites in pools of five first-morning urines collected across pregnancy. K-means clustering identified women with distinct patterns of biomarker concentrations and principal component analysis (PCA) identified principal component (PC) profiles of biomarkers that exist together. We used multivariable regression models to evaluate associations of predictors with identified k-means clusters and PCs. RESULTS: K-means clustering identified two clusters of women: 1) low phthalate/di(2-ethylhexyl) terephthalate (∑DEHTP) and 2) high phthalate/∑DEHTP biomarker concentrations. PCA identified four PCs with loadings heaviest for biomarkers of plasticizer phthalates [di-isononyl, di-isodecyl, di-n-octyl phthalates] (PC1), of other phthalates [dibenzyl, di-n-butyl, di-iso-butyl phthalates] (PC2), of phthalate replacements [∑DEHTP, di(isononyl) cyclohexane-1,2-dicarboxylate (∑DiNCH)] (PC3), and of monoethyl phthalate [MEP] (PC4). Overall, age, marital status, income, parity, pre-pregnancy BMI, caffeine intake, enrollment year, and conception season were independently associated with k-means cluster membership and at least one PC. Additionally, race/ethnicity, education, employment, pregnancy intention, smoking status, alcohol intake, and diet were associated with at least one PC. For instance, women who conceived in the spring, summer, and/or fall months had lower odds of high phthalate/∑DEHTP cluster membership and had lower plasticizer phthalate, phthalate replacement, and MEP PC scores. CONCLUSIONS: Conception season, enrollment year, and several sociodemographic/lifestyle factors were predictive of phthalate/replacement biomarker profiles. Future studies should corroborate these findings, with a special focus on replacements to which pregnant women are becoming increasingly exposed.

Midlife Urinary Phthalate Metabolite Concentrations and Prior Uterine Fibroid Diagnosis.

Fibroid etiology is poorly understood but is likely hormonally mediated. Therefore, we evaluated associations between midlife phthalates (hormone-altering chemicals) and prior fibroid diagnosis, and considered differences by weight gain status. Women (ages: 45−54; n = 754) self-reported past fibroid diagnosis. We pooled 1−4 urines collected after fibroid diagnosis over the consecutive weeks to analyze nine phthalate metabolites and calculate relevant molar sums (e.g., di(2-ethylhexyl) phthalate, ΣDEHP; anti-androgenic phthalates, ΣAA; all metabolites, ΣPhthalates). Using Poisson regression, we evaluated associations between phthalate biomarkers and the risk of having fibroid diagnosis. We explored if associations differed by weight gain from age 18 to 45−54 or in women diagnosed with fibroids within 5 years of phthalate assessment. Our major finding was that women had a 13% (RR: 1.13; 95%CI: 1.02, 1.26) and 16% (RR: 1.16; 95% CI: 1.03, 1.31) greater risk of prior fibroid diagnosis for each two-fold increase in ΣDEHP or ΣAA, respectively. These associations were strongest in women who became overweight/obese from age 18 to 45−54 and in those diagnosed <5 years before phthalate assessment. Based on these results, prospective studies should corroborate our findings related to associations between phthalates and fibroids, and may consider evaluating the role that weight gain may play in these associations.