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BACKGROUND: Bisphenol A (BPA) is a high-production-volume chemical associated with a wide range of health outcomes in animal and human studies. BPA is used as a developer in thermal paper products, including cash register receipt paper; however, little is known about exposure of cashiers to BPA and alternative compounds in receipt paper. OBJECTIVE: We determined whether handling receipt paper results in measurable absorption of BPA or the BPA alternatives bisphenol S (BPS) and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP). METHODS: Cashiers (n = 77) and non-cashiers (n = 25) were recruited from the Raleigh-Durham-Chapel Hill region of North Carolina during 2011-2013. Receipts were analyzed for the presence of BPA or alternatives considered for use in thermal paper. In cashiers, total urine and serum BPA, BPS, and BPSIP levels in post-shift samples (collected ≤ 2 hr after completing a shift) were compared with pre-shift samples. Levels of these compounds in urine from cashiers were compared to levels in urine from non-cashiers. RESULTS: Each receipt contained 1-2% by weight of the paper of BPA, BPS, or BPSIP. The post-shift geometric mean total urinary BPS concentration was significantly higher than the pre-shift mean in 33 cashiers who handled receipts containing BPS. The mean urine BPA concentrations in 31 cashiers who handled BPA receipts were as likely to decrease as to increase after a shift, but the mean post-shift concentrations were significantly higher than those in non-cashiers. BPSIP was detected more frequently in the urine of cashiers handling BPSIP receipts than in the urine of noncashiers. Only a few cashiers had detectable levels of total BPA or BPS in serum, whereas BPSIP tended to be detected more frequently. CONCLUSIONS: Thermal receipt paper is a potential source of occupational exposure to BPA, BPS, and BPSIP. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol S (BPS) has been widely substituted for bisphenol A (BPA) on thermal papers, but little is known about its skin absorption. OBJECTIVES: We compared the percutaneous absorption and biotransformation of BPS and BPA in vitro and in a controlled human trial. METHODS: Absorption and biotransformation of BPS and BPA were monitored across reconstructed human epidermis at two environmentally relevant doses over 25 h. In the human trial, five male participants handled thermal receipts containing BPS and washed their hands after 2 h. Urine (0-48 h) and serum (0-7.5h) were analyzed for target bisphenols, and one participant repeated the experiment with extended monitoring. BPS data were compared with published data for isotope-labeled BPA (BPA-d16) in the same participants. RESULTS: At doses of 1.5 and 7:7 lg=cm2 applied to reconstructed human epidermis, the permeability coefficient of BPS (0.009 and 0:003 cm=h, respectively) was significantly lower than for BPA (0.036 and 0:033 cm=h, respectively), and metabolism of both bisphenols was negligible. In participants handling thermal receipts, the quantities of BPS and BPA-d16 on hands was significantly correlated with maximum urinary event flux (lg), but the slope was lower for BPS than BPA (b=0:12 and 1.1, respectively). As a proportion of total urinary bisphenol, free BPS [mean±standard deviation ðSDÞ: 6:9±2:8%] was higher than for free BPA (2:7±1:9%). Postexposure maximum urinary BPS concentrations (0.93 to 3:0 ng=mL; n=5) were in the 93-98th percentile range of BPS in background Canadians (0:91-3:2 ng=mL; n=467). CONCLUSION: Both the in vitro and human studies suggested lower percutaneous absorption of BPS compared with BPA, but a lower biotransformation efficiency of BPS should also be considered in its evaluation as a BPA substitute. [ABSTRACT FROM AUTHOR]

BACKGROUND: Globally, nearly 3 billion people rely on solid fuels for cooking and heating, the vast majority residing in low- and middle-income countries (LMICs). The resulting household air pollution (HAP) is a leading environmental risk factor, accounting for an estimated 1.6 million premature deaths annually. Previous interventions of cleaner stoves have often failed to reduce exposure to levels that produce meaningful health improvements. There have been no multicountry field trials with liquefied petroleum gas (LPG) stoves, likely the cleanest scalable intervention. OBJECTIVE: This paper describes the design and methods of an ongoing randomized controlled trial (RCT) of LPG stove and fuel distribution in 3,200 households in 4 LMICs (India, Guatemala, Peru, and Rwanda). METHODS: We are enrolling 800 pregnant women at each of the 4 international research centers from households using biomass fuels. We are randomly assigning households to receive LPG stoves, an 18-month supply of free LPG, and behavioral reinforcements to the control arm. The mother is being followed along with her child until the child is 1 year old. Older adult women (40 to <80 years of age) living in the same households are also enrolled and followed during the same period. Primary health outcomes are low birth weight, severe pneumonia incidence, stunting in the child, and high blood pressure (BP) in the older adult woman. Secondary health outcomes are also being assessed. We are assessing stove and fuel use, conducting repeated personal and kitchen exposure assessments of fine particulate matter with aerodynamic diameter =2.5 ηm (PM2.5), carbon monoxide (CO), and black carbon (BC), and collecting dried blood spots (DBS) and urinary samples for biomarker analysis. Enrollment and data collection began in May 2018 and will continue through August 2021. The trial is registered with ClinicalTrials.gov (NCT02944682). CONCLUSIONS: This study will provide evidence to inform national and global policies on scaling up LPG stove use among vulnerable populations. [ABSTRACT FROM AUTHOR]

BACKGROUND: In spring 2013, groundwater of a vast area of the Veneto Region (northeastern Italy) was found to be contaminated by perfluoroalkyl substances (PFAS) from a PFAS manufacturing plant active since the late 1960s. Residents were exposed to high concentrations of PFAS, particularly perfluorooctanoic acid (PFOA), through drinking water until autumn 2013. A publicly funded health surveillance program is under way to aid in the prevention, early diagnosis, and treatment of chronic disorders possibly associated with PFAS exposure. OBJECTIVES: The objectives of this paper are: a) to describe the organization of the health surveillance program, b) to report serum PFAS concentrations in adolescents and young adults, and c) to identify predictors of serum PFAS concentrations in the studied population. METHODS: The health surveillance program offered to residents of municipalities supplied by contaminated waterworks includes a structured interview, routine blood and urine tests, and measurement of 12 PFAS in serum by high-performance liquid chromatography–tandem mass spectrometry. We studied 18,345 participants born between 1978 and 2002, 14–39 years of age at recruitment. Multivariable linear regression was used to identify sociodemographic, lifestyle, dietary, and reproductive predictors of serum PFAS concentrations. RESULTS: The PFAS with the highest serum concentrations were PFOA [median 44.4 ng/mL, interquartile range (IQR) 19.3–84.9], perfluorohexanesulfonic acid (PFHxS) (median 3.9 ng/mL, IQR 1.9–7.4), and perfluorooctanesulfonic acid (PFOS) (median 3.9 ng/mL, IQR 2.6–5.8). The major predictors of serum levels were gender, municipality, duration of residence in the affected area, and number of deliveries. Overall, the regression models explained 37%, 23%, and 43% of the variance of PFOA, PFOS, and PFHxS, respectively. CONCLUSIONS: Serum PFOA concentrations were high relative to concentrations in populations with background residential exposures only. Interindividual variation of serum PFAS levels was partially explained by the considered predictors. [ABSTRACT FROM AUTHOR]

BACKGROUND: Newborns in neonatal intensive care units (NICUs) are in contact with a variety of medical products whose production might include synthetic chemicals with hormonal activity. OBJECTIVES: Our aim was to assess the content of bisphenol A (BPA) and parabens (PBs) and the hormone-like activities of a subset of medical products commonly used in NICUs in prolonged intimate contact with NICU newborns. METHODS: Fifty-two NICU items were analyzed, determining the concentrations of BPA and PBs [methyl- (MeP), ethyl- (EtP), propyl- (PrP), and butylparaben (BuP)] and using the E-Screen and PALM-luciferase assays to measure the in vitro (anti-)estrogenic and (anti-)androgenic activity, respectively, of the extracts. Items found to have elevated BPA/PB content or hormone-like activities were further extracted using leaching methodologies. RESULTS: BPA was found in three-fifths and PBs in four-fifths of tested NICU items, and ~25% and ~10% of extracts evidenced estrogenic and anti-androgenic activity, respectively. The highest BPA content was found in the three-way stopcock (>7.000 ng/g), followed by patterned transparent film dressing, gastro-duodenal feeding tubes, sterile gloves, single-lumen umbilical catheters, and intravenous (IV) infusion extension sets (concentrations ranged from 100 to 700 ng/g BPA). A total PB concentration (?PPBs) >100 ng/g was observed in several items, including light therapy protection glasses, patterned transparent film dressing, winged IV catheters, IV infusion extension sets, and textile tape. The highest estrogenic activity [>450 pM estradiol equivalent (E2eq)] was found in small dummy nipples, three-way stopcocks, and patterned transparent film dressing and the highest anti-androgenic activity [>5 mM procymidone equivalent units per gram (Proceq/g)] in small dummy nipples and three-way stopcocks. DISCUSSION: According to these findings, neonates might be exposed to multiple sources of BPA and PBs in NICUs via inhalation, dermal, oral, and IV/parenteral routes. There is a need to address the future health implications for these extremely vulnerable patients and to adopt precautionary preventive measures as a matter of urgency. [ABSTRACT FROM AUTHOR]

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: Bisphenol S (BPS) has increasingly been used as a substitute for bisphenol A (BPA) in some “BPA-free” consumer goods and in thermal papers. Wide human exposure to BPS has been reported; however, the biological and potential toxic effects of BPS are poorly understood. Objective: In this study, we sought to elucidate the sex-specific rapid effect of BPS in rat hearts and its underlying mechanism. Methods: We examined the rapid effects of BPS in rat hearts using electrophysiology, confocal and conventional fluorescence imaging, and immunoblotting. Treatment was administered via acute perfusion of excised hearts or isolated cardiac myocytes. Results: In female rat hearts acutely exposed to 10-9 M BPS, the heart rate was increased; in the presence of catecholamine-induced stress, the frequency of ventricular arrhythmia events was markedly increased. BPS-exposed hearts showed increased incidence of arrhythmogenic-triggered activities in female ventricular myocytes and altered myocyte Ca2+ handling, particularly spontaneous Ca2+ release from the sarcoplasmic reticulum. The dose responses of BPS actions were inverted U‑shaped. The impact of BPS on myocyte Ca2+ handling was mediated by estrogen receptor β signaling and by rapid increases in the phosphorylation of key Ca2+ handling proteins, including ryanodine receptor and phospholamban. The proarrhythmic effects of BPS were female specific; male rat hearts were not affected by BPS at the organ, myocyte, or protein levels. Conclusion: Rapid exposure to low-dose BPS showed proarrhythmic impact on female rat hearts; these effects at the organ, cellular, and molecular levels are remarkably similar to those reported for BPA. Evaluation of the bioactivity and safety of BPS and other BPA analogs is necessary before they are used as BPA alternatives in consumer products. Citation: Gao X, Ma J, Chen Y, Wang HS. 2015. Rapid responses and mechanism of action for low-dose bisphenol S on ex vivo rat hearts and isolated myocytes: evidence of female-specific proarrhythmic effects. Environ Health Perspect 123:571-578; [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: This paper presents an application of quantitative ion character-activity relationship (QICAR) to estimate associations of human cardiovascular (CV) diseases (CVDs) with a set of metal ion properties commonly observed in ambient air pollutants. QICAR has previously been used to predict ecotoxicity of inorganic metal ions based on ion properties. Objectives: The objective of this work was to examine potential associations of biological end points with a set of physical and chemical properties describing inorganic metal ions present in exposures using QICAR. Methods: Chemical and physical properties of 17 metal ions were obtained from peer-reviewed publications. Associations of cardiac arrhythmia, myocardial ischemia, myocardial infarction, stroke, and thrombosis with exposures to metal ions (measured as inference scores) were obtained from the Comparative Toxicogenomics Database (CTD). Robust regressions were applied to estimate the associations of CVDs with ion properties. Results: CVD was statistically significantly associated (Bonferroni-adjusted significance level of 0.003) with many ion properties reflecting ion size, solubility, oxidation potential, and abilities to form covalent and ionic bonds. The properties are relevant for reactive oxygen species (ROS) generation, which has been identified as a possible mechanism leading to CVDs. Conclusion: QICAR has the potential to complement existing epidemiologic methods for estimating associations between CVDs and air pollutant exposures by providing clues about the underlying mechanisms that may explain these associations. [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]

BACKGROUND: The current production and use of chlorinated paraffins (CPs) at >1 million tons/y likely exceeds the lifetime production of polychlorinated biphenyls (PCBs). These persistent organic pollutants (POPs) are a concern to human health. OBJECTIVES: The United Nations Environment Programme conducts global surveys of human milk samples from individual countries as a noninvasive method of investigating levels and trends in human exposures to POPs such as CPs. We measured CP concentrations and assessed their relation to other POPs in pooled samples collected during 2012–2019. METHODS: We analyzed 57 official nationwide pooled milk samples from 53 countries on five continents (Africa, Central/South America, Asia, Europe, and Australia/Oceania). CP concentrations were further characterized by subgroups and compared with concentrations of 19 other POPs, including PCBs and a variety of pesticides. RESULTS: CPs were detected in pooled samples from all 53 countries, with concentrations of 23–700 ng/g lipid. CPs accounted for 18–46% of the total summed POPs in human milk, second only to dichlorodiphenyltrichloroethane (DDT). CP concentrations exceeded PCB concentrations in pooled samples from most countries. DISCUSSION: The presence of CPs in all samples, including samples from isolated locations (e.g., Pacific Island countries), emphasizes the ubiquitous presence of these compounds, whereas differences in subgroup ratios indicate a delay in the shift toward nonregulated medium-chain CPs (MCCPs) for these regions. The predominance of MCCPs in samples from many countries suggests a need for regulation and research on health effects. [ABSTRACT FROM AUTHOR]

BACKGROUND: We have previously shown that adult male mice exposure to low doses of an ubiquitous endocrine disruptor, di(2-ethylhexyl) phthalate (DEHP), alters courtship behavior. OBJECTIVE: The effects of adult exposure to low doses of DEHP alone or in an environmental phthalate mixture on estrous cyclicity, reproductive behavior, and underlying neural structures were analyzed in female mice. METHODS: Two-month-old C57BL/6J females were exposed orally for 6 wk to DEHP alone (0, 5 or 50 µg/kg/d) or to DEHP (5 µg/kg/d) in a phthalate mixture. Estrous cyclicity was analyzed in intact mice, and behavior [lordosis, olfactory preference, partner preference, ability to stimulate male ultrasonic vocalizations (USVs)] was measured in ovariectomized mice primed with estradiol and progesterone. Immunohistochemical studies were conducted in the neural structures involved in behavior for estrogen receptor (ER) a and progesterone receptor (PR). RESULTS: Exposure to DEHP alone or in mixture lengthened the estrous cycle duration, with a shorter proestrus and longer estrus and metestrus stages. Under normalized hormonal levels, females exposed to DEHP alone or in mixture exhibited altered olfactory preference. A lower lordosis behavior and ability to attract and stimulate male emission of courtship USVs was observed, probably due to modifications of pheromonal emission in exposed females. The behavioral alterations were associated with a lower number of PR-expressing neurons, without changes in ERa, in the neural circuitry underlying sexual behavior. The majority of effects observed was comparable between the two DEHP doses and were driven by DEHP in the mixture. CONCLUSIONS: Exposure to environmental doses of DEHP alone or in mixture altered several components of female sexual behavior in mice, probably through selective disruption of neural PR signaling. Together with the previously reported vulnerability of male mice, this finding suggests a major impact of exposure to phthalates on sexual reproduction, including in other species with similar neural regulatory processes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Climate change models predict that atmospheric carbon dioxide [CO2] levels will be between 700 and 900 ppm within the next 80 y. Despite this, the direct physiological effects of exposure to slightly elevated atmospheric CO2 (as compared with ~410 ppm experienced today), especially when exposures extend from preconception to adulthood, have not been thoroughly studied. OBJECTIVES: In this study we aimed to assess the respiratory structure and function effects of long-term exposure to 890 ppm CO2 from preconception to adulthood using a mouse model. METHODS: We exposed mice to CO2 (~890 ppm) from prepregnancy, through the in utero and early life periods, until 3 months of age, at which point we assessed respiratory function using the forced oscillation technique, and lung structure. RESULTS: CO2 exposure resulted in a range of respiratory impairments, particularly in female mice, including higher tissue elastance, longer chord length, and lower lung compliance. Importantly, we also assessed the lung function of the dams that gave birth to our experimental subjects. Even though these mice had been exposed to the same level of increased CO2 for a similar amount of time (~8 wk), we measured no impairments in lung function. This suggests that the early life period, when lungs are undergoing rapid growth and development, is particularly sensitive to CO2. DISCUSSION: To the best of our knowledge, this study, for the first time, shows that long-term exposure to environmentally relevant levels of CO2 can impact respiratory function in the mouse. [ABSTRACT FROM AUTHOR]

BACKGROUND: From 1980 to 2017, a fluorochemical manufacturing facility discharged wastewater containing poorly understood per- and polyfluoroalkyl substances (PFAS) to the Cape Fear River, the primary drinking water source for Wilmington, North Carolina, residents. Those PFAS included several fluoroethers including HFPO-DA also known as GenX. Little is known about the bioaccumulation potential of these fluoroethers. OBJECTIVE: We determined levels of fluoroethers and legacy PFAS in serum samples from Wilmington residents. METHODS: In November 2017 and May 2018, we enrolled 344 Wilmington residents ≥6 years of age into the GenX Exposure Study and collected blood samples. Repeated blood samples were collected from 44 participants 6 months after enrollment. We analyzed serum for 10 fluoroethers and 10 legacy PFAS using liquid chromatography-high-resolution mass spectrometry. RESULTS: Participants' ages ranged from 6 to 86 y, and they lived in the lower Cape Fear Region for 20 y on average (standard deviation: 16 y). Six fluoroethers were detected in serum; Nafion by-product 2, PFO4DA, and PFO5DoA were detected in >85% of participants. PFO3OA and NVHOS were infrequently detected. Hydro-EVE was present in a subset of samples, but we could not quantify it. GenX was not detected above our analytical method reporting limit (2 ng/mL). In participants with repeated samples, the median decrease in fluoroether levels ranged from 28% for PFO5DoA to 65% for PFO4DA in 6 months due to wastewater discharge control. Four legacy PFAS (PFHxS, PFOA, PFOS, PFNA) were detected in most (=97%) participants; these levels were higher than U.S. national levels for the 2015-2016 National Health and Nutrition Examination Survey. The sum concentration of fluoroethers contributed 24% to participants' total serum PFAS (median: 25.3 ng/mL). CONCLUSION: Poorly understood fluoroethers released into the Cape Fear River by a fluorochemical manufacturing facility were detected in blood samples from Wilmington, North Carolina, residents. Health implications of exposure to these novel PFAS have not been well characterized. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies suggest associations between oil and gas development (OGD) and adverse birth outcomes, but few epidemiological studies of oil wells or inactive wells exist, and none in California. OBJECTIVE: Our study aimed to investigate the relationship between residential proximity to OGD and birth outcomes in California. METHODS: We conducted a retrospective cohort study of 2,918,089 births to mothers living within 10 km of at least one production well between January 1, 2006 and December 31, 2015. We estimated exposure during pregnancy to inactive wells count (no inactive wells, 1 well, 2–5 wells, 6+ wells) and production volume from active wells in barrels of oil equivalent (BOE) (no BOE, 1–100 BOE/day, >100 BOE=day). We used generalized estimating equations to examine associations between overall and trimester-specific OGD exposures and term birth weight (tBW), low birth weight (LBW), preterm birth (PTB), and small for gestational age birth (SGA). We assessed effect modification by urban/rural community type. RESULTS: Adjusted models showed exposure to active OGD was associated with adverse birth outcomes in rural areas; effect estimates in urban areas were close to null. In rural areas, increasing production volume was associated with stronger adverse effect estimates. High (>100 BOE=day) vs. no production throughout pregnancy was associated with increased odds of LBW [odds ratio(OR)= 1.40, 95% confidence interval (CI): 1.14, 1.71] and SGA (OR = 1.22, 95% CI: 1.02, 1.45), and decreased tBW (mean difference = -36 grams, 95% CI: -54, -17), but not with PTB (OR = 1.03, 95% CI: 0.91, 1.18). CONCLUSION: Proximity to higher production OGD in California was associated with adverse birth outcomes among mothers residing in rural areas. Future studies are needed to confirm our findings in other populations and improve exposure assessment measures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease. OBJECTIVE: We performed mutually independent EWAS on transportation noise and air pollution exposures. METHODS: We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations. We applied multiexposure linear mixed-effects regressions with participant-level random intercept to identify significant Cytosine-phosphate-Guanine (CpG) sites and differentially methylated regions (DMRs) in relation to 1-y average aircraft, railway, and road traffic day-evening-night noise (Lden); nitrogen dioxide (NO2); and particulate matter (PM) with aerodynamic diameter <2.5 lm (PM2.5). We performed candidate (CpG-based; cross-systemic phenotypes, combined into “allostatic load”) and agnostic (DMR-based) pathway enrichment tests, and replicated previously reported air pollution EWAS signals. RESULTS: We found no statistically significant CpGs at false discovery rate <0.05. However, 14, 48, 183, 8, and 71 DMRs independently associated with aircraft, railway, and road traffic Lden; NO2; and PM2.5, respectively, with minimally overlapping signals. Transportation Lden and air pollutants tendentially associated with decreased and increased methylation, respectively. We observed significant enrichment of candidate DNA methylation related to C-reactive protein and body mass index (aircraft, road traffic Lden, and PM2.5), renal function and “allostatic load” (all exposures). Agnostic functional networks related to cellular immunity, gene expression, cell growth/proliferation, cardiovascular, auditory, embryonic, and neurological systems development were enriched. We replicated increased methylation in cg08500171 (NO2) and decreased methylation in cg17629796 (PM2.5). CONCLUSIONS: Mutually independent DNA methylation was associated with source-specific transportation noise and air pollution exposures, with distinct and shared enrichments for pathways related to inflammation, cellular development, and immune responses. These findings contribute in clarifying the pathways linking these exposures and age-related diseases but need further confirmation in the context of mediation analyses. [ABSTRACT FROM AUTHOR]

BACKGROUND: Embryo implantation relies on precise hormonal regulation, associated gene expression changes, and appropriate female reproductive tract tissue architecture. Female mice exposed neonatally to the phytoestrogen genistein (GEN) at doses similar to those in infants consuming soy-based infant formulas are infertile due in part to uterine implantation defects. OBJECTIVES: Our goal was to determine the mechanisms by which neonatal GEN exposure causes implantation defects. METHODS: Female mice were exposed to GEN on postnatal days (PND)1-5 and uterine tissues collected on PND5, PND22-26, and during pregnancy. Analysis of tissue weights, morphology, and gene expression was performed using standard histology, confocal imaging with three-dimensional analysis, real-time reverse transcription polymerase chain reaction (real-time RT-PCR), and microarrays. The response of ovariectomized adults to 17β-estradiol (E2) and artificial decidualization were measured. Leukemia inhibitory factor (LIF) injections were given intraperitoneally and implantation sites visualized. Gene expression patterns were compared with curated data sets to identify upstream regulators. RESULTS: GEN-exposed mice exhibited reduced uterine weight gain in response to E2 treatment or artificial decidualization compared with controls; however, expression of select hormone responsive genes remained similar between the two groups. Uteri from pregnant GEN-exposed mice were posteriorized and had reduced glandular epithelium. Implantation failure was not rescued by LIF administration. Microarray analysis of GEN-exposed uteri during early pregnancy revealed significant overlap with several conditional uterine knockout mouse models, including Foxa2, Wnt4, and Sox17. These models exhibit reduced endometrial glands, features of posteriorization and implantation failure. Expression of Foxa2, Wnt4, and Sox17, as well as genes important for neonatal uterine differentiation (Wnt7a, Hoxa10, and Msx2), were severely disrupted on PND5 in GEN-exposed mice. DISCUSSION: Our findings suggest that neonatal GEN exposure in mice disrupts expression of genes important for uterine development, causing posteriorization and diminished gland function during pregnancy that contribute to implantation failure. These findings could have implications for women who consumed soy-based formulas as infants. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor targeting estrogen receptors (ERs), has been implicated in the promotion of breast cancer. Perinatal exposure of BPA could induce longitudinal alteration of DNA hydroxymethylation in imprinted loci of mouse blood cells. To date, no data has been reported on the effects of BPA on DNA hydroxymethylation in breast cells. Therefore, we asked whether BPA can induce DNA hydroxymethylation change in human breast cells. Given that dysregulated epigenetic DNA hydroxymethylation is observed in various cancers, we wondered how DNA hydroxymethylation modulates cancer development, and specifically, whether and how BPA and its analogs promote breast cancer development via DNA hydroxymethylation. OBJECTIVES: We aimed to explore the interplay of the estrogenic activity of bisphenols at environmental exposure dose levels with TET dioxygenase-catalyzed DNA hydroxymethylation and to elucidate their roles in the proliferation of ER+ breast cancer cells as stimulated by environmentally relevant bisphenols. METHODS: Human MCF-7 and T47D cell lines were used as ER-dependent breast cell proliferation models, and the human MDA-MB-231 cell line was used as an ER-independent breast cell model. These cells were treated with BPA or bisphenol S (BPS) to examine BPA/BPS-related proliferation. Ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) and enzyme-linked immunosorbent assays (ELISAs) were used to detect DNA hydroxymethylation. Crispr/Cas9 and RNA interference technologies, quantitative polymerase chain reaction (qPCR), and Western blot analyses were used to evaluate the expression and function of genes. Co-immunoprecipitation (Co-IP), bisulfite sequencing-PCR (BSP), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to identify the interactions of target proteins. RESULTS: We measured higher proliferation in ER+ breast cancer cells treated with BPA or its replacement, BPS, accompanied by an ERα-dependent decrease in genomic DNA hydroxymethylation. The results of our overexpression, knockout, knockdown, and inhibition experiments suggested that TET2-catalyzed DNA hydroxymethylation played a suppressive role in BPA/BPS-stimulated cell proliferation. On the other hand, we observed that TET2 was negatively regulated by the activation of ERα (dimerized and phosphorylated), which was also induced by BPA/BPS binding. Instead of a direct interaction between TET2 and ERa, data of our Co-IP, BSP, and ChIP-qPCR experiments indicated that the activated ERα increased the DNA methyltransferase (DNMT)-mediated promoter methylation of TET2, leading to an inhibition of the TET2 expression and DNA hydroxymethylation. CONCLUSIONS: We identified a new feedback circuit of ERα activation–DNMT-TET2-DNA hydroxymethylation in ER+ breast cancer cells and uncovered a pivotal role of TET2-mediated DNA hydroxymethylation in modulating BPA/BPS-stimulated proliferation. Moreover, to our knowledge, we for the first time established a linkage among chemical exposure, DNA hydroxymethylation, and tumor-associated proliferation. These findings further clarify the estrogenic activity of BPA/BPS and its profound implications for the regulation of epigenetic DNA hydroxymethylation and cell proliferation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and cooking. However, the key components of coal that drive lung cancer risk have not been identified. OBJECTIVES: We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer. METHODS: Using a population-based case-control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables. RESULTS: The strongest association with lung cancer was for a cluster of 25 PAHs [odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change], within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide (NO2) was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter =2:5 lm (PM2:5) were associated with lung cancer in the multipollutant models. CONCLUSIONS: To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. [ABSTRACT FROM AUTHOR]

BACKGROUND: Given its hormonal activity, bisphenol S (BPS) as a substitute for bisphenol A (BPA) could actually increase the risk of endocrine disruption if its toxicokinetic (TK) properties, namely its oral availability and systemic persistency, were higher than those of BPA. OBJECTIVES: The TK behavior of BPA and BPS was investigated by administering the two compounds by intravenous and oral routes in piglet, a known valid model for investigating oral TK. METHODS: Experiments were conducted in piglets to evaluate the kinetics of BPA, BPS, and their glucuronoconjugated metabolites in plasma and urine after intravenous administration of BPA, BPS, and BPS glucuronide (BPSG) and gavage administration of BPA and BPS. A population semiphysiologically based TK model describing the disposition of BPA and BPS and their glucuronides was built from these data to estimate the key TK parameters that drive the internal exposure to active compounds. RESULTS: The data indicated that almost all the BPS oral dose was absorbed and transported into the liver where only 41% of BPS was glucuronidated, leading to a systemic bioavailability of 57.4%. In contrast, only 77% of the oral dose of BPA was absorbed and underwent an extensive firstpass glucuronidation either in the gut (44%) or in the liver (53%), thus accounting for the low systemic bioavailability of BPA (0.50%). Due to the higher systemic availability of BPS, in comparison with BPA, and its lower plasma clearance (3.5 times lower), the oral BPS systemic exposure was on average about 250 times higher than for BPA for an equal oral molar dose of the two compounds. CONCLUSION: Given the similar digestive tracts of pigs and humans, our results suggest that replacing BPA with BPS will likely lead to increased internal exposure to an endocrine-active compound that would be of concern for human health. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to light at night (LAN) can perturb the biological clock and affect sleep and health. Previous epidemiological studies have evaluated LAN levels measured by satellites, but the validity of this measure as a proxy for personal LAN exposure is unclear. In addition, outdoor satellite-measured LAN levels are higher in urban environments, which means that this measure could potentially represent a proxy for other, likely urban, environmental exposures. OBJECTIVES: We evaluated correlations of satellite-assessed LAN with measured bedroom light levels and explored correlations with other environmental exposures, in particular, air pollution, green space, and area-level socioeconomic position (SEP). METHODS: We compared satellite measurements with evening and nighttime bedroom measurements of illuminance (in units of lux) for 256 children, and we evaluated correlations between satellite-based measures and other urban exposures such as air pollution, area-level SEP, and surrounding green space for 3,021 children. RESULTS: Satellite-measured LAN levels (nanowatts per centimeter squared per steradian) were not correlated with measured evening or nighttime lux levels [Spearman correlation coefficients (rS) -0:11 to 0.04]. There was a weak correlation with measurements during the darkest time period if parents and their children reported that outdoor light sometimes or usually influenced indoor light levels (rS =0:31, n=28). In contrast, satellitemeasured LAN levels were correlated with air pollution (rS =0:76 with NO2, rS =0:71 with PM10), and surrounding green space (rS = -0:71 for green space within 1 km of the home). A weak correlation with area-level SEP was also observed (rS =0:24). CONCLUSIONS: Outdoor satellite-assessed outdoor LAN exposure levels were correlated with urban environmental exposures, but they were not a good proxy for indoor evening or nighttime personal exposure as measured in our study population of 12-y-old children. Studies planning to evaluate potential risks from LAN should consider such modifying factors as curtains and indoor lighting and the use of electronic devices and should include performing indoor or personal measurements to validate any exposure proxies. The moderate-to-strong correlation of outdoor LAN with other environmental exposures should be accounted for in epidemiological investigations. [ABSTRACT FROM AUTHOR]

BACKGROUND: The placenta performs crucial physiological functions to ensure normal fetal development. Few epidemiological studies investigated placental weight sensitivity to phthalates and phenols. OBJECTIVE: Our goal was to explore whether maternal exposure to select phthalates and phenols is associated with changes in placental weight at birth and in placental-to-birth weight ratio (PFR). METHODS: Placental weight and birth weight were available for 473 mother-son pairs in the EDEN (Etude des Déterminants pré et postnatals du développement et de la santé de l'Enfant) cohort for whom 9 phenols (4 parabens, 2 dichlorophenols, triclosan, benzophenone-3, bisphenol A) and 11 phthalate metabolites were measured in spot urine samples collected between weeks 23 and 29 of gestation. We used adjusted Elastic Net penalized regression models (ENET) to select biomarkers associated with placental weight, birth weight and PFR. Unpenalized effect estimates were then obtained by fitting linear regression models simultaneously adjusted for the ENET-selected biomarkers and a priori chosen confounders. RESULTS: The multipollutant ENET model for placental weight retained four biomarkers: triclosan and monocarboxy-isononyl phthalate (MCNP), which were negatively associated with placental weight, and benzophenone-3 and the sum of parabens, which were positively associated with this outcome. The ENET model for PFR retained two phthalate metabolites [MCNP and monocarboxy-isooctyl phthalate (MCOP)], which were negatively associated with this outcome. DISCUSSION: The positive association between the sum of parabens and placental weight was consistent with results of a previous study among 49 male births. Our results provide preliminary evidence of possible associations between other compounds such as triclosan, benzophenone-3, MCNP, and MCOP and both placental weight and PFR. These associations were not reported in previous studies and should be seen as hypothesis generating. Studies relying on repeated assessments of exposure in prospective mother-child cohorts are needed to substantiate the plausibility of the hypotheses generated by our results. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is growing evidence that exposure to ultrafine particles (UFP; particles smaller than 100 nm) may play an underexplored role in the etiology of several illnesses, including cardiovascular disease (CVD). OBJECTIVES: We aimed o investigate the relationship between long-term exposure to ambient UFP and incident cardiovascular and cerebrovascular disease (CVA). As a secondary objective, we sought to compare effect estimates for UFP with those derived for other air pollutants, including estimates from two-pollutant models. METHODS: Using a prospective cohort of 33,831 Dutch residents, we studied the association between long-term exposure to UFP (predicted via land use regression) and incident disease using Cox proportional hazard models. Hazard ratios (HR) for UFP were compared to HRs for more routinely monitored air pollutants, including particulate matter with aerodynamic diameter =10 lm (PM10), PM with aerodynamic diameter =2:5 (PM2:5), and NO2. RESULTS: Long-term UFP exposure was associated with an increased risk for all incident CVD [HR=1:18 per 10,000 particles=cm3; 95% confidence interval (CI): 1.03, 1.34], myocardial infarction (MI) (HR=1:34; 95% CI: 1.00, 1.79), and heart failure (HR=1:76; 95% CI: 1.17, 2.66). Positive associations were also estimated for NO2 (HR for heart failure=1:22; 95% CI: 1.01, 1.48 per 20 lg=m3) and coarse PM (PMcoarse; HR for all CVD=1:21; 95% CI: 1.01, 1.45 per 10 lg=m3). CVD was not positively associated with PM2:5 (HR for all CVD=0:95; 95% CI: 0.75, 1.28 per 5 lg=m3). HRs for UFP and CVAs were positive, but not significant. In two-pollutant models (UFP+NO2 and UFP+PMcoarse), positive associations tended to remain for UFP, while HRs for PMcoarse and NO2 generally attenuated towards the null. CONCLUSIONS: These findings strengthen the evidence that UFP exposure plays an important role in cardiovascular health and that risks of ambient air pollution may have been underestimated based on conventional air pollution metrics. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous work determined that early life exposure to low-dose Bisphenol A (BPA) increased rat prostate cancer risk with aging. Herein, we report on prostate-specific results from CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity), which aims to resolve uncertainties regarding BPA toxicity. OBJECTIVES: We sought to a) reassess whether a range of BPA exposures drives prostate pathology and/or alters prostatic susceptibility to hormonal carcinogenesis, and b) test whether chronic low-dose BPA targets prostate epithelial stem and progenitor cells. METHODS: Sprague-Dawley rats were gavaged daily with vehicle, ethinyl estradiol (EE) or 2:5-25,000 lg BPA/kg-BW during development or chronically, and prostate pathology was assessed at one year. One developmentally exposed cohort was given testosterone plus estradiol (T+E) implants at day 90 to promote carcinogenesis with aging. Epithelial stem and progenitor cells were isolated by prostasphere (PS) culture from dorsolateral prostates (DLP) of rats continuously exposed for six months to 2:5-250 lg BPA/kg-BW. Gene expression was analyzed by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Exposure to BPA alone at any dose did not drive prostate pathology. However, rats treated with EE, 2.5, 250, or 25,000 lg BPA/kg-BW plus T+E showed greater severity of lateral prostate intraepithelial neoplasia (PIN), and DLP ductal adenocarcinoma multiplicity was markedly elevated in tumor-bearing rats exposed to 2:5 lg BPA=kg-BW. DLP stem cells, assessed by PS number, doubled with chronic EE and 2:5 lg BPA=kg-BW exposures. PS size, reflecting progenitor cell proliferation, was greater at 25 and 250 lg BPA doses, which also shifted lineage commitment toward basal progenitors while reducing luminal progenitor cells. CONCLUSIONS: Together, these results confirm and extend previous evidence using a rat model and human prostate epithelial cells that low-dose BPA augments prostate cancer susceptibility and alters adult prostate stem cell homeostasis. Therefore, we propose that BPA exposures may contribute to the increased carcinogenic risk in humans that occurs with aging. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies have investigated the associations between perfluoroalkyl acids (PFAAs) in women and time to pregnancy (TTP). Inconsistent results may be explained by differences in conditioning on parity. OBJECTIVES: We used causal directed acyclic graphs to illustrate potential confounding related to previous pregnancies and exposure measurement error due to differences in the interpregnancy interval in pregnancy-based studies that include parous women. We exemplified the potential importance of these issues using data from the Danish National Birth Cohort. METHODS: We used discrete time survival models to estimate associations between maternal plasma PFAAs in early pregnancy and TTP in 638 nulliparous and 613 parous women. RESULTS: PFAA quartiles were not associated with the TTP in nulliparous women. In parous women, higher PFAA quartiles were associated with longer TTP. The strongest associations were estimated for perfluorohexane sulfonate and perfluorooctane sulfonate. PFAA concentrations were higher in women with longer interpregnancy intervals. Accounting for the interpregnancy interval attenuated the estimated associations. CONCLUSIONS: Associations between PFAAs and TTP in parous women may be biased by confounders related to previous pregnancies and exposure measurement error. To avoid these biases, studies that include parous women may need to condition on a) common causes of PFAAs and the TTP in the index pregnancy, b) previous births (a descendant of a collider), c) PFAA levels or common causes of PFAA levels and the TTP in the previous pregnancy (to alleviate collider stratification bias caused by conditioning on previous births), and d) the interpregnancy interval (in pregnancy-based studies). Alternatives would be to restrict studies to nulliparous women or to use toxicokinetic modeling to correct exposure estimates in parous women. These recommendations may be extended to studies of other chemicals with similar toxicokinetic properties. [ABSTRACT FROM AUTHOR]

BACKGROUND: Subclinical cardiovascular changes have been associated with ambient particulate matter (PM) exposures within hours. Although the U.S. Environmental Protection Agency continues to look for additional evidence of effects associated with sub-daily PM exposure, this information is still limited because most studies of clinical events have lacked data on the onset time of symptoms to assess rapid increased risk. OBJECTIVE: Our objective was to investigate associations between sub-daily exposures to PM and acute cardiac events using telemedicine data. METHODS: We conducted a case-crossover study among telemedicine participants =50 y of age who called a service center for cardiac-related symptoms and were transferred to a hospital in Tel Aviv and Haifa, Israel (2002-2013). Ambient PM2:5 and PM10-2:5 measured by monitors located in each city during the hours before the patient called with symptoms were compared with matched control periods. We investigated the sensitivity of these associations to more accurate symptom onset time and greater certainty of diagnosis. RESULTS: We captured 12,661 calls from 7,617 subscribers experiencing ischemic (19%), arrhythmic (31%), or nonspecific (49%) cardiac events. PM concentrations were associated with small increases in the odds of cardiac events. For example, odds ratios for any cardiac event in association with a 10-μg=m³ increase in 6-h and 24-h average PM2:5 were 1.008 [95% confidence interval (CI): 0.998, 1.018] and 1.006 (95% CI: 0.995, 1.018), respectively, and for PM10-2:5 were 1.003 (95% CI: 1.001, 1.006) and 1.003 (95% CI: 1.000, 1.007), respectively. Associations were stronger when using exposures matched to the call time rather than calendar date and for events with higher certainty of the diagnosis. CONCLUSIONS: Our analysis of telemedicine data suggests that risks of cardiac events in telemedicine participants =50 y of age may increase within hours of PM exposures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Emerging evidence suggests that perfluoroalkyl substances (PFASs) are endocrine disruptors and may contribute to the etiology of type 2 diabetes (T2D), but this hypothesis needs to be clarified in prospective human studies. OBJECTIVES: Our objective was to examine the associations between PFAS exposures and subsequent incidence of T2D in the Nurses' Health Study II (NHSII). In addition, we aimed to evaluate potential demographic and lifestyle determinants of plasma PFAS concentrations. METHODS: A prospective nested case-control study of T2D was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in 1995-2000 [(mean±SD): 45:3±4:4 y) of age]. We identified and ascertained 793 incident T2D cases through 2011 (mean±SD) years of follow-up: 6:7±3:7 y). Each case was individually matched to a control (on age, month and fasting status at sample collection, and menopausal status and hormone replacement therapy). Plasma concentrations of five major PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonate, perfluorononanoic acid, and perfluorodecanoic acid were measured. Odds ratios (ORs) of T2D by PFAS tertiles were estimated by conditional logistic regression. RESULTS: Shorter breastfeeding duration and higher intake of certain foods, such as seafood and popcorn, were significantly associated with higher plasma concentrations of PFASs among controls. After multivariate adjustment for T2D risk factors, including body mass index, family history, physical activity, and other covariates, higher plasma concentrations of PFOS and PFOA were associated with an elevated risk of T2D. Comparing extreme tertiles of PFOS or PFOA, ORs were 1.62 (95% CI: 1.09, 2.41; ptrend =0:02) and 1.54 (95% CI: 1.04, 2.28; ptrend =0:03), respectively. Other PFASs were not clearly associated with T2D risk. CONCLUSIONS: Background exposures to PFASs in the late 1990s were associated with higher T2D risk during the following years in a prospective case-control study of women from the NHSII. These findings support a potential diabetogenic effect of PFAS exposures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with cardiovascular mortality, but underlying pathophysiologic mechanisms are not fully understood. Hypothalamic inflammation, characterized by the activation of Inhibitor kappaB kinase 2/Nuclear factor kappaB (IKK2/NF-κB) signaling pathway, may play an important role in the pathogenesis of cardiovascular diseases. We recently demonstrated that hypothalamic inflammation is increased in mice exposed to concentrated ambient PM2.5 (CAP). OBJECTIVES: In the present study, we used a neuron-specific IKK2 knockout mouse model to examine the role of neural IKK2 expression and hypothalamic inflammation in the pathophysiologic effects of PM2.5. METHODS: We assessed inflammatory and vascular responses in Nestin-creIKK2flox/flox (IKK2Neu-KO) and littermate Nestin-creIKK2flox/+ (control) mice after 4 mo of exposure to filtered air (FA) or CAP. RESULTS: CAP exposure was associated with significantly higher tumor necrosis factor-α (TNFα) and interleukin (IL)-6 mRNA in the hypothalamus of control mice, but not IKK2Neu-KO mice. In addition, CAP exposure-induced increases in bronchoalveolar lavage fluid (BALF) leukocytes, pulmonary macrophage infiltration and IL-6 expression, plasma TNFα and IL-1β levels, adipose macrophage infiltration and IL-1β expression, and endothelial dysfunction were reduced or absent in IKK2Neu-KO mice compared with controls. CONCLUSIONS: Our findings support a role of neural IKK2 in CAP exposure-induced local and systemic pro-inflammatory cytokine expression, pulmonary and adipose inflammation, and endothelial dysfunction, thus providing insight into pathophysiologic mechanisms that may mediate effects of PM2.5 exposure. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that might be harmful to human health. Recently, there has been widespread usage of bisphenol chemicals (BPs), such as bisphenol AF (BPAF) and bisphenol S (BPS), as replacements for BPA. However, the potential biological actions, toxicity, and the molecular mechanism of these compounds are still poorly understood. OBJECTIVES: Our objective was to examine the estrogenic effects of BPA, BPAF, and BPS and the molecular mechanisms of action in the estrogen receptor alpha (ERa) complex. METHODS: In vitro cell models were used to compare the estrogenic effects of BPA, BPAF, and BPS to estrogen. Microarray Assay for Real-Time Coregulator-Nuclear receptor Interaction (MARCoNI) analysis was used to identify coregulators of BPA, BPAF, and BPS, and molecular dynamic (MD) simulations were used to determine the compounds binding in the ERα complex. RESULTS: We demonstrated that BPA and BPAF have agonistic activity for both ERα and ERb, but BPS has ERα-selective specificity. We concluded that coregulators were differentially recruited in the presence of BPA, BPAF, or BPS. Interestingly, BPS recruited more corepressors when compared to BPA and BPAF. From a series of MD analysis, we concluded that BPA, BPAF, and BPS can bind to the ER-ligand-binding domain with differing energetics and conformations. In addition, the binding surface of coregulator interactions on ERα was characterized for the BPA, BPAF, and BPS complexes. CONCLUSION: These findings further our understanding of the molecular mechanisms of EDCs, such as BPs, in ER-mediated transcriptional activation, biological activity, and their effects on physiological functions in human health. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sex-specific associations have been reported between phthalates, bisphenol A (BPA), and child behavior. No data on large study populations are available for other phenols with possible endocrine-disrupting properties. OBJECTIVES: We aimed to study associations between prenatal exposure to phthalates and several phenols on behavior among male infants. METHODS: We quantified 11 phthalate metabolites and nine phenols (four parabens, benzophenone-3, BPA, two dichlorophenols, triclosan) in spot urine samples collected during pregnancy among EDEN cohort mothers who delivered a boy. Mothers completed the Strength and Difficulties Questionnaire (SDQ) when their children were 3.1 (n=529) and 5.6 (n=464) y old. RESULTS: BPA was positively associated with the relationship problems subscale at 3 y [incidence rate ratio (IRR): 1.11; 95% confidence interval (CI): 1.03, 1.20] and the hyperactivity-inattention subscale scores at 5 y (IRR: 1.08; 95% CI: 1.01, 1.14). Mono-n-butyl phthalate (MnBP) was positively associated with internalizing behavior, relationship problem, and emotional symptom scores at 3 y. Monobenzyl phthalate (MBzP) was positively associated with internalizing behavior and relationship problems scores at 3 y. After dichotomizing SDQ scores, triclosan tended to be positively associated with emotional symptom subscales at both 3 and 5 y. CONCLUSIONS: The observed associations between BPA, MnBP, and behavior in boys are consistent with previous findings. Further health impact assessment studies based on dose-response functions corrected for exposure misclassification are required to quantify the public health burden possibly entailed by such associations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)'s National Drinking Water Advisory Council (NDWAC) recommended establishment of a "health-based, household action level" for lead in drinking water based on children's exposure. OBJECTIVES: The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine what drinking water lead concentrations keep children's blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. METHODS: A modeling approach using the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. RESULTS: Modeled BLLs compared well with nationally representative BLLs (0-23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. CONCLUSIONS: This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. [ABSTRACT FROM AUTHOR]

BACKGROUND: The impact of different transportation noise sources and noise environments on arterial stiffness remains unknown. OBJECTIVES: We evaluated the association between residential outdoor exposure to annual average road, railway, and aircraft noise levels, total noise intermittency (IR), and total number of noise events (NE) and brachial-ankle pulse wave velocity (baPWV) following a cross-sectional design. METHODS: We measured baPWV (meters/second) in 2,775 participants (49-81 y old) at the second follow-up (2010-2011) of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). We assigned annual average road, railway, and aircraft noise levels (Ldensource), total day- and nighttime NEtime and IRtime (percent fluctuation=0%, none or constant noise; percent fluctuation=100%, high fluctuation) at the most exposed façade using 2011 Swiss noise models. We applied multivariable linear mixed regression models to analyze associations. RESULTS: Medians [interquartile ranges (IQRs)] were baPWV=13:4 (3.1) m/s; Ldenair ð57:6%exposedÞ=32:8 (8.0) dB; Ldenrail ð44:6% exposedÞ=30:0 (8.1) dB; Ldenroad (99.7% exposed): 54.2 (10.6) dB; NEnight =123 (179); NEday =433 (870); IRnight =73% (27); and IRday =63:8% (40.3). We observed a 0.87% (95% CI: 0.31, 1.43%) increase in baPWV per IQR of Ldenrail, which was greater with IRnight >80% or with daytime sleepiness. We observed a nonsignificant positive association between Ldenroad and baPWV in urban areas and a negative tendency in rural areas. NEnight, but not NEday, was associated with baPWV. Associations were independent of the other noise sources and air pollution. Conclusions: Long-term exposure to railway noise, particularly in an intermittent nighttime noise environment, and to nighttime noise events, mainly related to road noise, may affect arterial stiffness, a major determinant of cardiovascular disease. Ascertaining noise exposure characteristics beyond average noise levels may be relevant to better understand noise-related health effects. [ABSTRACT FROM AUTHOR]

BACKGROUND: Humans are commonly exposed to multiple environmental chemicals, including tetrabromobisphenol A (TBBPA; a flame retardant), triclosan (an antimicrobial agent), and bisphenol A (BPA; polycarbonate plastics). These chemicals are readily absorbed and may interact with each other. OBJECTIVES: We sought to determine whether TBBPA, given alone or in combination with triclosan, can modulate the concentrations of BPA and 17b-estradiol (E2). METHODS: Female and male CF-1 mice were each given a subcutaneous injection of 0-27 mg TBBPA, with or without concurrent 0:33 mg triclosan, followed by dietary administration of 50 μg=kg body weight 14C-BPA. Radioactivity was measured in blood serum and tissues through liquid scintillation counting. In subsequent experiments, female and male CF-1 mice were each given a subcutaneous injection of 0 or 1 mg TBBPA and E2 was measured in urine 2-12 h after injection. RESULTS: Doses as low as 1 mg TBBPA significantly elevated 14C-BPA concentrations in the uterus and ovaries of females; in the testes, epididymides, vesicular-coagulating glands, and preputial glands of males; and in blood serum, heart, lungs, and kidneys of both sexes; urinary E2 concentrations were also elevated. Lower doses of TBBPA or triclosan that had no effects on their own elevated 14C-BPA concentrations when the two substances were given concurrently. CONCLUSION: These data indicate that TBBPA, triclosan, and BPA interact in vivo, consistent with evidence that TBBPA and triclosan inhibit enzymes that are critical for BPA and E2 metabolism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hair is a commonly used exposure biomarker for metals and other trace elements, but concern has been raised regarding its appropriateness for assessing the internal dose. OBJECTIVES: The aim of the present study was to evaluate children's hair as biomarker of internal dose for toxic (As, Mn, Cd, Pb) and essential elements (Mg, Ca, Fe, Co, Cu, Zn, Se, Mo). METHODS: In 207 children (9-10 years of age), originating from a population-based cohort in rural Bangladesh, we measured concentrations of the selected elements in hair (2 cm closest to the scalp) using ICP-MS. We compared these with previously measured concentrations in erythrocytes, urine, and water. For a subset of children (n=19), we analyzed four consecutive 2 cm pieces of hair. RESULTS: There were strong associations between hair As and the other biomarkers (erythrocytes: rs=0.73, p<0.001; urine: rS=0.66, p<0.001); and water (rs=0.60, p<0.001); and there were significant correlations between Se in hair and erythrocytes (overall rs=0.38, p<0.001), and urine (rs=0.29, p<0.001). Hair Co and Mo showed weak correlations with concentrations in erythrocytes. Hair Mn was not associated with Mn in erythrocytes, urine, or water, and the geometric mean concentration increased almost five times from the 2 cm closest to the head to the 7th-8th cm (p<0.001). Also Mg, Ca, Co, Cd, and Pb increased from the scalp outward (>50% higher in 7th-8th cm compared with 1st-2nd cm, p<0.001). CONCLUSIONS: Hair was found to be a useful exposure biomarker of absorbed As and Se only. Of all measured elements, hair Mn seemed the least reflective of internal dose. [ABSTRACT FROM AUTHOR]

BACKGROUND: Environmental manganese exposure has been associated with adverse neurodevelopmental outcomes among school-aged children; yet, few studies have evaluated prenatal exposure. OBJECTIVES: Our study examines associations between prenatal manganese concentrations and placental transfer of manganese with neurodevelopment in 224 2-y-old children residing near the Tar Creek Superfund Site. METHODS: We collected maternal and cord blood at delivery, measured manganese using inductively coupled plasma mass spectrometry, and assessed neurodevelopment using the Bayley Scales of Infant Development-II. Associations between manganese and mental (MDI) and psychomotor (PDI) development indices were estimated in multivariable models. Placental transfer, approximated by cord/maternal manganese ratio, cord/total manganese ratio (total=maternal+cord), and by joint classification according to high or low (above or below median) maternal and cord manganese, was evaluated as a predictor of neurodevelopment. RESULTS: Median levels [interquartile ranges (IQR)] of manganese in maternal and cord blood, respectively, were 24.0 (19.5-29.7) and 43.1 (33.5-52.1) μg/L. Adjusting for lead, arsenic, and other potential confounders, an IQR increase in maternal manganese was associated with -3.0 (95% CI: -5.3, -0.7) points on MDI and -2.3 (95% CI: -4.1, -0.4) points on PDI. Cord manganese concentrations were not associated with neurodevelopment scores. Cord/maternal and cord/total manganese ratios were positively associated with MDI [cord/maternal: β=2.6 (95% Cl: -0.04, 5.3); cord/total: β=22.0 (95% Cl: 3.2, 40.7)] and PDI (cord/maternal: β=1.7 (95% Cl: -0.5, 3.9); cord/total: β=15.6 (95% Cl: 0.3, 20.9)). Compared to mother-child pairs with low maternal and cord manganese, associations with neurodevelopment scores were negative for pairs with either high maternal, high cord, or high maternal and cord manganese. CONCLUSIONS: Maternal blood manganese concentrations were negatively associated with early childhood neurodevelopment scores in our study. Findings highlight the importance of understanding maternal exposures during pregnancy and factors influencing placental transfer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive. OBJECTIVES: The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring. METHODS: Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to 0.5 μg/kg BW/d (BPA0.5; n=21) or 50 μg/kg BW/d (BPA50; n=16), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (n=26). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring. RESULTS: Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels (0.81±0.10 mmol/L compared with 0.57±0.03 mmol/L, females BPA50 p=0.04; 0.81±0.05 mmol/L compared with 0.61±0.04 mmol/L, males BPA0.5 p=0.005) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls (68.2±4.4 number of adipocytes/HPF compared with 55.9±1.5 number of adipocytes/HPF; p=0.03) and by 123% in BPA0.5 females compared with BPA50 animals (68.2±4.4 number of adipocytes/high power field (HPF) compared with 55.3±2.9 number of adipocytes/HPF; p=0.04). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals (69.9±5.1 number of adipocytes/HPF compared with 54.0±3.4 number of adipocytes/HPF; p=0.03). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex. CONCLUSIONS: Developmental exposure to 0.5 μg/kg BW/d of BPA, which is 8-10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of 4 μg/kg BW/d and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at 0.5 μg/kg BW/d were compared with the offspring of unexposed controls. [ABSTRACT FROM AUTHOR]

BACKGROUND: Early-life arsenic exposure has been associated with reduced cell-mediated immunity, but little is known about its effects on humoral immunity. OBJECTIVE: We evaluated whether prenatal and childhood arsenic exposure was associated with humoral immune function in school-aged children. METHODS: Children born in a prospective mother–child cohort in rural Bangladesh were immunized with measles, mumps, and rubella (MMR) vaccines at 9 years of age (n=525). Arsenic exposure was assessed in urine (U-As), from mothers during pregnancy and their children at 4.5 and 9 years of age. Total IgG (tIgG), tIgE, tIgA, and MMR-specific IgG concentrations were measured in plasma using immunoassays. RESULTS: Arsenic exposure was positively associated with child tIgG and tIgE, but not tIgA. The association with tIgG was mainly apparent in boys (p for interaction=0.055), in whom each doubling of maternal U-As was related to an increase in tIgG by 28 mg/dL. The associations of U-As at 9 years with tIgG and tIgE were evident in underweight children (p for interaction <0.032). Childhood arsenic exposure tended to impair mumps-specific vaccine response, although the evaluation was complicated by high preimmunization titers. Postimmunization mumps–specific IgG titers tended to decrease with increasing U-As at 4.5 and 9 years of age [regression coefficient (β)=-0.16; 95% confidence interval (CI): -0.33, 0.01; p=0.064 and β=-0.12; 95% CI: -0.27, -0.029; p=0.113, respectively) in 25% children with the lowest preexisting mumps-specific IgG titers. CONCLUSIONS: Arsenic exposure increased tIgG and tIgE in plasma, and tended to decrease mumps-specific IgG in children at 9 years of age. [ABSTRACT FROM AUTHOR]

BACKGROUND: Providing infrastructure and land uses to encourage active travel (i.e., bicycling and walking) are promising strategies for designing health-promoting cities. Population-level exposure to air pollution during active travel is understudied. OBJECTIVES: Our goals were a) to investigate population-level patterns in exposure during active travel, based on spatial estimates of bicycle traffic, pedestrian traffic, and particulate concentrations; and b) to assess how those exposure patterns are associated with the built environment. METHODS: We employed facility-demand models (active travel) and land use regression models (particulate concentrations) to estimate block-level (n = 13,604) exposure during rush-hour (1600-1800 hours) in Minneapolis, Minnesota. We used the model-derived estimates to identify land use patterns and characteristics of the street network that are health promoting. We also assessed how exposure is correlated with indicators of health disparities (e.g., household income, proportion of nonwhite residents). Our work uses population-level rates of active travel (i.e., traffic flows) rather than the probability of walking or biking (i.e., "walkability" or "bikeability") to assess exposure. RESULTS: Active travel often occurs on high-traffic streets or near activity centers where particulate concentrations are highest (i.e., 20-42% of active travel occurs on blocks with high population-level exposure). Only 2-3% of blocks (3-8% of total active travel) are "sweet spots" (i.e., high active travel, low particulate concentrations); sweet spots are located a) near but slightly removed from the city-center or b) on off-street trails. We identified 1,721 blocks (~ 20% of local roads) where shifting active travel from high-traffic roads to adjacent low-traffic roads would reduce exposure by ~ 15%. Active travel is correlated with population density, land use mix, open space, and retail area; particulate concentrations were mostly unchanged with land use. CONCLUSIONS: Public health officials and urban planners may use our findings to promote healthy transportation choices. When designing health-promoting cities, benefits (physical activity) as well as hazards (air pollution) should be evaluated. CITATION: Hankey S, Lindsey G, Marshall JD. 2017. Population-level exposure to particulate air pollution during active travel: planning for low-exposure, health-promoting cities. Environ Health Perspect 125:527-534; http://dx.doi.org/10.1289/EHP442 [ABSTRACT FROM AUTHOR]

Background: Endocrine-disrupting chemicals (EDCs) are suspected of altering estrogenic signaling through estrogen receptor (ER) α or ss (mERss1 in mice). Several EDC effects have been reported in animal studies and extrapolated to human studies. Unlike humans, rodents express a novel isoform of ERss (mERss2) with a modified ligand-binding domain sequence. EDC activity through this isoform remains uncharacterized. Objectives: We identified the expression pattern of mERss2 in mouse tissues and assessed the estrogenic activity of EDCs through mERss2. Methods: mERss2 mRNA expression was measured in mouse tissues. HepG2 cells were used to assess the transactivation activity of mERss isoforms with EDCs and ER co-activators. 293A cells transiently transfected with mER isoforms were used to detect EDC-mediated changes in endogenous ER target gene expression. Results: Expression of mERss2 mRNA was detected in mouse reproductive tissues (ovary, testis, and prostate) and lung and colon tissues from both female and male mice. Five (E2, DES, DPN, BPAF, Coum, 1-BP) of 16 compounds tested by reporter assay had estrogenic activity through mERss2. mERss2 had a compound-specific negative effect on ERss/ligand-mediated activity and ER target genes when co-expressed with mERss1. mERss2 recruited coactivators SRC2 or SRC3 in the presence of EDCs, but showed less recruitment than mERss1. Conclusion: mERss2 showed weaker estrogenic activity than mERss1 in our in vitro system, and can dampen mERss1 activity. In vivo models of EDC activity and ER-mediated toxicity should consider the role of mERss2, as rodent tissue responses involving mERss2 may not be reproduced in human biology. CITATION: Donoghue LJ, Neufeld TI, Li Y, Arao Y, Coons LA, Korach KS. 2017. Differential activation of a mouse estrogen receptor ss isoform (mERss2) with endocrine-disrupting chemicals (EDCs). Environ Health Perspect 125:634-642; http://dx.doi.org/10.1289/EHP396 [ABSTRACT FROM AUTHOR]

BACKGROUND: Growing evidence suggests that pesticide use may contribute to respiratory symptoms. OBJECTIVE: We evaluated the association of currently used pesticides with allergic and non-allergic wheeze among male farmers. METHODS: Using the 2005-2010 interview data of the Agricultural Health Study, a prospective study of farmers in North Carolina and Iowa, we evaluated the association between allergic and non-allergic wheeze and self-reported use of 78 specific pesticides, reported by ≥ 1% of the 22,134 men interviewed. We used polytomous regression models adjusted for age, BMI, state, smoking, and current asthma, as well as for days applying pesticides and days driving diesel tractors. We defined allergic wheeze as reporting both wheeze and doctor-diagnosed hay fever (n = 1,310, 6%) and non-allergic wheeze as reporting wheeze but not hay fever (n = 3,939, 18%); men without wheeze were the referent. RESULTS: In models evaluating current use of specific pesticides, 19 pesticides were significantly associated (p < 0.05) with allergic wheeze (18 positive, 1 negative) and 21 pesticides with non-allergic wheeze (19 positive, 2 negative); 11 pesticides were associated with both. Seven pesticides (herbicides: 2,4-D and simazine; insecticides: carbaryl, dimethoate, disulfoton, and zeta-cypermethrin; and fungicide pyraclostrobin) had significantly different associations for allergic and non-allergic wheeze. In exposure-response models with up to five exposure categories, we saw evidence of an exposure-response relationship for several pesticides including the commonly used herbicides 2,4-D and glyphosate, the insecticides permethrin and carbaryl, and the rodenticide warfarin. CONCLUSIONS: These results for farmers implicate several pesticides that are commonly used in agricultural and residential settings with adverse respiratory effects. CITATION: Hoppin JA, Umbach DM, Long S, London SJ, Henneberger PK, Blair A, Alavanja M, Beane Freeman LE, Sandler DP. 2017. Pesticides are associated with allergic and non-allergic wheeze among male farmers. Environ Health Perspect 125:535-543; http://dx.doi.org/10.1289/EHP315 [ABSTRACT FROM AUTHOR]

BACKGROUND: Human exposure to parabens and other antimicrobial chemicals is continual and pervasive. The hormone-disrupting properties of these environmental chemicals may adversely affect human reproduction. OBJECTIVE: We aimed to prospectively assess couples' urinary concentrations of antimicrobial chemicals in the context of fecundity, measured as time to pregnancy (TTP). METHODS: In a prospective cohort of 501 couples, we examined preconception urinary chemical concentrations of parabens, triclosan and triclorcarban in relation to TTP; chemical concentrations were modeled both continuously and in quartiles. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) adjusting for a priori-defined confounders. In light of TTP being a couple-dependent outcome, both partner and couple-based exposure models were analyzed. In all models, FOR estimates < 1.0 denote diminished fecundity (longer TTP). RESULTS: Overall, 347 (69%) couples became pregnant. The highest quartile of female urinary methyl paraben (MP) concentrations relative to the lowest reflected a 34% reduction in fecundity (aFOR = 0.66; 95% CI: 0.45, 0.97) and remained so when accounting for couples' concentrations (aFOR = 0.63; 95% CI: 0.41, 0.96). Similar associations were observed between ethyl paraben (EP) and couple fecundity for both partner and couple-based models (p-trend = 0.02 and p-trend = 0.05, respectively). No associations were observed with couple fecundity when chemicals were modeled continuously. CONCLUSIONS: Higher quartiles of preconception urinary concentrations of MP and EP among female partners were associated with reduced couple fecundity in partner-specific and couple-based exposure models. CITATION: Smarr MM, Sundaram R, Honda M, Kannan K, Buck Louis GM. 2016. Urinary concentrations of parabens and other antimicrobial chemicals and their association with couples' fecundity. Environ Health Perspect 124:730-736; http://dx.doi.org/10.1289/EHP189 [ABSTRACT FROM AUTHOR]