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    Concentrations of polybrominated diphenyl ethers (PBDEs) and 2,4,6-tribromophenol in human placental tissues. Leonetti Christopher,Butt Craig M,Hoffman Kate,Miranda Marie Lynn,Stapleton Heather M Environment international Legacy environmental contaminants such as polybrominated diphenyl ethers (PBDEs) are widely detected in human tissues. However, few studies have measured PBDEs in placental tissues, and there are no reported measurements of 2,4,6-tribromophenol (2,4,6-TBP) in placental tissues. Measurements of these contaminants are important for understanding potential fetal exposures, as these compounds have been shown to alter thyroid hormone regulation in vitro and in vivo. In this study, we measured a suite of PBDEs and 2,4,6-TBP in 102 human placental tissues collected between 2010 and 2011 in Durham County, North Carolina, USA. The most abundant PBDE congener detected was BDE-47, with a mean concentration of 5.09ng/g lipid (range: 0.12-141ng/g lipid; detection frequency 91%); however, 2,4,6-TBP was ubiquitously detected and present at higher concentrations with a mean concentration of 15.4ng/g lipid (range:1.31-316ng/g lipid; detection frequency 100%). BDE-209 was also detected in more than 50% of the samples, and was significantly associated with 2,4,6-TBP in placental tissues, suggesting they may have a similar source, or that 2,4,6-TBP may be a degradation product of BDE-209. Interestingly, BDE-209 and 2,4,6-TBP were negatively associated with age (rs=-0.16; p=0.10 and rs=-0.17; p=0.08, respectively). The results of this work indicate that PBDEs and 2,4,6-TBP bioaccumulate in human placenta tissue and likely contribute to prenatal exposures to these environmental contaminants. Future studies are needed to determine if these joint exposures are associated with any adverse health measures in infants and children. 10.1016/j.envint.2015.12.002
    Associations between in utero exposure to polybrominated diphenyl ethers, pathophysiological state of fetal growth and placental DNA methylation changes. Zhao Yingya,Song Qi,Ge Wenzhen,Jin Yuting,Chen Shangqin,Zhao Yan,Xiao Xirong,Zhang Yunhui Environment international BACKGROUND:Polybrominated diphenyl ethers (PBDEs) are environmental chemicals with harmful effects on pregnancy, but their effects on adverse developmental outcomes are not fully understood. The placental DNA methylation is strongly influenced by prenatal environmental factors and has been linked to fetal growth. OBJECTIVE:To evaluate the association between in utero PBDEs exposure, placental DNA methylation changes (growth regulatory genes), and pathophysiology of fetal growth (birth outcomes, fetal growth retardation) in a population-based pregnancy cohort study. METHODS:This was a nested case-control study within the prospective Wenzhou Birth Cohort including 130 fetal growth retardation (FGR) cases and 130 healthy controls and their mothers recruited from June 2016 to June 2017. FGR was diagnosed based on the comprehensive evaluation of ultrasound results at 24, 28, and 32 weeks of gestation. Neonatal birth measurements were obtained from medical records. Gestational exposure to 19 PBDEs, including 13 lower BDE congeners (BDE-17-190) and 6 higher brominated BDE congeners (BDE-196-209), were determined by gas chromatography tandem mass spectrometry in the umbilical cord blood. Placental DNA methylation changes of one repetitive element (LINE1) and two candidate genes (HSD11B2, IGF2) were characterized by quantitative polymerase chain reaction-pyrosequencing. Multiple linear regression and logistic regression models were used to examine the associations among PBDEs exposure, fetal growth indicators, and DMR (differential methylation region) methylation fractions. Sobel tests were conducted to assess DNA methylation as a mediator in multivariate models. RESULTS:After excluding women who withdrew from the study or were lost to follow-up or failed to provide placenta or umbilical cord blood, 249 mother-newborn pairs (124 FGR cases, 125 controls) were included in the final analysis. Elevated BDE-206 (OR: 1.569, 95% CIs: 1.053-2.338), BDE-17-190 (OR: 2.860, 95% CIs: 1.233-6.634), BDE-196-209 (OR: 1.688, 95% CIs: 1.024-2.783) and ∑PBDEs (OR: 2.387, 95% CIs: 1.220-4.668) concentrations were associated with increased risk of FGR in newborns. FGR birth was also associated with increased DNA methylation of HSD11B2 (OR: 1.145, 95% CIs: 1.032-1.270) and decreased DNA methylation of IGF2 (OR: 0.892, 95% CIs: 0.845-0.941). In addition, BDE-17-190 showed significant associations with DNA methylation of HSD11B2 and IGF2 (β: 1.127, 95% CIs: 0.069-2.186; β: -3.452, 95% CIs: -5.512-1.392), indicating placental DNA methylation changes of HSD11B2 and IGF2 were related to both lower BDE congeners exposure and fetal growth. Further mediation analyses showed that IGF2 methylation mediated about 40% of the effects of BDE-17-190 in umbilical cord blood on neonatal FGR. CONCLUSION:We report an inverse association between in utero exposures to PBDEs and fetal growth and provide evidence supporting epigenetic gene plasticity in these associations. Changes in placental DNA methylation might be part of the underlying biological pathway between prenatal PBDEs exposure and adverse fetal growth. 10.1016/j.envint.2019.105255
    Association of Maternal Exposure to Persistent Organic Pollutants in Early Pregnancy With Fetal Growth. Ouidir Marion,Buck Louis Germaine M,Kanner Jenna,Grantz Katherine L,Zhang Cuilin,Sundaram Rajeshwari,Rahman Mohammad L,Lee Sunmi,Kannan Kurunthachalam,Tekola-Ayele Fasil,Mendola Pauline JAMA pediatrics Importance:Prenatal exposure to persistent organic pollutants (POPs) has been associated with birth size, but data on fetal growth and among racially/ethnically diverse pregnant women remain scarce. Objectives:To assess the association between maternal plasma POPs in early pregnancy and fetal growth and by infant sex and maternal race/ethnicity. Design, Setting, and Participants:This cohort study used the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, which recruited nonobese, low-risk pregnant women before 14 weeks' gestation between July 1, 2009, and January 31, 2013, in 12 community-based clinics throughout the United States. Participants self-identified their race/ethnicity, self-reported their behavioral risk factors, and were followed up throughout their pregnancy. Data were analyzed from July 31, 2018, to June 3, 2019. Exposures:Levels of 76 POPs in early gestation plasma were measured: 11 perfluoroalkyl and polyfluoroalkyl substances, 1 polybrominated biphenyl, 9 polybrominated diphenyl ethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 organochlorine pesticides (OCPs). The bayesian kernel machine regression method was used to examine chemical class mixtures, and generalized additive mixed model was used to analyze individual chemicals. Main Outcomes and Measures:Fourteen fetal biometrics were measured, including head circumference, abdominal circumference, and femur length, within 5 ultrasonography appointments. Results:A total of 2284 low-risk pregnant women were included: 606 women (26.5%) self-identified as white with a mean (SD) age of 30.3 (4.4) years, 589 (25.8%) as black with a mean (SD) age of 25.5 (5.5) years, 635 (27.8%) as Hispanic with a mean (SD) age of 27.1 (5.5) years, and 454 (19.9%) as Asian with a mean (SD) age of 30.5 (4.5) years. A comparison between the 75th and 25th percentile of exposure revealed that the OCP mixture was negatively associated with most fetal growth measures, with a reduction of 4.7 mm (95% CI, -6.7 to -2.8 mm) in head circumference, 3.5 mm (95% CI, -4.7 to -2.2 mm) in abdominal circumference, and 0.6 mm (95% CI, -1.1 to -0.2 mm) in femur length. Higher exposure to the PBDE mixture was associated with reduced abdominal circumference (-2.4 mm; 95% CI, -4.0 to -0.5 mm) and femur length (-0.5 mm; 95% CI, -1.0 to -0.1 mm), and the dioxin-like PCB mixture was associated with reduced head circumference (-6.4 mm; 95% CI, -8.4 to -4.3 mm) and abdominal circumference (-2.4 mm; 95% CI, -3.9 to -0.8 mm). Associations with individual chemicals were less consistent. There were some interactions by fetal sex, although most of the results did not vary by maternal race/ethnicity. For example, oxychlordane (-0.98 mm; 95% CI, -1.60 to -0.36 mm; P for interaction <.001), trans-nonachlor (-0.31 mm; 95% CI, -0.54 to -0.08 mm; P for interaction = .005), and p,p'-dichlorodiphenyldichloroethylene (-0.19 mm; 95% CI, -0.22 to -0.09 mm; P for interaction = .006) were associated with shorter femur length among boys only. Conclusions and Relevance:This study found that, among pregnant women with low POP levels, a mixture of OCPs was negatively associated with most fetal growth measures and that mixtures of PBDEs and dioxin-like PCBs were associated with reduced abdominal circumference. These findings suggested that, although exposures may be low, associations with fetal growth are apparent. 10.1001/jamapediatrics.2019.5104
    Gestational Exposure to Common Endocrine Disrupting Chemicals and Their Impact on Neurodevelopment and Behavior. Nesan Dinushan,Kurrasch Deborah M Annual review of physiology Endocrine disrupting chemicals are common in our environment and act on hormone systems and signaling pathways to alter physiological homeostasis. Gestational exposure can disrupt developmental programs, permanently altering tissues with impacts lasting into adulthood. The brain is a critical target for developmental endocrine disruption, resulting in altered neuroendocrine control of hormonal signaling, altered neurotransmitter control of nervous system function, and fundamental changes in behaviors such as learning, memory, and social interactions. Human cohort studies reveal correlations between maternal/fetal exposure to endocrine disruptors and incidence of neurodevelopmental disorders. Here, we summarize the major literature findings of endocrine disruption of neurodevelopment and concomitant changes in behavior by four major endocrine disruptor classes:bisphenol A, polychlorinated biphenyls, organophosphates, and polybrominated diphenyl ethers. We specifically review studies of gestational and/or lactational exposure to understand the effects of early life exposure to these compounds and summarize animal studies that help explain human correlative data. 10.1146/annurev-physiol-021119-034555
    Respiratory health and indoor air pollutants based on quantitative exposure assessments. Hulin Marion,Simoni Marzia,Viegi Giovanni,Annesi-Maesano Isabella The European respiratory journal We reviewed the main epidemiological studies that evaluate the respiratory effects of indoor air pollutants quantitatively in industrialised countries. Consistent results support short-term (aggravation) and, although more rarely, long-term (prevalence augmentation) effects on asthma, chronic bronchitis and chronic obstructive pulmonary disease (COPD) in indoor settings with poor air quality. Environmental tobacco smoke is one of the most important risks for respiratory symptoms and diseases worldwide. The evidence is also reliable for indoor nitrogen dioxide and particulate matter, which have been associated with asthma, bronchitis and COPD. Whereas formaldehyde and volatile organic compounds seem to be the main pollutants in indoor settings, relevant papers on their respiratory effects are still scarce, and limited to asthma and bronchitis. Moulds have been associated with an increased risk of asthma and COPD. Contradictory results have been found between endotoxins and asthma. The role of phthalates, persistent organic pollutants and flame retardants in respiratory diseases remains to be established. Results from rural areas of industrialised countries indicate that exposure to some indoor bio-contaminants might be protective in early life, while it is associated with adverse respiratory adverse effects in adulthood. Studies focusing on indoor air pollutants should be developed to better understand their involvement in the inception and aggravation of respiratory diseases. 10.1183/09031936.00159011
    Endocrine-disrupting chemicals: implications for human health. Kahn Linda G,Philippat Claire,Nakayama Shoji F,Slama Rémy,Trasande Leonardo The lancet. Diabetes & endocrinology Since reports published in 2015 and 2016 identified 15 probable exposure-outcome associations, there has been an increase in studies in humans of exposure to endocrine-disrupting chemicals (EDCs) and a deepened understanding of their effects on human health. In this Series paper, we have reviewed subsequent additions to the literature and identified new exposure-outcome associations with substantial human evidence. Evidence is particularly strong for relations between perfluoroalkyl substances and child and adult obesity, impaired glucose tolerance, gestational diabetes, reduced birthweight, reduced semen quality, polycystic ovarian syndrome, endometriosis, and breast cancer. Evidence also exists for relations between bisphenols and adult diabetes, reduced semen quality, and polycystic ovarian syndrome; phthalates and prematurity, reduced anogenital distance in boys, childhood obesity, and impaired glucose tolerance; organophosphate pesticides and reduced semen quality; and occupational exposure to pesticides and prostate cancer. Greater evidence has accumulated than was previously identified for cognitive deficits and attention-deficit disorder in children following prenatal exposure to bisphenol A, organophosphate pesticides, and polybrominated flame retardants. Although systematic evaluation is needed of the probability and strength of these exposure-outcome relations, the growing evidence supports urgent action to reduce exposure to EDCs. 10.1016/S2213-8587(20)30129-7
    Endocrine disruptors: Flame retardants and increased risk of thyroid cancer. Mughal Bilal B,Demeneix Barbara A Nature reviews. Endocrinology 10.1038/nrendo.2017.123
    Evaluation of in vitro vs. in vivo methods for assessment of dermal absorption of organic flame retardants: a review. Abdallah Mohamed Abou-Elwafa,Pawar Gopal,Harrad Stuart Environment international There is a growing interest to study human dermal exposure to a large number of chemicals, whether in the indoor or outdoor environment. Such studies are essential to predict the systemic exposure to xenobiotic chemicals for risk assessment purposes and to comply with various regulatory guidelines. However, very little is currently known about human dermal exposure to persistent organic pollutants. While recent pharmacokinetic studies have highlighted the importance of dermal contact as a pathway of human exposure to brominated flame retardants, risk assessment studies had to apply assumed values for percutaneous penetration of various flame retardants (FRs) due to complete absence of specific experimental data on their human dermal bioavailability. Therefore, this article discusses the current state-of-knowledge on the significance of dermal contact as a pathway of human exposure to FRs. The available literature on in vivo and in vitro methods for assessment of dermal absorption of FRs in human and laboratory animals is critically reviewed. Finally, a novel approach for studying human dermal absorption of FRs using in vitro three-dimensional (3D) human skin equivalent models is presented and the challenges facing future dermal absorption studies on FRs are highlighted. 10.1016/j.envint.2014.09.012
    Children's exposure to brominated flame retardants in indoor environments - A review. Malliari Eleftheria,Kalantzi Olga-Ioanna Environment international The aim of this review is to present up-to-date research on children's exposure to brominated flame retardants (BFRs) in indoor environments. Large geographical variations were observed for all BFRs [polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCDD), tetrabromobisphenol A (TBBPA)], with the highest concentrations of PBDEs measured in North America (BDE-47) and Europe (BDE-209), where higher concentrations of PBDEs are present in dust from houses, daycare centers and primary schools. In Asia the highest PBDE concentrations were measured in China, near e-waste recycling areas. In the Middle East, Australia and Africa BFR levels were low in most indoor spaces. Asian countries also have the highest concentrations of TBBPA and HBCDD, followed by European countries. Fewer studies have been conducted measuring novel and emerging BFRs (NBFRs or EBFRs), of which decabromodiphenylethane (DBDPE) has the highest concentration in indoor environments, especially in China. The vast majority of children's exposure studies have been conducted in houses, sampling either dust or air, and considerably fewer in schools, daycare centers, cars and public facilities, despite BFR levels being comparable to (or sometimes even higher than) house dust. Relatively fewer studies focused on children's tissues such as serum, and only two studied exposure via mouthing toys. Alternative noninvasive sampling matrices that may act as surrogates for exposure to BFRs such as handwipes and silicone wristbands have recently started to gain momentum, because of the ease of sampling, faster collection time and better correlations to serum than house dust. Feces sampling is another promising alternative to children's serum that warrants further research. While many studies have associated different indoor environment characteristics, there is a knowledge gap on the association between children's behaviour and activity patterns and their exposure to BFRs, as well as data on infant exposure to BFRs via baby products. Results from the studies showed that dust ingestion was the dominant exposure pathway for most studied BFRs compared to indoor air inhalation and dermal contact, especially for infants and toddlers who have higher exposures than older children. 10.1016/j.envint.2017.08.011
    A review on organophosphate Ester (OPE) flame retardants and plasticizers in foodstuffs: Levels, distribution, human dietary exposure, and future directions. Li Jianhua,Zhao Luming,Letcher Robert J,Zhang Yayun,Jian Kang,Zhang Jinhua,Su Guanyong Environment international Given the ongoing studies on the adverse effects of organophosphate ester (OPE) flame retardants and plasticizers on human health, there is an increasing scientific interest in the risk of exposure to OPEs via dietary intake. Using peer-reviewed literature published up to 2018, this review surveyed and compiled the available and reported data on the concentrations and distributions of 30 OPEs based on their occurrence in various food samples from around the world. Regardless of sampling locations or food categories, 22 OPEs were detectable in at least one of analyzed sample, and there were clear variations in OPE levels among samples from different locations or food categories. For instance, cereals and fats/oils were the most contaminated by OPEs in China and Belgium, whereas fats/oils and desserts were the main polluted products in Sweden. In contrast, vegetables, fruits, fluid dairy products, and cereals were reported as the primary categories of food polluted by OPEs in Australia. Animal-based food categories such as eggs, fish and meat were the least contaminated, whereas the highest median OPE concentrations were found in meat and fish from the United State. The levels and distribution patterns of OPEs in foodstuffs demonstrated a tremendous difference even when collected from the same country and the same food item. Rice from China had the highest tris(2‑chloroethyl) phosphate (TCEP, mean: 29.8 ng/g dw) levels, whereas 2‑ethylhexyl‑diphenyl phosphate (EHDPP, mean: 4.17 ng/g ww), triphenyl phosphate (TPHP, mean: 26.14 ng/g ww), tris(2-chloroisopropyl) phosphate (TCIPP, mean: 0.87 ng/g ww) and tributyl phosphate (TNBP, median: 0.55 ng/g ww) concentrations were the highest in the same food category from Sweden, Belgium, Australia, and the United States, respectively. These discrepancies may be due to a variety of reasons such as differences in OPE physico-chemical properties, extent of usage, uptake, metabolic pathways, industrial food manufacturing processes, OPE level differences as a function of habitat, and accumulation and degradability of OPEs in different species. It is worth noting that, due to its worldwide usage in food packaging materials, EHDPP was more prominently found in processed food compared to non-processed food. Based on reported OPE levels in various foods, this review conducted a preliminary assessment of human exposure to OPEs through dietary intake, which suggested that the OPE estimated daily intake (EDI) for humans was around 880 ng/kg bw/day (95th percentile). This value was well below the corresponding OPE health reference dose given by the U.S. EPA (≥15,000 ng/kg bw/day). Even so, dietary exposure to OPEs via food intake may be not negligible based on some important factors such as dilution effects, cooking processes, and the contribution of as yet unknown means of OPE exposure. Overall, this review highlights several gaps in our understanding of OPEs in foodstuffs: 1) the investigation of contamination levels of OPEs in foodstuffs should be extended to other regions, especially North America and European countries, where OPEs are widely used and frequently detected in environmental samples, and 2) newly identified OPE derivatives/by-products, e.g., OP diesters and hydroxylated metabolites, which have been reported as end-products of OPE enzymatic metabolism or degradation through aqueous hydrolysis, and which may co-exist with parent OPEs, could also be screened with precursor OPEs in foodstuffs in future studies. 10.1016/j.envint.2019.03.009