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BACKGROUND: Cadmium (Cd) is a highly toxic and widespread environmental oxidative stressor that causes a myriad of health problems, including osteoporosis and bone damage. Although nuclear factor erythroid 2-related factor 2 (NRF2) and its Cap ‘n’ Collar and basic region Leucine Zipper (CNC-bZIP) family member nuclear factor erythroid 2-related factor 1 (NRF1) coordinate various stress responses by regulating the transcription of a variety of antioxidant and cytoprotective genes, they play distinct roles in bone metabolism and remodeling. However, the precise roles of both transcription factors in bone loss induced by prolonged Cd exposure remain unclear. OBJECTIVES: We aimed to understand the molecular mechanisms underlying Cd-induced bone loss, focusing mainly on the roles of NRF2 and NRF1 in osteoclastogenesis provoked by Cd. METHODS: Male wild-type (WT), global Nrf2-knockout (Nrf2-/-) and myeloid-specific Nrf2 knockout [Nrf2(M)-KO] mice were administered Cd (50 or 100 ppm) via drinking water for 8 or 16 wk, followed by micro-computed tomography, histological analyses, and plasma biochemical testing. Osteoclastogenesis was evaluated using bone marrow-derived osteoclast progenitor cells (BM-OPCs) and RAW 264.7 cells in the presence of Cd (10 or 20 nM) with a combination of genetic and chemical modulations targeting NRF2 and NRF1. RESULTS: Compared with relevant control mice, global Nrf2-/- or Nrf2(M)-KO mice showed exacerbated bone loss and augmented osteoclast activity following exposure to 100 ppm Cd in drinking water for up to 16 wk. In vitro osteoclastogenic analyses suggested that Nrf2-deficient BM-OPCs and RAW 264.7 cells responded more robustly to low levels of Cd (up to 20 nM) with regard to osteoclast differentiation compared with WT cells. Further mechanistic studies supported a compensatory up-regulation of long isoform of NRF1 (L-NRF1) and subsequent induction of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1 (NFATc1) as the key molecular events in the Nrf2 deficiency-worsened and Cd-provoked osteoclastogenesis. L-Nrf1 silenced (via lentiviral means) Nrf2-knockdown (KD) RAW cells exposed to Cd showed dramatically different NFATc1 and subsequent osteoclastogenesis outcomes compared with the cells of Nrf2-KD alone exposed to Cd, suggesting a mitigating effect of the Nrf1 silencing. In addition, suppression of reactive oxygen species by exogenous antioxidants N-acetyl-L-cysteine (2 mM) and mitoquinone mesylate (MitoQ; 0.2 μM) mitigated the L-NRF1-associated effects on NFATc1-driven osteoclastogenesis outcomes in Cd-exposed Nrf2-KD cells. CONCLUSIONS: This in vivo and in vitro study supported the authors’ hypothesis that Cd exposure caused bone loss, in which NRF2 and L-NRF1 responded to Cd and osteoclastogenic stimuli in a cooperative, but contradictive, manner to coordinate Nfatc1 expression, osteoclastogenesis and thus bone homeostasis. Our study suggests a novel strategy targeting NRF2 and L-NRF1 to prevent and treat the bone toxicity of Cd. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preterm birth (PTB), defined as birth before 37 wk gestation, is associated with hypertension, diabetes, inadequate prenatal care, unemployment or poverty, and metal exposure. Indigenous individuals are more likely to have maternal risk factors associated with PTB compared with other populations in the United States; however, the role of environmental metals on PTB among pregnant Indigenous women remains uncertain. Previous research identified associations between PTB and individual metals, but there is limited investigation on metal mixtures and this birth outcome. OBJECTIVES: We used a mixtures analysis framework to investigate the association between metal mixtures and PTB among pregnant Indigenous women from the Navajo Birth Cohort Study (NBCS). METHODS: Maternal urine and blood samples were collected at the time of study enrollment and analyzed for metals by inductively coupled plasma dynamic reaction cell mass spectrometry. Bayesian Profile Regression was used to identify subgroups (clusters) of individuals with similar patterns of coexposure and to model association with PTB. RESULTS: Results indicated six subgroups of maternal participants with distinct exposure profiles, including one group with low exposure to all metals and one group with total arsenic, cadmium, lead, and uranium concentrations exceeding representative concentrations calculated from the National Health and Nutrition Examination Survey (NHANES). Compared with the reference group (i.e., the lowest exposure subgroup), the subgroup with the highest overall exposure had a relative risk of PTB of 2.9 times (95% credible interval: 1.1, 6.1). Exposures in this subgroup were also higher overall than NHANES median values for women 14–45 years of age. DISCUSSION: Given the wide range of exposures and elevated PTB risk for the most exposed subgroups in a relatively small study, follow-up investigation is recommended to evaluate associations between metal mixture profiles and other birth outcomes and to test hypothesized mechanisms of action for PTB and oxidative stress caused by environmental metals. [ABSTRACT FROM AUTHOR]

BACKGROUND: Glyphosate is one of the most heavily used pesticides in the world, but little is known about sources of glyphosate exposure in pregnant people living in agricultural regions. OBJECTIVE: Our objective was to evaluate glyphosate exposure during pregnancy in relation to residential proximity to agriculture as well as agricultural spray season. METHODS: We quantified glyphosate concentrations in 453 urine samples collected biweekly from a cohort of 40 pregnant people in southern Idaho from February through December 2021. We estimated each participant’s glyphosate exposure as the geometric mean (GM) of glyphosate concentrations measured in all samples (average 푛= 11 samples/participant), as well as the GM of samples collected during the pesticide “spray season” (defined as those collected 1 May–15 August; average 푛= 5 samples/participant) and the “nonspray season” (defined as those collected before 1 May or after 15 August; average 푛= 6 samples/participant). We defined participants who resided < 0.5 km from an actively cultivated agriculture field to live “near fields” and those residing = 0.5 km from an agricultural field to live “far from fields” (푛= 22 and 18, respectively). RESULTS: Among participants living near fields, urinary glyphosate was detected more frequently and at significantly increased GM concentrations during the spray season in comparison with the nonspray season (81% vs. 55%; 0.228 μg/L vs. 0.150 μg/L, 푝 < 0.001). In contrast, among participants who lived far from fields, neither glyphosate detection frequency nor GMs differed in the spray vs nonspray season (66% vs. 64%; 0.154 μg/L vs. 0.165 μg/L, 푝= 0.45). Concentrations did not differ by residential proximity to fields during the nonspray season (0.154 μg/L vs. 0.165μg/L, for near vs. far, 푝= 0.53). DISCUSSION: Pregnant people living near agriculture fields had significantly increased urinary glyphosate concentrations during the agricultural spray season than during the nonspray season. They also had significantly higher urinary glyphosate concentrations during the spray season than those who lived far from agricultural fields at any time of year, but concentrations did not differ during the nonspray season. These findings suggest that agricultural glyphosate spray is a source of exposure for people living near fields. [ABSTRACT FROM AUTHOR]

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are chemical substances spread throughout the environment worldwide. Exposure during pregnancy represents a specific window of vulnerability for child health. OBJECTIVE: Our objective was to assess the impact of prenatal exposure to multiple PFAS on emotional and behavioral functions in 12-y-old children. METHOD: In the PELAGIE mother–child cohort (France), prenatal exposure to nine PFAS was measured from concentrations in cord serum samples. Behavior was assessed at age 12 y using the parent-reported Strengths and Difficulties Questionnaire (SDQ) and the self-reported Dominic Interactive for Adolescents (DIA) for 444 children. Associations were estimated using negative binomial models for each PFAS. Bayesian kernel machine regression (BKMR) models were performed to assess the exposure mixture effect on children’s behavior. RESULTS: In our study population, 73% of mothers had spent more than 12 y in education. Higher scores on SDQ externalizing subscale were observed with increasing cord-serum concentration of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) [adjusted mean ratio (aMR)=1.18, 95% confidence interval (CI): 1.03, 1.34, and aMR=1.14 (95% CI: 1.00, 1.29) for every doubling of concentration, respectively]. Results for the hyperactivity score were similar [aMR=1.20 (95% CI: 1.04, 1.40) and aMR=1.18 (95% CI: 1.02, 1.36), respectively]. With regard to major depressive disorder and internalizing subscales, perfluorodecanoic acid (PFDA) was associated with higher self-reported DIA scores [aMR=1.14 (95% CI: 1.01, 1.27) and aMR=1.11 (95% CI: 1.02, 1.21), respectively]. In terms of the anxiety subscale, PFDA and PFNA were associated with higher scores [aMR=1.11 (95% CI: 1.02, 1.21) and aMR=1.10 (95% CI: 1.01, 1.19), respectively]. Concurrent increases in the PFAS concentrations included in the BKMR models showed no change in the SDQ externalizing and DIA internalizing subscales scores. CONCLUSION: Prenatal exposure to PFNA and PFOA were associated with increasing scores for measures of externalizing behaviors, specifically hyperactivity. We also identified associations between PFNA and PFDA prenatal exposure levels and increasing scores related to internalizing behaviors (general anxiety and major depressive disorder), which adds to the as yet sparse literature examining the links between prenatal exposure to PFAS and internalizing disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Widespread insecticide exposure might be a risk factor for neurodevelopment of our children, but few studies examined the mixture effect of maternal coexposure to organophosphate insecticides (OPPs), pyrethroids (PYRs), and neonicotinoid insecticides (NNIs) during pregnancy on child neurodevelopment, and critical windows of exposure are unknown. OBJECTIVES: We aimed to evaluate the association of prenatal exposure to multiple insecticides with children’s neurodevelopment and to identify critical windows of the exposure. METHODS: Pregnant women were recruited into a prospective birth cohort study in Wuhan, China, from 2014–2017. Eight metabolites of OPPs (mOPPs), three metabolites of PYRs (mPYRs), and nine metabolites of NNIs (mNNIs) were measured in 3,123 urine samples collected at their first, second, and third trimesters. Children’s neurodevelopment [mental development index (MDI) and psychomotor development index (PDI)] was assessed using the Bayley Scales of Infant Development at 2 years of age (푁 = 1,041). Multivariate linear regression models, generalized estimating equation models, and weighted quantile sum (WQS) regression were used to estimate the association between the insecticide metabolites and Bayley scores. Potential sex-specific associations were also examined. RESULTS: Single chemical analysis suggested higher urinary concentrations of some insecticide metabolites at the first trimester were significantly associated with lower MDI and PDI scores, and the associations were more prominent among boys. Each 1-unit increase in ln-transformed urinary concentrations of two mOPPs, 3,5,6-trichloro-2-pyridinol and 4-nitrophenol, was associated with a decrease of 3.16 points [95% confidence interval (CI): -5:59, -0:74] and 3.06 points (95% CI: -5.45, -0.68) respectively in boys’ MDI scores. Each 1-unit increase in that of trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (trans-DCCA; an mPYR) was significantly associated with a decrease of 2.24 points (95% CI: -3.89, -0.58) in boys’ MDI scores and 1.90 points (95% CI: -3.16, -0.64) in boys’ PDI scores, respectively. Significantly positive associations of maternal urinary biomarker concentrations [e.g., dimethyl phosphate (a nonspecific mOPP) and desmethyl-clothianidin (a relatively specific mNNI)] with child neurodevelopment were also observed. Using repeated holdout validation, a 1-quartile increase in the WQS index of the insecticide mixture (in the negative direction) at the first trimester was significantly associated with a decrease of 3.02 points (95% CI: -5.47, -0.57) in MDI scores among the boys, and trans-DCCA contributed the most to the association (18%). CONCLUSIONS: Prenatal exposure to higher levels of certain insecticides and their mixture were associated with lower Bayley scores in children, particularly in boys. Early pregnancy may be a sensitive window for such an effect. Future studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to environmental pollutants, including benzo[a]pyrene (BaP), has been implicated in allergic diseases and intestinal microbiota homeostasis, but the environment–microbiota–immunity triangular relationship and to what extent BaP-induced remodeling of the gut microbiota contributes to intestinal allergic inflammation remain to be established. OBJECTIVES: We investigated the impact of BaP on intestinal allergic inflammation and examined the relationship between this effect and gut microbiota dysbiosis. We explored the potential ability of intestinal bacteria to degrade BaP and alleviate cytotoxicity as a detoxification strategy to counteract the effects of BaP exposure. METHODS: We combined microbiome shotgun metagenomics with animal histological and intestinal allergic inflammatory responses to assess the effects of BaP (50 μg/mouse per day) in a 23-d toxicity test in antigen-induced allergic female mice. In addition, genome annotation, quantitative analysis of BaP, and in vitro cytotoxicity-tests using CaCo-2 cells were conducted to infer the role of intestinal bacteria in BaP detoxification. RESULTS: BaP exposure impacted the taxonomic composition and the functional potential of the gut microbiota and aggravated antigen-induced intestinal allergic inflammatory responses. The level of inflammatory cytokines correlated with the abundance of specific bacterial taxa, including Lachnospiraceae bacterium 28-4 and Alistipes inops. We identified 614 bacteria harboring genes implicated in the degradation of BaP, and 4 of these bacterial strains were shown to significantly reduce the cytotoxicity of BaP to CaCo-2 cells in vitro. DISCUSSION: Using allergic female mice as a model, we investigated the relationship between BaP, microbiota, and host immune reactions, highlighting the role of gut bacteria in BaP-aggravated allergic reactions. Our findings offer novel insight toward establishing the causal relationship between BaP exposure and the occurrence of allergic disorders. Identifying gut bacteria that degrade BaP may provide new strategies for ameliorating BaP cytotoxicity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been previously linked to polycystic ovarian syndrome (PCOS), but only a few legacy PFAS were examined. OBJECTIVES: This study aimed to explore this association with a variety of PFAS, including legacy, branched-chain isomers, and emerging alternatives, as well as a PFAS mixture. METHODS: From 2014 to 2016, we conducted a multicenter, hospital-based case–control study on environmental endocrine disruptors and infertility in China. Three hundred sixty-six women with PCOS-related infertility and 577 control participants without PCOS were included in the current analysis. Twenty-three PFAS, including 3 emerging PFAS alternatives, 6 linear and branched PFAS isomers, 6 short-chain PFAS, and 8 legacy PFAS, were quantified in the plasma. Logistic regression and two multipollutant models [quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods] were used to assess the association of individual PFAS and PFAS mixture with PCOS, as well as the potential interactions among the congeners. RESULTS: After adjusting for potential confounders, Each 1-standard deviation higher difference in ln-transformed 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA) and hexafluoropropylene oxide dimer acid (HFPO-DA) level was significantly associated with a 29% (95% CI: 1.11, 1.52) and 39% (95% CI:1.16, 1.68) higher odds of PCOS, respectively. Meanwhile, branched isomers of perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) (i.e., br-PFHxS, n-PFOS, 1m-PFOS, Σ3,4,5m-PFOS), short-chain PFAS (i.e., PFPeS and PFHxA) and other legacy PFAS [i.e., total concentrations of PFOS (T-PFOS), and perfluorododecanoic acid (PFDoA)] were significantly associated with increased odds of PCOS. The PFAS mixture was positively related to PCOS in the BKMR model. A similar trend was observed in QGC model, a ln-unit increase in the PFAS mixture was associated with a 20% increased risk of PCOS [adjusted odds ratio (aOR)=1.20 (95% CI: 1.06, 1.37)]. After controlling for other PFAS homologs, 6:2 Cl-PFESA, HFPO-DA, Σ3,4,5m-PFOS, and PFDoA were the major contributors based on the QGC and BKMR models. The associations were more pronounced in overweight/obese women. CONCLUSIONS: In this group of women, environmental exposure to a PFAS mixture was associated with an elevated odds of PCOS, with 6:2 Cl- PFESA, HFPO-DA, Σ3,4,5m-PFOS, and PFDoA being the major contributors, especially in overweight/obese women. [ABSTRACT FROM AUTHOR]

BACKGROUND: Toxic metals, such as lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), may be associated with a higher risk of gestational hypertension and preeclampsia, whereas manganese (Mn) is an essential metal that may be protective. OBJECTIVES: We estimated the individual, independent, and joint associations of Pb, Cd, As, Hg, and Mn on the risk of developing gestational hypertension and preeclampsia in a cohort of Canadian women. METHODS: Metal concentrations were analyzed in first and third trimester maternal blood (푛=1,560). We measured blood pressure after 20 wk gestation to diagnose gestational hypertension, whereas proteinuria and other complications defined preeclampsia. We estimated individual and independent (adjusted for coexposure) relative risks (RRs) for each doubling of metal concentrations and examined interactions between toxic metals and Mn. We used quantile g-computation to estimate the joint effect of trimester-specific exposures. RESULTS: Each doubling of third trimester Pb (RR = 1.54; 95% CI: 1.06, 2.22) and first trimester blood As (RR = 1.25; 95% CI: 1.01, 1.58) was independently associated with a higher risk of developing preeclampsia. First trimester blood As (RR = 3.40; 95% CI: 1.40, 8.28) and Mn (RR = 0.63; 95% CI: 0.42, 0.94) concentrations were associated with a higher and lower risk, respectively, of developing gestational hypertension. Mn modified the association with As such that the deleterious association with As was stronger at lower concentrations of Mn. First trimester urinary dimethylarsinic acid concentrations were not associated with gestational hypertension (RR = 1.31; 95% CI: 0.60, 2.85) or preeclampsia (RR = 0.92; 95% CI: 0.68, 1.24). We did not observe overall joint effects for blood metals. DISCUSSION: Our results confirm that even low blood Pb concentrations are a risk factor for preeclampsia. Women with higher blood As concentrations combined with lower Mn in early pregnancy were more likely to develop gestational hypertension. These pregnancy complications impact maternal and neonatal health. Understanding the contribution of toxic metals and Mn is of public health importance. [ABSTRACT FROM AUTHOR]

BACKGROUND: Evidence for a potential link between air pollution and rheumatoid arthritis (RA) is inconsistent, and the modified effect of genetic susceptibility on the relationship between air pollution and RA has not been well studied. OBJECTIVE: Using a general population cohort from the UK Biobank, this study aimed to investigate the associations between various air pollutants and the risk of incident RA and to further estimate the impact of combined exposure to ambient air pollutants on the risk of developing RA under the modification effect of genetic predisposition. METHODS: A total of 342,973 participants with completed genotyping data and who were free of RA at baseline were included in the study. An air pollution score was constructed by summing the concentrations of each pollutant weighted by the regression coefficients with RA from single-pollutant models to assess the combined effect of air pollutants, including particulate matter (PM) with diameters ≤ 2.5 µm (PM2.5), between 2.5 and 10 µm (PM2.5–10), and ≤ 10 µm (PM10), as well as nitrogen dioxide (NO2) and nitrogen oxides (NOx). In addition, the polygenic risk score (PRS) of RA was calculated to characterize individual genetic risk. The Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of associations of single air pollutant, air pollution score, or PRS with incident RA. RESULTS: During a median follow-up time of 8.1 y, 2,034 incident events of RA were recorded. The HRs (95% CIs) of incident RA per interquartile range increment in PM2.5, PM2.5-10, PM10, NO2, and NOx were 1.07 (1.01, 1.13), 1.00 (0.96, 1.04), 1.01 (0.96, 1.07), 1.03 (0.98, 1.09), and 1.07 (1.02, 1.12), respectively. We also found a positive exposure-response relationship between air pollution score and RA risk (푝Trend = 0.000053). The HR(95% CI) of incident RA was 1.14 (1.00, 1.29) in the highest quartile group compared with the lowest quartile group of the air pollution score. Furthermore, the results of the combined effect of air pollution score and PRS on the RA risk showed that the risk of RA incidence in the highest genetic risk and air pollution score group was almost twice that of the lowest genetic risk and air pollution score group [incidence rate (IR) per 100,000 person-years: 98.46 vs. 51.19, and HR= 1.73 (95% CI: 1.39, 2.17) vs. 1 (reference)], although no statistically significant interaction between the air pollution and genetic risk for incident RA was found (푝Interaction >0.05). DISCUSSION: The results revealed that long-term combined exposure to ambient air pollutants might increase the risk of RA, particularly in those with high genetic risk. [ABSTRACT FROM AUTHOR]

BACKGROUND: Household air pollution (HAP) from biomass fuel combustion remains a leading environmental risk factor for morbidity worldwide. OBJECTIVE: Measure the effect of liquefied petroleum gas (LPG) interventions on HAP exposures in Puno, Peru. METHODS: We conducted a 1-y randomized controlled trial followed by a 1-y pragmatic crossover trial in 180 women age 25-64 y. During the first year, intervention participants received a free LPG stove, continuous fuel delivery, and regular behavioral messaging, whereas controls continued their biomass cooking practices. During the second year, control participants received a free LPG stove, regular behavioral messaging, and vouchers to obtain LPG tanks from a nearby distributor, whereas fuel distribution stopped for intervention participants. We collected 48-h kitchen area concentrations and personal exposures to fine particulate matter (PM) with aerodynamic diameter ≤ 2.5 µm (PM 2.5), black carbon (BC), and carbon monoxide (CO) at baseline and 3-, 6-, 12-, 18-, and 24-months post randomization. RESULTS. Baseline mean ± standard deviation (SD) PM2.5 (kitchen area concentrations 1,220 ± 1,010 vs. 1,190 ± 880 µg/m³; personal exposure 126 ± 214 vs. 104 ± 100 µg/m³), CO (kitchen 53 ± 49 vs. 50 ± 41 ppm; personal 7 ± 8 vs. 7 ± 8 ppm), and BC (kitchen 180 ± 120 vs. 210 ± 150 µg/m³; personal 19 ± 16 vs. 21 ± 22 µg/m³) were similar between control and intervention participants. Intervention participants had consistently lower mean (± SD) concentrations at the 12-month visit for kitchen (41 ± 59 µg/m³, 3±6 µg/m³, and 8 ± 13 ppm) and personal exposures (26 ± 34 µg/m³, 2±3 µg/m³, and 3 ± 4 ppm) to PM2.5, BC, and CO when compared to controls during the first year. In the second year, we observed comparable HAP reductions among controls after the voucher-based intervention for LPG fuel was implemented (24-month visit PM2.5, BC, and CO kitchen mean concentrations of 34 ± 74 µg/m³,3±5 µg/m³, and 6 ± 6 ppm and personal exposures of 17 ± 15 µg/m³,2±2 µg/m³, and 3 ± 4 ppm, respectively), and average reductions were present among intervention participants even after free fuel distribution stopped (24-month visit PM2.5, BC, and CO kitchen mean concentrations of 561 ± 1,251 µg/m³, 82 ± 124 µg/m³, and 23 ± 28 ppm and personal exposures of 35 ± 38 µg/m³,6±6 µg/m³, and 4 ± 5 ppm, respectively). DISCUSSION: Both home delivery and voucher-based provision of free LPG over a 1-y period, in combination with provision of a free LPG stove and longitudinal behavioral messaging, reduced HAP to levels below 24-h World Health Organization air quality guidelines. Moreover, the effects of the intervention on HAP persisted for a year after fuel delivery stopped. Such strategies could be applied in LPG programs to reduce HAP and potentially improve health. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol A (BPA) exposure has been linked to miscarriages and pregnancy complications in humans. In contrast, the potential reproductive toxicity of BPA analogs, including tetrabromobisphenol A (TBBPA), is understudied. Furthermore, although environmental exposure has been linked to altered immune mediators, the effects of BPA and TBBPA on maternal–fetal immune tolerance during pregnancy have not been studied. The present study investigated whether exposure resulted in higher rates of pregnancy loss in mice, lower number of regulatory T cells (Tregs), and lower indoleamine 2,3 deoxygenase 1 (Ido1) expression, which provided evidence for mechanisms related to immune tolerance in pregnancy. OBJECTIVES: The purpose of this investigation was to characterize the effects of BPA and TBBPA exposure on pregnancy loss in mice and to study the percentage and number of Tregs and Ido1 expression and DNA methylation. METHODS: Analysis of fetal resorption and quantification of maternal and fetal immune cells by flow cytometry were performed in allogeneic and syngeneic pregnancies. Ido1 mRNA and protein expression, and DNA methylation in placentas from control and BPA- and TBBPA-exposed mice were analyzed using real-time quantitative polymerase chain reaction, immunofluorescence, and bisulfite sequencing analyses. RESULTS: BPA and TBBPA exposure resulted in higher rates of hemorrhaging in early allogeneic, but not syngeneic, conceptuses. In allogeneic pregnancies, BPA and TBBPA exposure was associated with higher fetal resorption rates and lower maternal Treg number. Importantly, these differences were associated with lower IDO1 protein expression in trophoblast giant cells and higher mean percentage Ido1 DNA methylation in embryonic day 9.5 placentas from BPA- and TBBPA-exposed mice. DISCUSSION: BPA- and TBBPA-induced pregnancy loss in mice was associated with perturbed IDO1-dependent maternal immune tolerance. [ABSTRACT FROM AUTHOR]

BACKGROUND: Maternal exposure to environmental chemicals during pregnancy can influence various maternal and offspring health parameters. Modification of maternal metabolism by environmental exposure may be an important pathway for these impacts. However, there is limited evidence regarding exposure to a wide array of chemicals and the metabolome during pregnancy. OBJECTIVES: We investigated the relationship between the urinary exposome and metabolome during pregnancy. METHODS: Urine samples were collected in the first and third trimesters from 1,024 pregnant women recruited in prenatal clinics in Jiangsu Province, China. The exposome was analyzed using the first trimester sample with ultra-high performance liquid chromatography–high resolution accurate mass spectrometry (UHPLC-HRMS) and inductively coupled plasma mass spectrometry. The metabolome was analyzed using the third trimester sample with UHPLC-HRMS. We evaluated associations between each of 106 exposures in the first trimester with 139 metabolites in the third trimester. RESULTS: We identified 1,245 significant associations (푝<3.39 × 10-6, Bonferroni correction) between chemical exposures and maternal metabolism during pregnancy. Among elements, the largest number of the significant metabolic associations were observed for magnesium, and among organic compounds, for 4-tert-octylphenol. We used exposome–metabolome associations to explore mechanisms underlying published associations between prenatal chemical exposures and offspring health outcomes. This integration of the literature with our results suggests that reported associations between 10 analytes and birth weight, gestational age, fat deposition, neurobehavioral development, immunological disorders, and hypertension may be partially mediated by metabolites associated with these exposures. DISCUSSION: This high-dimensional analysis of the urinary exposome and metabolome identified many associations between chemical exposures and maternal metabolism during pregnancy. Integration of these associations with the literature on health outcomes of exposure suggests that environmental modulation of the maternal metabolome may play a role in the association between prenatal exposure on pregnancy and child health outcomes. [ABSTRACT FROM AUTHOR]