Mixtures Of Endocrine Disrupting Chemicals Research Articles

Prenatal exposures to mixtures of endocrine disrupting chemicals and sex-specific associations with children’s BMI and overweight at 5.5 years of age in the SELMA study

BackgroundPrenatal exposure to mixtures of endocrine disrupting chemicals (EDC) has the potential to disrupt human metabolism. Prenatal periods are especially sensitive as many developmental processes are regulated by hormones. Prenatal exposure to EDCs has inconsistently been associated with children’s body mass index (BMI) and obesity. The objective of this study was to investigate if prenatal exposure to a mixture of EDCs was associated with children’s BMI and overweight (ISO-BMI ≥ 25) at 5.5 years of age, and if there were sex-specific effects. MethodsA total of 1,105 mother–child pairs with complete data on prenatal EDCs concentrations (e.g., phthalates, non-phthalate plasticizers, phenols, PAH, pesticides, PFAS, organochlorine pesticides, and PCBs), children’s measured height and weight, and selected covariates in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study were included in this analysis. The mixture effect of EDCs with children’s BMI and overweight was assessed using WQS regression with 100 repeated holdouts. A positively associated WQS index with higher BMI and odds of overweight was derived. Models with interaction term and stratified weights by sex was applied in order to evaluate sex-specific associations. ResultsA significant WQS*sex interaction term was identified and associations for boys and girls were in opposite directions. Higher prenatal exposure to a mixture of EDCs was associated with lower BMI (Mean β = -0.19, 95%CI: −0.40, 0.01) and lower odds of overweight (Mean OR = 0.72, 95%CI: 0.48, 1.04) among girls with borderline significance. However, the association among boys did not reach statistical significance. Among girls, the possible chemicals of concern were MEP, 2-OHPH, BPF, BPS, DPP and PFNA. ConclusionPrenatal exposure to a mixture of EDCs was associated with lower BMI and overweight among girls, and non-significant associations among boys. Chemicals of concern for girls included phthalates, non-phthalate plasticizers, bisphenols, PAHs, and PFAS.

Association of endocrine disrupting chemicals exposure with human chorionic gonadotropin concentrations in pregnancy

BackgroundHuman chorionic gonadotropin (hCG) is produced by the placenta and plays an essential role in the maintenance of pregnancy. Endocrine disrupting chemicals (EDCs) have the potential to interfere with functions related to the production and secretion of hCG; however associations between exposure to EDCs and hCG concentrations in humans remain to be elucidated. ObjectivesTo investigate the association of urinary, serum and plasma concentrations of EDCs during pregnancy with serum hCG concentrations. MethodsWe utilized data form the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. We investigated the association of 26 EDCs measured in early pregnancy urine or blood with serum hCG concentrations using multi-variable adjusted linear regression models per EDC and Weighted Quantile Sum (WQS) regression with repeated holdout validation for the EDCs mixture. ResultsIn 2,039 included women, higher exposure to bisphenol A was associated with lower hCG (beta [95% CI]: −0.06 [−0.11 to −0.002]) while higher triclosan exposure was associated with a higher hCG (0.02 [0.003 to 0.04]). Higher exposure to several phthalates, including mono-ethyl and mono-butyl phthalates (MEP and MBP) as well as metabolites of di-2-ethylhexyl phthalate (DEHP) was associated with a lower hCG (beta [95% CI] for sum of DEHP metabolites: −0.13 [−0.19 to −0.07]). Likewise, higher exposure to several polychlorinated biphenyls (PCBs) was associated with a lower hCG. In the WQS regression, each quartile increase in the EDCs mixture was associated with −0.27 lower hCG (95% CI: −0.34 to −0.19). DiscussionHigher exposure to several EDCs during pregnancy was associated with a lower hCG; and despite the small effect sizes, still indicating that the exposure may negatively affect production or secretion of hCG by the placenta. Our results provide the impetus for future experimental studies to investigate the placenta as a target organ for adverse effects of EDCs.

Environmentally relevant doses of endocrine disrupting chemicals affect male fertility by interfering with sertoli cell glucose metabolism in mice

The growing global deterioration in several aspects of human health has been partly attributed to hazardous effects of endocrine-disrupting chemicals (EDCs) exposure. Therefore, experts and government regulatory agencies have consistently advocated for studies on the combined effects of EDCs that model human exposure to multiple environmental chemicals in real life. Here, we investigated how low concentrations of bisphenol A (BPA), and phthalates compounds affect the Sertoli cell glucose uptake/lactate production in the testis and male fertility. An EDC mixture containing a detected amount of each chemical compound in humans, called daily exposure (DE), and DE increased in magnitude by 25 (DE25), 250 (DE250), and 2500 (DE2500), and corn oil (control) were administered for six weeks to male mice. We found that DE activated estrogen receptor beta (Erβ) and glucose-regulated protein 78 (Grp 78) and disrupted the estradiol (E2) balance. In addition, DE25, DE250, and DE2500 doses of the EDC mixture via binding with Sertoli cells’ estrogen receptors (ERs) inhibited the glucose uptake and lactate production processes by downregulating glucose transporters (GLUTs) and glycolytic enzymes. As a result, endoplasmic reticulum stress (ERS), marked by unfolded protein response (UPR) activation, was induced. The accompanying upregulation of activating transcription factor 4 (ATF4), inositol requiring enzyme-1 (IRE1), C/EBP homologous protein (CHOP), and mitogen-activated protein kinase (MAPK) signaling promoted antioxidant depletion, testicular cell apoptosis, abnormal regulation of the blood−testis barrier, and decreased sperm count. Therefore, these findings suggest that human and wildlife exposure to multiple environmental chemicals can produce a wide range of reproductive health complications in male mammals.

O-091 The impact of endocrine disruptors on early pregnancy and clinical outcomes in IVF

Abstract The impact of endocrine disruptors on early pregnancy and clinical outcomes in IVF Moncef Benkhalifa (1,2,3), Debbie Montjean (2), Hafida Corsi-Cauet (3), Henri Copin (1,3), Véronique Bach (3), Pierre Miron (2), Rosalie Cabry (1,3) (1) Reproductive Medicine and Reproductive Genetics, University Hospital & School of Medicine. Picardie University Jules Verne. Amiens France (2) ART Centers. Laval and Brossard. Fertilys International Inc. Laval. Québec. Canada (3) PERITOX Laboratory. Picardie University Jules Verne. Amiens. France Since more than 40 years, there are annual increasing of studies, meta-analysis reporting and discussing the potential associations between endocrine disrupting chemicals (EDCs) and human fertility potential declining. Today it’s accepted that a substantial number of environmental and exposition factors affect the fertility and fecundity capacity of couples during the peri and post conception period. It’s accepted that most of EDCs interfere with or mimic steroid hormone action; predominantly by affecting estrogen, androgen and thyroid hormones signaling pathways and disturbing specific molecular process on relation with single or multiple biological functions. Some of EDCs can interact with the male and female reproductive system and lead to endocrine disruption in the testis and ovary. they exert their effects mainly via binding transcription factor receptors, EDCs can alter endocrine function through a variety of mechanisms. At fertility age EDCs may alter the expression and/or activity of enzymes required for synthesis and/or catabolism of testicular and ovarian sex steroids and the expression of hormone receptors and/or their ability to bind their and endogenous ligands. For example, in male, the literature reported a negative correlation between disrupted spermatogenesis and lifestyle factors (environmental-professional expositions) such as alcohol consumption, cigarette smoking, drug use, and obesity caused by high-energy diet. In female infertility diseases, the negative impact of chemicals ED has been studied in animals. Many disorders have been described, such as low ovarian weight, impaired folliculogenesis, a high aneuploidy rate and the acceleration of follicular atresia. Indeed, women exposed to some endocrine-disrupting pesticides (such as atrazine, lindane) have an elevated risk of long menstrual cycles or anovulation but the most serious consequence is POF and endometriosis pathophysiology’s. In our IVF experience in Picardie region (France), we observed that various pesticides with an endocrine-disrupting action are associated with poor oocyte quality (maturation and competency), embryonic defects and poor IVF outcomes, and some pesticide compounds are linked to specific causes of female infertility, such as premature ovarian insufficiency, polycystic ovarian syndrome, and endometriosis. It was reported that EDCs can reduce embryo implantation chances and increase miscarriage, placenta and post-natal abnormalities. for endometrium receptivity and implantation failure EDCs can play by modifying keys elements of the immune response relevant to pregnancy, and disrupt immune tolerance required for robust placentation, optimal fetal development and be a as contributing risk factors in recurrent miscarriage, preeclampsia, preterm birth and related pathologic gestation Environmental insults, including endocrine disrupting chemicals during critical periods of fetal development, can alter DNA methylation patterns, leading to inappropriate developmental gene expression and disease risks. Similar to environmental factors, endocrine-disrupting chemicals can influence gene expression without modifying the DNA sequence. It is commonly accepted that the transgenerational inheritance of parentally acquired traits is conveyed by epigenetic alterations risks also known as “epimutations”. In Conclusion, the negative impact of exposure to various endocrine-disrupting is becoming now a worldwide public health. Indeed, the community should be informed about the fertility decline, low ongoing pregnancy rates, and elevated risk of miscarriage associated with exposure to high doses of pesticides for example. We must keep in mind that humans are exposed to EDCs mixtures composed of hundreds of chemicals every day and not a single chemical in isolation.

Mixed and single effects of endocrine disrupting chemicals in follicular fluid on likelihood of diminished ovarian reserve: A case-control study

Endocrine-disrupting chemicals (EDCs) are a group of the most widely spread pollutants. Their impacts on reproductive health have become public concerns. Diminished ovarian reserve (DOR) is a disorder of ovarian function. Associations between EDC and DOR have been inconsistent. Very little research investigated the joint effects of multiple EDCs. Here, we performed a case-control study among 64 DOR women and 86 controls. Twenty-one EDC chemicals were assessed in follicular fluid, including parabens, phenols, phthalates and poly-fluoroalkyl substances. Both mixed and single effects of EDCs on DOR were evaluated and validated with a Bayesian kernel machine and logistic regressions. We found that the likelihood of DOR significantly increased with rising levels of the 21-EDC mixture, with an odds ratio (OR) and 95% confidence interval (CI) of 2.12 (1.17–3.83) for the 75th percentile compared to its median level. The overall effect was higher than effects of each subgroup. BP4, MECPP, and PFHxA were driving the association to the mixture, and their single effects were validated, with individual ORs of 8.25 (95%CI:3.45–12.21), 1.92 (95%CI:1.02–4.09), and 1.84 (95%CI:1.08–3.86), respectively. In conclusion, we provided new pollutant markers for DOR and emphasized the importance of the effects of EDC mixtures on female reproductive health.

Exposure to endocrine-disrupting chemicals and implications for neurodevelopment.

Human brain development is a complex multistep process that is partly coordinated by the endocrine system. Any interference with the endocrine system might affect this process and result in deleterious outcomes. Endocrine-disrupting chemicals (EDCs) represent a large group of exogenous chemicals with the capacity of interfering with endocrine functions. In different population-based settings, associations between exposure to EDCs, particularly in prenatal life, and adverse neurodevelopmental outcomes have been demonstrated. These findings are strengthened by numerous experimental studies. Although mechanisms underlying these associations are not entirely delineated, disruption of thyroid hormone and, to a lesser extent, sex hormone signalling have been shown to be involved. Humans are constantly exposed to mixtures of EDCs, and further research combining epidemiological and experimental settings is required to improve our understanding of the link between real-life exposures to these chemicals and their impact on neurodevelopment.

Removal of endocrine-disrupting chemical mixtures in water using chlorination and photolysis

Abstract Micropollutants have been continuously detected in freshwater. In parallel, the potential adverse effects of human exposure to endocrine-disrupting chemicals (EDCs) through drinking water have been gaining the attention of researchers and health authorities. Given this fact, this study aimed to evaluate the effectiveness of chlorination and photolysis to remove the estrogenic activity caused by mixtures of EDCs in water: estrone (E1: 100 ng L−1), 17β-estradiol (E2: 100 ng L−1), ethinylestradiol (EE2: 50 ng L−1), and nonylphenol (NP: 1,000 ng L−1) under operating conditions applicable for water treatment plants. The tests were performed using freshwater spiked with the following mixtures: E1 + E2, E1 + E2 + EE2, E1 + E2 + NP, and E1 + E2 + EE2 + NP). Removal efficiencies of up to 99.7% were achieved at a chlorine dose of 2.75 mg L–1 and 30 min of contact time. In photolysis, estrogenic activity removal was higher than 99.9% at a UV dose of 186 mJ cm–2. Results indicated that both chlorination and photolysis can be efficient to remove the estrogenic activity caused by the tested EDC mixtures in water. Furthermore, experiments suggested that EDC mixtures can be efficiently removed at feasible water disinfection operating conditions.

Impact of endocrine disrupting chemicals and pharmaceuticals on Sertoli cell development and functions.

Sertoli cells play essential roles in male reproduction, from supporting fetal testis development to nurturing male germ cells from fetal life to adulthood. Dysregulating Sertoli cell functions can have lifelong adverse effects by jeopardizing early processes such as testis organogenesis, and long-lasting processes such as spermatogenesis. Exposure to endocrine disrupting chemicals (EDCs) is recognized as contributing to the rising incidence of male reproductive disorders and decreasing sperm counts and quality in humans. Some drugs also act as endocrine disruptors by exerting off-target effects on endocrine tissues. However, the mechanisms of toxicity of these compounds on male reproduction at doses compatible with human exposure are still not fully resolved, especially in the case of mixtures, which remain understudied. This review presents first an overview of the mechanisms regulating Sertoli cell development, maintenance, and functions, and then surveys what is known on the impact of EDCs and drugs on immature Sertoli cells, including individual compounds and mixtures, and pinpointing at knowledge gaps. Performing more studies on the impact of mixtures of EDCs and drugs at all ages is crucial to fully understand the adverse outcomes these chemicals may induce on the reproductive system.

Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes.

Perinatal exposure to endocrine disrupting chemicals (EDCs) has been shown to affect male reproductive functions. However, the effects on male reproduction of exposure to EDC mixtures at doses relevant to humans have not been fully characterized. In previous studies, we found that in utero exposure to mixtures of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and the soy-based phytoestrogen genistein (Gen) induced abnormal testis development in rats. In the present study, we investigated the molecular basis of these effects in adult testes from the offspring of pregnant SD rats gavaged with corn oil or Gen + DEHP mixtures at 0.1 or 10 mg/kg/day. Testicular transcriptomes were determined by microarray and RNA-seq analyses. A protein analysis was performed on paraffin and frozen testis sections, mainly by immunofluorescence. The transcription factor forkhead box protein 3 (FOXA3), a key regulator of Leydig cell function, was identified as the most significantly downregulated gene in testes from rats exposed in utero to Gen + DEHP mixtures. FOXA3 protein levels were decreased in testicular interstitium at a dose previously found to reduce testosterone levels, suggesting a primary effect of fetal exposure to Gen + DEHP on adult Leydig cells, rather than on spermatids and Sertoli cells, also expressing FOXA3. Thus, FOXA3 downregulation in adult testes following fetal exposure to Gen + DEHP may contribute to adverse male reproductive outcomes.

Response to "Comment on 'A Permutation Test-Based Approach to Strengthening Inference on the Effects of Environmental Mixtures: Comparison between Single-Index Analytic Methods'".

Response to "Comment on 'A Permutation Test-Based Approach to Strengthening Inference on the Effects of Environmental Mixtures: Comparison between Single-Index Analytic Methods'".

A human-relevant mixture of endocrine disrupting chemicals induces changes in hippocampal DNA methylation correlating with hyperactive behavior in male mice

Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the programming role of hormones during this period. A previous epidemiological study has shown association between prenatal co-exposure to 8 EDCs (Mixture N1) and language delay in children, suggesting an effect of this mixture on neurodevelopment. Furthermore, in utero exposure to Mixture N1 altered gene expression and behavior in adult mice. In this study, we investigated whether epigenetic mechanisms could underlie the long term effects of Mixture N1 on gene expression and behavior. To this end, we analyzed DNA methylation at regulatory regions of genes whose expression was affected by Mixture N1 in the hippocampus of in utero exposed mice using bisulfite-pyrosequencing. We show that Mixture N1 decreases DNA methylation in males at three genes that are part of the hypothalamus-pituitary-adrenal (HPA) axis: Nr3c1, Nr3c2, and Crhr1, coding for the glucocorticoid receptor, the mineralocorticoid receptor, and the corticotropin releasing hormone receptor 1, respectively. Furthermore, we show that the decrease in Nr3c1 methylation correlates with increased gene expression, and that Nr3c1, Nr3c2, and Crhr1 methylation correlates with hyperactivity and reduction in social behavior. These findings indicate that an EDC mixture corresponding to a human exposure scenario induces epigenetic changes, and thus programming effects, on the HPA axis that are reflected in the behavioral phenotypes of the adult male offspring.

Association between endocrine-disrupting chemical mixture and metabolic indices among children, adolescents, and adults: A population-based study in Korea

Exposure to endocrine-disrupting chemicals (EDCs) play a role in the etiology of obesity and dyslipidemia. However, few studies have analyzed the combined effects of EDC mixtures. This study explored the association between concurrent exposure to EDCs and obesity or dyslipidemia in children, adolescents, and adults. A total of 1454 children, 891 adolescents, and 3758 (for BMI) and 3424 (for TG/HDL) adults from the Korean National Environmental Health Survey 2015 to 2017 were included in this cross-sectional study. Urinary concentrations of eight phthalate metabolites, three phenols, three parabens, and one pyrethroid pesticides metabolite were quantified. Body mass index (BMI) was measured for all participants, and triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c) levels were measured for adolescents and adults. Associations between combined EDC mixtures with the BMI and TG to HDL-c ratio were evaluated using Bayesian Kernel Machine Regression (BKMR). In all age groups, most of the chemical exposures, with the exception of BPF and BPS, were detected in more than 90% of participants. There were significant moderate to high correlations within phthalate metabolites and a high correlation within parabens. The BKMR showed that EDC mixtures were associated with higher BMI in both adolescents and adults, with greater significance in adults compared with adolescents, and a higher TG/HDL in male adolescents. In adolescents, MEP and MCPP drove the main effects on BMI and TG/HDL, respectively. In adults, 3PBA and BPA drove the main effects on BMI. The findings of this study suggest that exposure to EDC mixtures is associated with higher BMI and TG/HDL, and adolescence may be a critical period for EDC mixture in terms of both outcomes. Further studies are needed, but strategies to reduce EDC exposure from early life stages may be necessary to lower the risk of metabolic disease.

Exposure to mixtures of phenols, phthalate metabolites, parabens, and pesticide and BMI and lipid profiles in adolescents age 12-18

Background and aim Endocrine disrupting chemicals (EDCs) interfere endocrine system and lead to the imbalance in the regulation of lipid metabolism and body weight. Some recent studies suggest that EDCs may increase the risk for obesity or dyslipidemia, but most previous studies have evaluated the health effects of individual EDCs in isolation. We evaluated the association of combined exposure of EDCs with body mass index (BMI) and lipid profiles in a representative sample of a general population from Korea. Methods Urinary concentrations of exposures including three phenols (bisphenol A, bisphenol F, bisphenol S), eight phthalate metabolites (mono- (2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-n-butyl phthalate, monobenzyl phthalate, mono-(2-ethyl-5-carboxypentayl) phthalate, mono-(carboxyoctyl) phthalate, mono-(carboxynonyl) phthalate, mono(3-carboxylpropyl) phthalate), three parabens (methyl paraben, ethyl paraben, propyl paraben), and pyrethroid pesticides metabolite (3-phenoxybenzoic acid) and outcomes of interest including BMI, triglycerides (TG), total cholesterol, and high-density lipoprotein cholesterol (HDL-c) were measured in 891 adolescents. Age, sex, monthly household income, mother’s education level, frequency of fast-food, physical activity, smoking status, and alcohol consumption were adjusted. The association was examined using Bayesian Kernel Machine Regression (BKMR), and the analyses were stratified by sex to assess the potential effect modification. Results BMI, TG to HDL-c ratio (TG/HDL), and total cholesterol to HDL ratio (TC/HDL) showed significant increasing trends when all the chemicals were at different levels from 25th percentile to 75th percentile, although the confidence intervals were wide. And the overall effects were more significant among males compared to female. For BMI, parabens showed the highest group posterior inclusion probability (PIP). On the other hand, for TG/HDL and TC/HDL, phthalate metabolites showed the highest group PIP. Conclusions Our findings suggest that higher exposure to EDCs mixture is associated with higher BMI, TG/HDL, TC/HDL, particularly in male adolescents. Key workds endocrine disrupting chemicals, mixture, BKMR, BMI, TG, HDL, total cholesterol, adolescents

Relationships between levels of endocrine-disrupting chemicals and immune markers in maternal circulation during mid-pregnancy

Background and Aim: Prenatal exposure to endocrine-disrupting chemicals (EDCs) has been linked to child neurodevelopmental disorders. Maternal immune activation during pregnancy is associated with adverse child developmental outcomes. Whether EDCs influence maternal immune physiology is unclear. Methods: We analyzed data from general population controls (n=439) of the Early Markers for Autism (EMA) Study, a case-control study of children born during 2000-2003 in Southern California. Eleven polychlorinated biphenyls (PCBs), 6 brominated flame retardants (BFRs), 2 organochlorine pesticides (OCPs), 6 polyfluoroalkyl substances (PFAS), and 22 cytokines/chemokines were measured in maternal serum samples collected 15-20 weeks into pregnancy. We assessed individual relationships between log-transformed EDC levels and immune markers with spearman correlations and adjusted linear regression models. We further explored overall associations of EDC mixtures with specific immune markers using Bayesian kernel machine regression (BKMR). Results: After adjustment for false-discovery rate, 28 correlations between EDCs and maternal immune markers were statistically significant (spearman rho ranging from -0.25 to 0.24). These top correlations comprised 14 chemicals (9 PCBs, 3 PFAS, 1 BFR, and 1 OCP), and 8 immune markers. In adjusted linear models, all PCBs were inversely associated with levels of soluble interleukin-2 receptor alpha (sIL-2ra), with PCB99 showing the strongest relationship (adj-β[95%CI]: -0.48[-0.69, -0.27]). In BKMR, increasing all congeners in the PCB mixture from their 50th to their 95th percentiles was associated with decreased sIL-2ra (adj-β[95%CrI]: -0.43[-0.84, -0.02] and PCB99 had the highest relative importance in this mixture. Among other EDCs, p,p´-DDE, an OCP, was inversely associated with multiple markers (IL-12p40, IL-13, and IL-1ra). In contrast, others, such as Et-FOSAA, a PFAS, were positively associated with multiple immune markers, including IL-12p70, GM-CSF, IL-1ra, and IL-10. Conclusions: These findings suggest that specific EDCs may affect diverse immune and inflammatory pathways during pregnancy. These relationships may have implications for child development. Keywords: EDCs; prenatal; immune

Association between trimester-specific exposure to thirteen endocrine disrupting chemicals and preterm birth: Comparison of three statistical models

BackgroundGrowing evidence indicated that maternal exposure to some endocrine disrupting chemicals (EDCs) may increase the risk of preterm birth (PTB). However, few studies have evaluated the joint effect of EDCs on PTB. ObjectivesThis study aimed to evaluate the associations of maternal EDCs mixture in the 1st, 2nd, and 3rd trimesters during pregnancy with PTB, and identify the vital components that mainly contribute to PTB. MethodsThis study included 847 pregnant women that provided urine samples for all three trimesters. Urinary concentrations of thirteen EDC metabolites (four phthalates, two parabens, three phenols, and four benzotriazoles and benzothiazoles) were examined. Logistic regression model, quantile g-computation and Bayesian kernel machine regression (BKMR) models were applied to study the association. ResultsLogistic regression model suggested that only bisphenol A (BPA) in the 1st trimester significantly increased the OR of PTB after adjusting for BPA exposure in the 2nd and 3rd trimesters. Quantile g-computation model identified that urinary EDCs mixture in the 1st trimester were positively associated with PTB [OR (95 % CI): 1.98 (1.10, 3.58)], and the most heavily weighted component for PTB was BPA (26 %), followed by mono-2ethylhexyl phthalate (MEHP) (22 %). BKMR model determined a significant association between EDCs mixture in the 1st trimester and PTB when all EDC concentrations were at or above their 55th percentile compared with the median. The BKMR model found that BPA and MEHP were associated with an increase in the estimated probability of PTB, when the other EDCs were held to their 50th and 75th percentiles, respectively, in the 1st trimester. ConclusionsThe results of mixture analysis models indicated that exposure to higher EDCs mixture in the 1st trimester may increase the risk of PTB. BPA was considered as the most contributing factor for PTB among the detected EDCs.

Association of Prenatal Exposure to Endocrine-Disrupting Chemicals With Liver Injury in Children

Prenatal exposures to endocrine-disrupting chemicals (EDCs) may increase the risk for liver injury in children; however, human evidence is scarce, and previous studies have not considered potential EDC-mixture effects. Furthermore, the association between prenatal EDC exposure and hepatocellular apoptosis in children has not been studied previously. To investigate associations of prenatal exposure to EDC mixtures with liver injury risk and hepatocellular apoptosis in childhood. This prospective cohort study used data collected from April 1, 2003, to February 26, 2016, from mother-child pairs from the Human Early-Life Exposome project, a collaborative network of 6 ongoing, population-based prospective birth cohort studies from 6 European countries (France, Greece, Lithuania, Norway, Spain, and the UK). Data were analyzed from April 1, 2021, to January 31, 2022. Three organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 3 phenols, 4 parabens, 10 phthalates, 4 organophosphate pesticides, 5 perfluoroalkyl substances, and 9 metals. Child serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and CK-18 were measured at 6 to 11 years of age. Risk for liver injury was defined as having ALT, AST, and/or GGT levels above the 90th percentile. Associations of liver injury or cytokeratin 18 (CK-18) levels with each chemical group among the 45 EDCs measured in maternal blood or urine samples collected in pregnancy were estimated using 2 complimentary exposure-mixture methods: bayesian weighted quantile sum (BWQS) and bayesian kernel machine regression. The study included 1108 mothers (mean [SD] age at birth, 31.0 [4.7] years) and their singleton children (mean [SD] age at liver assessment, 8.2 [1.6] years; 598 [54.0%] boys). Results of the BWQS method indicated increased odds of liver injury per exposure-mixture quartile increase for organochlorine pesticides (odds ratio [OR], 1.44 [95% credible interval (CrI), 1.21-1.71]), PBDEs (OR, 1.57 [95% CrI, 1.34-1.84]), perfluoroalkyl substances (OR, 1.73 [95% CrI, 1.45-2.09]), and metals (OR, 2.21 [95% CrI, 1.65-3.02]). Decreased odds of liver injury were associated with high-molecular-weight phthalates (OR, 0.74 [95% CrI, 0.60-0.91]) and phenols (OR, 0.66 [95% CrI, 0.54-0.78]). Higher CK-18 levels were associated with a 1-quartile increase in polychlorinated biphenyls (β, 5.84 [95% CrI, 1.69-10.08] IU/L) and PBDEs (β, 6.46 [95% CrI, 3.09-9.92] IU/L). Bayesian kernel machine regression showed associations in a similar direction as BWQS for all EDCs and a nonlinear association between phenols and CK-18 levels. With a combination of 2 state-of-the-art exposure-mixture approaches, consistent evidence suggests that prenatal exposures to EDCs are associated with higher risk for liver injury and CK-18 levels and constitute a potential risk factor for pediatric nonalcoholic fatty liver disease.

Identification of combinations of endocrine disrupting chemicals in household chemical products that require mixture toxicity testing

People are exposed to various chemicals contained in consumer products for which the risks are poorly characterized. There is growing evidence that exposure to endocrine disrupting chemicals (EDCs) through product use potentially affects development, behavior, and reproduction. However, limited information is available about common combinations of chemicals based on their appearance and potential health effects. The present study listed the ingredients contained in 11064 household chemical products from a publicly available database, and identified EDCs related to estrogenicity, androgenicity, thyroid hormone disruption, and changes in steroidogenesis. Association rule mining was applied to the dataset to identify frequent combinations of chemicals or commonly occurring EDCs contained in a single product. Among the target products, ingredient names were matched with 1241 chemical identifiers. A total of 293 chemicals were related to endocrine disruption, and nearly two-thirds of the products contained more than one of these chemicals. Cleaning products, synthetic detergents, fabric softeners, air fresheners, and deodorants have several hotspots for fragrances, isothiazolinones, glycol ethers, and parabens. The three most prevalent EDCs in household chemical products were added to act as fragrances and preservatives. The present study demonstrated that commonly occurring chemical combinations can be derived using an association rule mining algorithm. The results of this study will be useful in prioritizing chemical combinations and developing management plans for EDC mixture in consumer products.

Correlates of non-persistent endocrine disrupting chemical mixtures among reproductive-aged Black women in Detroit, Michigan

Some studies indicate that Black women have higher exposure to multiple non-persistent endocrine disrupting chemicals (EDCs) than white women, but little is known about correlates of exposure to EDC mixtures. Using baseline data from a prospective cohort study of reproductive-aged Black women (N = 751), we characterized profiles of EDC mixtures and identified correlates of exposure. At baseline, we quantified biomarkers of 16 phthalates, 7 phenols, 4 parabens, and triclocarban in urine and collected covariate data through self-administered questionnaires and interviews. We used principal component (PC) analysis and k-means clustering to describe EDC mixture profiles. Associations between correlates and PCs were estimated as the mean difference (β) in PC scores, while associations between correlates and cluster membership were estimated as the odds ratio (OR) of cluster membership. Personal care product use was consistently associated with profiles of higher biomarker concentrations of non-persistent EDCs. Use of nail polish, menstrual and vaginal products (e.g., vaginal powder, vaginal deodorant), and sunscreen was associated with a mixture of phthalate and some phenol biomarkers using both methods. Current vaginal ring use, a form of hormonal contraception placed inside the vagina, was strongly associated with higher concentrations of high molecular weight phthalate biomarkers (k-means clustering: OR = 2.42, 95% CI = 1.28, 4.59; PCA: β = −0.32, 95% CI = −0.71, 0.07). Several dietary, reproductive, and demographic correlates were also associated with mixtures of EDC biomarkers. These findings suggest that personal care product use, diet, and contraceptive use may be sources of exposure to multiple non-persistent EDCs among reproductive-aged Black women. Targeted interventions to reduce exposure to multiple EDCs among Black women are warranted.

Prenatal Exposure to an EDC Mixture, NeuroMix: Effects on Brain, Behavior, and Stress Responsiveness in Rats.

Humans and wildlife are exposed to endocrine-disrupting chemicals (EDCs) throughout their lives. Environmental EDCs are implicated in a range of diseases/disorders with developmental origins, including neurodevelopment and behavior. EDCs are most often studied one by one; here, we assessed outcomes induced by a mixture designed to represent the real-world situation of multiple simultaneous exposures. The choice of EDCs, which we refer to as “NeuroMix,” was informed by evidence for neurobiological effects in single-compound studies and included bisphenols, phthalates, vinclozolin, and perfluorinated, polybrominated, and polychlorinated compounds. Pregnant Sprague Dawley rats were fed the NeuroMix or vehicle, and then offspring of both sexes were assessed for effects on postnatal development and behaviors and gene expression in the brain in adulthood. In order to determine whether early-life EDCs predisposed to subsequent vulnerability to postnatal life challenges, a subset of rats were also given a stress challenge in adolescence. Prenatal NeuroMix exposure decreased body weight and delayed puberty in males but not females. In adulthood, NeuroMix caused changes in anxiety-like, social, and mate preference behaviors only in females. Effects of stress were predominantly observed in males. Several interactions of NeuroMix and stress were found, especially for the mate preference behavior and gene expression in the brain. These findings provide novel insights into how two realistic environmental challenges lead to developmental and neurobehavioral deficits, both alone and in combination, in a sex-specific manner.

A Mixture of Endocrine Disrupting Chemicals Associated with Lower Birth Weight in Children Induces Adipogenesis and DNA Methylation Changes in Human Mesenchymal Stem Cells.

Endocrine Disrupting Chemicals (EDCs) are man-made compounds that alter functions of the endocrine system. Environmental mixtures of EDCs might have adverse effects on human health, even though their individual concentrations are below regulatory levels of concerns. However, studies identifying and experimentally testing adverse effects of real-life mixtures are scarce. In this study, we aimed at evaluating an epidemiologically identified EDC mixture in an experimental setting to delineate its cellular and epigenetic effects. The mixture was established using data from the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) study where it was associated with lower birth weight, an early marker for prenatal metabolic programming. This mixture was then tested for its ability to change metabolic programming of human mesenchymal stem cells. In these cells, we assessed if the mixture induced adipogenesis and genome-wide DNA methylation changes. The mixture increased lipid droplet accumulation already at concentrations corresponding to levels measured in the pregnant women of the SELMA study. Furthermore, we identified differentially methylated regions in genes important for adipogenesis and thermogenesis. This study shows that a mixture reflecting human real-life exposure can induce molecular and cellular changes during development that could underlie adverse outcomes.