Polybrominated Diphenyl Ethers Exposure Research Articles

Sex‐Dependent Metabolic Syndrome Phenotype Produced By Developmental Exposure to Indoor Flame Retardants

Chronic low level exposure to endocrine disrupting chemicals such as polybrominated diphenyl ethers (PBDEs) have been associated with diabetogenic and obesogenic phenotypes but mechanistic studies are sparse.1–2 In this study, we examined effects of developmental exposure to DE‐71, an industrial mixture of mostly penta‐brominated PBDE congeners3, on cellular, organ and systems level processes associated with metabolic syndrome after adult and developmental exposure to DE‐71 in C57Bl/6 mice. In an effort to link chemical exposure to health effects via key events (KE), we designed experiments using an adverse outcome pathway framework. Toxicant Exposure: C57BI/6 dams were exposed daily to DE‐71 at low dose (LD, 0.1mg/kg/d), or high dose (HD, 0.4mg/kg/d) and compared to corn oil vehicle control (OD) via ingestion of infused corn flakes for 10wk (mating, gestation lactation). GC/ECNI‐MS showed that livers of female offspring at sacrifice (PND 100) contained only BDE‐25 and 153, whereas, other congeners were detected in dams: BDE 99>47=85=100=154=183. Adverse Outcomes: Glucose tolerance test indicated pronounced glucose intolerance in LD females and dams but not male offspring. Insulin tolerance test showed insensitivity in LD and HD female offspring (p<.05; n=5–10). Compared to LD female offspring, DE‐71 exposed male offspring and dams showed less pronounced glucose intolerance and insulin insensitivity. KE – Systems (Metabolic): Fasting hyperglycemia was observed in HD female offspring (p<.001; n=5–12); Only the LD female offspring showed elevated plasma cholesterol and liver lipids although but dams showed greatest fatty liver (p<.05, n=5–8). KE – Systems (Endocrine): Plasma insulin was significantly decreased in LD (p<.05, n=8–19) and HD female (p<.01, n=8–19) but not male offspring or dams. KEs – Molecular: Adult and developmental PBDE exposure at LD and HD produced liver oxidative stress as indicated by elevated glutathione S‐transferase (GST) and reduced glutathione reductase (GR) activity in male offspring, female offspring and dams when compared with OD (n=12–20/group; p<.01). PBDEs may alter hepatic glycogenesis and glyceroneogenesis and glucose oxidation since they reduce phosphenolpyruvate carboxykinase (PEPCK) and glutamate dehydrogenase (GDH) activity, respectively; both were decreased in LD and HD male offspring, female offspring and dams (n=8–11/group, p<.01). Exposed female offspring values were similar except that only HD showed reduced GR and PEPCK. Summary: The following sequence of KEs is proposed downstream of a yet unknown molecular initiating event: (1) Reduced GR and elevated GST (KE1); (2) Reduced GDH and PEPCK (KE2); (3) Liver lipids, Fatty liver; (4) Fasting hyperglycemia, glucose intolerance, insulin insensitivity and hyperlipidemia. Our results indicate that PBDEs promote a metabolic syndrome phenotype in parallel with hepatic oxidative stress injury. Support: UC MEXUS (MC), Sigma Xi Research Society Grant in Aid (EK), MARC fellowship (GG)Support or Funding InformationSupport: UC MEXUS (MC), Sigma Xi Research Society Grant in Aid (EK), MARC fellowship (GG)

Estimating polybrominated diphenyl ether (PBDE) exposure through seafood consumption in Switzerland using international food trade data

Seafood is a major source of human exposure to polybrominated diphenyl ethers (PBDEs). The intake of these globally distributed and bioaccumulative contaminants depends on both consumption patterns (which seafoods are consumed) and on their origins. Here, we investigate exposure to PBDEs through seafood consumption as a function of species, origins and consumption levels. We estimate the contribution of seafood consumption to PBDE exposures in the Swiss population using two approaches. The first approach estimates exposures by estimating the composition of the Swiss seafood diet using trade data and national statistics on total seafood consumption. This naïve approach could be used for any country for which no individually reported consumption data are available for a population. The second approach uses dietary survey data provided by the Swiss Federal Statistical Office as part of the menuCH study for exposure estimates. To support region- and species-specific estimates of exposures for both approaches, we built a database of PBDE concentrations in seafood by analysis of published PBDE levels in fish from food markets or freshwater resources from various countries. We find estimated PBDE exposures ranging from 0.15 to 0.65 ng/kg bw/day for the trade data-based diet. These were close to the median exposures of 0.68 ng/kg bw/day for the Swiss population based on the menuCH survey, indicating that the composition and consumption rate derived from trade data are appropriate for calculating exposures in the average adult population. However, it could not account for PBDE exposures of more vulnerable (high seafood consuming) populations captured only by the survey data. All estimates were lower than the PBDE Chronic Oral Reference Doses (RfD’s) suggested by the EPA, but could increase substantially to a value of 7 ng/kg bw/day if fish are sourced from the most contaminated origins, as in the case of Vietnamese shrimp/prawn, Norwegian salmon, and Swiss whitefish. Exposures as high as 8.50 ng/kg bw/day are estimated for the survey-based diet, which better captures the variability in consumption by individuals, including extreme high and low values. In general, the most frequently consumed species reported by Swiss consumers are consistent with those predicted using trade data.

Transcriptomic profiling of PBDE-exposed HepaRG cells unveils critical lncRNA- PCG pairs involved in intermediary metabolism.

Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 μM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.

Indoor polybrominated diphenyl ethers in urban China: An exposure and risk assessment based on settled dust from selected urban regions

In this study, measurements of seven typical polybrominated diphenyl ethers (PBDEs) in indoor settled dust were summarized in selected urban regions of China. BDE-209 was the most dominant congener in settled dust (1.4–101 μg/g), with a mean contribution of 95%. Indoor exposures to PBDEs were estimated via inhalation, dust ingestion, and dermal absorption. The average daily intake of ΣPBDE was 4.9 to 19.1 ng/day/kg for all the population groups, with >80% of the total exposures from dust ingestion. Exposures in commuting environments (contributing 60%–80% of the total exposures) were higher than those in other microenvironments. The means of hazard indexes ranged from 1.66 × 10−3 to 5.26 × 10−3, which were mainly as a result of exposure to BDE-209, BDE-47, and BDE-99. The average lifetime cancer risks were from 0.03 × 10−9 to 2.37 × 10−9, which indicated the acceptable health risks resulting from indoor PBDE exposure for the Chinese population. The present study could provide valuable information that could be helpful for decision-makers, analysts and researchers to develop, implement and evaluate the effectiveness of interventions for the reduction of exposures to semi-volatile organic compounds (SVOCs) for large population groups in China.

Serum elimination half-lives adjusted for ongoing exposure of tri-to hexabrominated diphenyl ethers: Determined in persons moving from North America to Australia

The objective of the study was to determine the human serum elimination half-life of polybrominated diphenyl ethers (PBDEs) adjusted for ongoing exposure in subjects moving from a higher exposure region (North America) to a lower exposure region (Australia).The study population was comprised of exchange students and long-term visitors from North America moving to Brisbane, Australia (N = 27) and local residents (N = 23) who were followed by repeated serum sampling every other month. The local residents were sampled to adjust for ongoing exposure in Australia. Only one visitor remained in Australia for a period of time similar to the elimination half-life and had a sufficiently high initial concentration of PBDEs to derive a half-life. This visitor arrived in Australia in March of 2011 and remained in the country for 1.5 years. Since the magnitude of PBDE exposure is lower in Australia than in North America we observed an apparent 1st order elimination curve over time from which we have estimated the serum elimination half-lives for BDE28, BDE47, BDE99, BDE100, and BDE153 to be 0.942, 1.19, 1.03, 2.16, and 4.12 years, respectively. Uncertainty in the estimates were estimated using a Monte Carlo simulation. The human serum elimination half-life adjusted for ongoing exposure can allow us to assess the effectiveness and reduction in exposure in the general population following phase out of commercial penta- and octaBDE in 2004 in the United States.

Lactational exposure of polybrominated diphenyl ethers and its association with infant developmental measurements

This study was designed to assess the effect of lactational polybrominated diphenyl ether (PBDE) exposure on early physical development of both healthy and fetal growth restriction (FGR) infants. Z scores of head circumference-for-age (ZHC), length-for-age (ZLEN), weight-for-age (ZWEI) and weight-for-length (ZWFL) were calculated according to the WHO Child Growth Standards. FGR infants had a higher PBDE exposure level and faster growth speed from 42 days to 6 months compared with healthy infants. Exposure of lower brominated BDEs (BDE28∼154) and the sum of 18 BDE congeners (BDE28∼209) negatively associated with ZHC [mean difference estimate (95 % CI): -0.71 (-1.22, -0.22) and -0.81 (-1.31, -0.33)] in FGR boys. Both BDE153 and BDE196 exposure had a significant correlation with ZLEN of boys in FGR group [mean difference estimate (95 % CI): -0.28 (-0.48, -0.07) and -0.52 (-0.91, -0.14)]. Each 10 ng/g lipid increase in the concentrations of BDE154 were respectively associated with 0.16 increase in ZWEI among boys in healthy group. No significant association was found in girls. Lactational PBDE exposure had effects on the early growth of both FGR and healthy infants. The encouragement of breastfeeding should therefore be considered in conjunction with PBDE contamination levels.

Polybrominated Diphenyl Ethers Quinone Induces NCOA4-Mediated Ferritinophagy through Selectively Autophagic Degradation of Ferritin.

Polybrominated diphenyl ethers (PBDEs) have been detected ubiquitously in biological and environmental samples. Growing epidemiological data suggested the obvious correlation of PBDEs exposure with adverse health outcomes toward human beings, but exact molecular mechanism(s) are limited. Especially, the toxicological information regarding PBDEs metabolites is missing. Thereafter, this study intends to explore unidentified cell death modalities caused by PBDEs reactive quinone-type metabolite, PBDEQ. We found that PBDEQ induces autophagy in an ROS-dependent manner. Interestingly, the results indicated that PBDEQ degraded ferritin and activated a selective autophagy (termed as ferritinophagy) by using NCOA4 as its cargo receptor. These processes may further promote the release of iron and ROS. These results suggested the incidence of ferritinophagy induced by PBDEQ, which may contribute to PBDE exposure-caused diseases and dysfunctions.

Can PBDEs affect the pathophysiologic complex of epithelium in lung diseases?

Brominated flame-retardant (BFRs) exposure promotes multiple adverse health outcomes involved in oxidative stress, inflammation, and tissues damage. We investigated BFR effects, known as polybrominated diphenyl ethers (PBDEs) (47, 99 and 209) in an air-liquid-interface (ALI) airway tissue derived from A549 cell line, and compared with ALI culture of primary human bronchial epithelial cells (pHBEC). The cells, exposed to PBDEs (47, 99 and 209) (0.01-1 μM) for 24 h, were studied for IL-8, Muc5AC and Muc5B (mRNAs and proteins) production, as well as NOX-4 (mRNA) expression. Furthermore, we evaluated tight junction (TJ) integrity by Trans-Epithelial Electrical Resistance (TEER) measurements, and zonula occludens-1 (ZO-1) expression in the cells, and pH variations and rheological properties (elastic G', and viscous G″, moduli) in apical washes of ALI cultures. N-acetylcysteine (NAC) (10 mM) effects were tested in our experimental model of A549 cells. PBDEs (47, 99 and 209) exposure decreased TEER, ZO-1 and pH values, and increased IL-8, Muc5AC, Muc5B (mRNAs and proteins), NOX-4 (mRNA), and rheological parameters (G', G″) in ALI cultures of A549 cell line and pHBEC. NAC inhibited PBDE effects in A549 cells. PBDE inhalation might impairs human health of the lungs inducing oxidative stress, inflammatory response, loss of barrier integrity, unchecked mucus production, as well as altered physicochemical and biological properties of the fluids in airway epithelium. The treatment with anti-oxidants restored the negative effects of PBDEs in epithelial cells.

Distribution of polybrominated diphenyl ethers (PBDEs) in Newfoundland seafood and associations with human serum thyroid hormone concentrations

OPS 20: Chemicals, biomarkers, omics, Room 110, Floor 1, August 27, 2019, 4:30 PM - 5:30 PM The marine ecosystem around the island portion of the province of Newfoundland and Labrador is contaminated with PBDEs from the St Lawrence River and the Labrador Current. Newfoundland has a long history of fishing and of consuming local seafood, therefore exposure to PBDEs through local seafood consumption could present a widespread health issue for the province. The aim of this study was to explore local seafood consumption as a possible PBDE exposure source in Newfoundland. Cod and turbot livers from Newfoundland were tested for PBDEs by gas chromatography mass spectrometry (GC-MS). Eighty residents from two communities on the north and south coasts of the island were surveyed for local seafood consumption, and tested for serum PBDE concentrations (GC-MS). ∑PBDE (28, 47, 99, 156, and 209) levels were higher in cod (38.7 ng/g) than in turbot (10.4 ng/g). ∑PBDEs from fish livers from the north (37.36 ng/g) and south (34.27 ng/g) coast of Newfoundland were not significantly different. Newfoundland residents consumed local cod more than any other species, and older participants ate more cod than younger participants (p=0.000). Participant serum concentrations of PBDEs were 0.03 mmol/g (PBDE-28), 1.04 mmol/g (PBDE-47), 0.03 mmol/g (PBDE-99), 0.40 mmol/g (PBDE-100), 2.99 mmol/g (PBDE-153) and 4.78 mmol/g (∑PBDEs). Concentrations of PBDE-153 (p=0.018) and ∑PBDEs (28, 33, 47, 99, 100, and 153; p=0.010) were positively associated with local cod consumption. Residents of the island Newfoundland show evidence pf PBDE exposure, with possible local seafood consumption as a source. Associations between seafood consumption and PBDE levels were found, but associations were congener-specific. Further studies are needed using larger population in other parts of the province, and exploring other possible sources of exposure.

An Interval for Unmeasured Residual Confounding

PDS 69: Methods and statistics, Johan Friso Foyer, Floor 1, August 26, 2019, 4:30 PM - 5:30 PM It can be challenging to conduct causal inference from observational or quasi-experimental studies. The distinction between observation and experiment is important, and between the extremes of a randomized experiment and a purely observational study there is a continuum. Natural experiments may be placed on this continuum, and their position can inform accurate assessment of uncertainty due to unmeasured or residual confounding. In this talk we introduce a mathematical algorithm that can be used to compute a confounding interval. This confounding interval differs from classical statistical confidence intervals in a few important ways to be discussed. This confounding interval has been designed for use within the field of environmental epidemiology. We demonstrate this causal inference methodology within the context of a study of the effects of polybrominated diphenyl ether exposure on neurodevelopment.

Bioaccumulation and biomagnification of PBDEs in a terrestrial food chain at an urban landfill

Biota samples from the Vancouver municipal landfill located in Delta, BC, Canada, have some of the highest polybrominated diphenyl ether (PBDE) levels reported from North America. We followed a population of European starlings (Sturnus vulgaris) breeding in a remediated area in the landfill to identify exposure routes and bioaccumulation of PBDEs in a simple terrestrial food chain. This population was compared to a reference farm site located 40 km east in Glen Valley. We analyzed samples of European starling eggs and nestling livers as well as invertebrate prey species consumed by starlings for PBDE concentrations. We also collected soil samples from starling foraging areas. All samples from the Delta landfill had higher PBDE congener concentrations compared to the Glen Valley reference site and were dominated by BDE-99 and BDE-47. Stable nitrogen (δ N15) and carbon (δ C13) isotope analysis of starling blood samples and provisioned invertebrates revealed that stable δC13 signatures differed between the sites indicating that the diet of starlings in the Delta landfill included a component of human refuse. Biota-soil accumulation factors (BSAFs) > 1 demonstrated that PBDEs were bioaccumulating in soil invertebrates, particularly earthworms, which were readily accessible to foraging starlings in the landfill. Biomagnification factors (BMFs) calculated from foraged food items and starling egg and liver samples were >1, indicating that a diet of soil invertebrates and refuse contributed substantially to the PBDE exposure of local starlings.

Associations of prenatal exposures to low levels of Polybrominated Diphenyl Ether (PBDE) with thyroid hormones in cord plasma and neurobehavioral development in children at 2 and 4 years

BackgroundNeurotoxic effects of Polybrominated Diphenyl Ethers (PBDEs) at low levels have not been well studied in human population, and whether the associations can be explained by thyroid hormones (THs) remains unclear. ObjectivesWe examined the associations of prenatal PBDE exposures with THs in cord plasma and neurobehavior of children at 2 and 4 years among general population in China. MethodsParticipants were mother-child pairs in the Shanghai-Minhang Birth Cohort Study. Nine PBDE congeners and THs (thyroid stimulating hormone, total thyroxine, free thyroxine, total triiodothyronine, and free triiodothyronine) were determined in cord plasma. Child Behavior Checklist (CBCL/1.5-5) were completed by caregivers to assess children's neurobehavioral development at 2 and 4 years. In the final analyses, 199 and 307 mother-child pairs at 2 and 4 years were included to examine associations of PBDEs with CBCL scores using Pearson-scale-adjusted Poisson regressions, and 339 subjects were included in linear regression models to investigate the associations between PBDEs and THs. ResultsBDE-47 had the highest detection rate of 83.82% with the median concentration of 0.19 ng/g lipid, followed by BDE-28, −99, −100 and −153 with detection rates nearly 50%. We found positive associations between prenatal PBDE concentrations and children's neurobehavior, including Somatic Complaints, Withdrawn, Sleep Problems and Internalizing Problems in girls, and Somatic Complaints and Attention Problems in boys. We also observed inverse associations of the sum of BDE-47, −28, −99, −100 and −153 with THs. However, by adding THs to the models examining associations between PBDEs and CBCL, the main results didn't measurably change. ConclusionsThis study adds new knowledge that prenatal PBDEs at low levels may be related to long-lasting behavioral abnormalities in children and reduced THs in cord plasma. However, the hypothesis that the neurotoxic impact of PBDEs may be explained by alterations in cord THs was not supported.

Cellular metabolomics reveals glutamate and pyrimidine metabolism pathway alterations induced by BDE-47 in human neuroblastoma SK-N-SH cells

Polybrominated diphenyl ethers (PBDEs) as potential neurotoxicants in environment may possess hazards to human health. Previous studies have reported that PBDEs exposure could induce oxidative stress and disturb mitochondrial functions in mammalian cells. However, the toxicological mechanism remains to be clarified. In this work, the neurotoxic effect and underlying mechanism of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) was investigated by using human neuroblastoma SK-N-SH cells as an effective model. A liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach combined with cell viability assay was applied to elucidate the metabolic perturbations and relevant toxicological pathways upon BDE-47 exposure. Our results shown that the SK-N-SH cell viability decreased in a dose-dependent manner after exposure to BDE-47 at 24 h within the concentration range of 5–250 μM, and an IC50 value of 88.8 μM was obtained. Based on the dose-response curve and cell morphological observation, the 5 and 10 μM BDE-47 doses (equal to IC5 and IC10, respectively) were used for metabolomics study to capture the sensitive metabolic response following BDE-47 exposure. After BDE-47 treatment, nine metabolites were identified as potential biomarkers, and the most disturbed metabolic pathways were mainly involved in alanine, aspartate and glutamate metabolism, glutathione metabolism, tyrosine and phenylalanine metabolism, and pyrimidine metabolism, which imply that metabolic changes related to neurotransmitters, oxidative stress, and nucleotide-mediated signal transduction systems were the sensitive pathways mostly influenced. Our findings reported here may provide potential neurotoxic effect biomarkers and prompt deep understanding of the molecular and metabolic mechanisms triggered by BDE-47 exposure.

Spectral Distribution and Pollution Characteristics of Polybrominated Diphenyl Ethers in the Air of an Office Building Clustered Area

To evaluate the pollution level, congener distribution, and human exposure of polybrominated diphenyl ethers (PBDEs) in the atmosphere of Beijing's office buildings, outdoor air samples (particles+gas) were collected from a typical scientific area and PBDEs concentrations were quantified using GC-MS. The results showed that the mass concentrations of PBDEs in the gas phase, PM2.5, and PM10 were 2.3-78.6 pg·m-3, 14.4-335.3 pg·m-3, and 11.6-431.7 pg·m-3, respectively, and the annual average mass concentrations were 21.7 pg·m-3, 96.9 pg·m-3, and 149.3 pg·m-3, respectively. BDE-209 was the predominant congener in particulates, accounting for 50% of the total concentration. The mass concentration of PBDEs in the particles decreased in the following order:autumn > winter > summer > spring, with an obvious change in winter and stability in summer. Tri-BDEs mainly existed in the gas phase, and the proportion of PBDEs in the particle phase increased with bromine number. Source analysis indicated that BDE-209 degradation was an important source of other PBDEs in the air. Exposure risk analysis showed that the respiratory intake of children and adults was 18.6 pg·(kg·d)-1 and 7.1 pg·(kg·d)-1, respectively, which is far below the recommended lowest observed adverse effect level of 1 mg·(kg·d)-1. Similarly, the carcinogenic risk values of BDE-209 for children and adults were 2.3×10-9 and 3.7×10-9, respectively, which were much smaller than the carcinogenic risk limit of 10-6, indicating that there was no health hazard from PBDEs in the atmosphere.

Developmental exposure to BDE-99 hinders cerebrovascular growth and disturbs vascular barrier formation in zebrafish larvae

Polybrominated diphenyl ethers (PBDEs) are distributed throughout the environment. Despite a moratorium on their use, concentrations of PBDEs in the atmosphere and in residential environments remain high due to their persistence. The environmental health risks remain concerning and one of the major adverse effects is neurodevelopmental toxicity. However, the early response and effects of PBDEs exposure on the developing brain remain unknown. In the present study, we investigated the impacts of 2,2′,4,4′,5-pentabrominated diphenyl ether (BDE-99) on vascular growth and vascular barrier function with an emphasis on cerebral blood vessels, in the early life stages, using a zebrafish model. No general toxicity was observed in exposing zebrafish larvae to 0-0.5 μM BDE-99 at 72 hpf. BDE-99 exposure resulted in neither general toxicity nor pronounced developmental impairment in somatic blood vessels, including intersegmental vessels (ISV) and common cardinal veins (CCV). Meanwhile, both 0.05 μM and 0.5 μM of BDE-99 reduced cerebrovascular density as well as down-regulation of VEGFA and VEGFR2 in the head. In addition, BDE-99 exposure increased vascular leakage, both in cerebral and truncal vasculature at 72 hpf. The accentuated vascular permeability was observed in the head. The mRNA levels of genes encoding tight junction molecules decreased in the BDE-99-exposed larvae, and more robust reductions in Cldn5, Zo1 and Jam were detected in the head than in the trunk. Moreover, proinflammatory factors including TNF-α, IL-1β and ICAM-1 were induced, and the expression of neurodevelopment-related genes was suppressed in the head following BDE-99 exposure. Taken together, these results reveal that developmental exposure to BDE-99 impedes cerebrovascular growth and disturbs vascular barrier formation. The cerebral vasculature in developing zebrafish, a more sensitive target for BDE-99, may be a promising tool for the assessment of the early neurodevelopmental effects due to PBDEs exposure.

Perigestational low-dose BDE-47 exposure alters maternal serum metabolome and results in sex-specific weight gain in adult offspring

Emerging evidence suggests environmental contaminant exposures during critical windows of development may contribute to the increasing prevalence of obesity. It has been shown that early life polybrominated diphenyl ethers exposures have critical impacts on child weight trajectories, however, little is known about their maternal mechanisms responsible for offspring obesity development. In this study, we investigated the effects of perigestational low-dose 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47) exposure on maternal metabolome, and its possible link to adult offspring bodyweight changes. Female Sprague-Dawley rats were exposed to daily doses of 0.1, or 1 mg/kg BDE-47 from 10 days prior to conception until offspring were weaned on postnatal day 21, and then a gas chromatography-mass spectrometry based metabolomics analysis was used to uncover the global metabolic response in dams. The pups continued to grow into adulthood for measurements of bodyweight. Perigestational BDE-47 exposure caused increased adult bodyweight in male but not in female offspring and dams. Metabolomics revealed significant changes in maternal serum metabolites that clearly distinguish BDE-47 from control rats. These differentially expressed metabolites were primarily implicated in amino acid, lipid, carbohydrate, and energy metabolisms, which was confirmed by pathway analysis. Importantly, most of these identified metabolites were decreased, a state similar to maternal malnutrition that can predispose adult male offspring to weight increase and adiposity in a postnatal environment with abundant calories. Collectively, our data suggest that perigestational exposure to low-dose BDE-47 produces altered maternal serum metabolome, which may be an additional contributing factor to weight gain in adult male offspring.

Polybrominated Diphenyl Ethers and Gut Microbiome Modulate Metabolic Syndrome-Related Aqueous Metabolites in Mice.

Polybrominated diphenyl ethers (PBDEs) are persistent environmental toxicants associated with increased risk for metabolic syndrome. Intermediary metabolism is influenced by the intestinal microbiome. To test the hypothesis that PBDEs reduce host-beneficial intermediary metabolites in an intestinal microbiome-dependent manner, 9-week old male conventional (CV) and germ-free (GF) C57BL/6 mice were orally gavaged once daily with vehicle, BDE-47, or BDE-99 (100 μmol/kg) for 4 days. Intestinal microbiome (16S rDNA sequencing), liver transcriptome (RNA-Seq), and intermediary metabolites in serum, liver, as well as small and large intestinal contents (SIC and LIC; LC-MS) were examined. Changes in intermediary metabolite abundances in serum, liver, and SIC, were observed under basal conditions (CV vs. GF mice) and by PBDE exposure. PBDEs altered the largest number of metabolites in the LIC; most were regulated by PBDEs in GF conditions. Importantly, intestinal microbiome was necessary for PBDE-mediated decreases in branched-chain and aromatic amino acid metabolites, including 3-indolepropionic acid, a tryptophan metabolite recently shown to be protective against inflammation and diabetes. Gene-metabolite networks revealed a positive association between the hepatic glycan synthesis gene α-1,6-mannosyltransferase (Alg12) mRNA and mannose, which are important for protein glycosylation. Glycome changes have been observed in patients with metabolic syndrome. In LIC of CV mice, 23 bacterial taxa were regulated by PBDEs. Correlations of certain taxa with distinct serum metabolites further highlight a modulatory role of the microbiome in mediating PBDE effects. In summary, PBDEs impact intermediary metabolism in an intestinal microbiome-dependent manner, suggesting that dysbiosis may contribute to PBDE-mediated toxicities that include metabolic syndrome.

Polybrominated diphenyl ethers (PBDEs) in chicken eggs and cow milk around municipal dumpsites in Abuja, Nigeria

Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in electronic equipment, as polymers in vehicles or construction, and in textiles. These additive flame retardants are emerging pollutants in Africa, released by the non-environmentally sound disposal of consumer products, often imported as secondhand, that have increasingly reached their end-of-life in the last decade. In Nigeria, which is a major receiver of e-waste and secondhand cars, there is a dearth of information regarding the levels of PBDEs in the environment, biota, and food. Thus, this study was designed to investigate the PBDE contamination of food samples of animal origin (chicken eggs and cow milk) around municipal waste dumpsites and background areas in Nigeria, to elucidate the role of dumpsites as potential sources of PBDE pollution and exposure in the country. Biological samples were collected over two years from two municipal waste dumpsites in Abuja.Fifty-six samples each of free-range chicken eggs and cow milk were collected. Control samples were collected approximately 5 km away from the dumpsites. After extraction and clean-up, the levels of POP-PBDEs listed in 2009 (major congeners of tetraBDE to heptaBDE), plus BDE-28 (Σ7PBDEs) were determined using GC-ECD. Data were analysed using descriptive statistics, t-test at α0.05. Levels of Σ7PBDEs (ng/g lipid weight (lw)) in chicken eggs at the two study sites ranged from 262.3 to 313.4 (ng/g lw), more than one order of magnitude higher than those at the control site in a village near the dumpsites (14.9 ± 3.73 ng/g lw), and two and more orders of magnitude higher compared to PBDE levels in these products in industrial countries and Nigerian supermarkets. Median PBDE levels in cow milk from the two dumpsites were 49.1 and 81.5 ng/g lw, respectively, considerably higher than levels in other studies. Proper disposal methods of waste polymers containing PBDEs such as co-incineration in BAT cement kilns and plastic recycling with separation is urgently needed in Nigeria and other parts of Africa, to prevent open burning as well as crude recycle to reduce PBDE levels in the environment and human food.

OR23-6 The Impact of PBDE Exposure, Fetal Sex, and Gestational Day on Thyroid Hormone Regulation in the Placenta

During pregnancy, supply of thyroid hormone (TH) is critically important for fetal growth, neural development, metabolism and maintenance of pregnancy. However, when circulating levels of THs in maternal serum are disrupted, there is an increased risk of several adverse pregnancy outcomes, such as neurodevelopmental delays. It is unclear what may be disrupting TH homeostasis, however, numerous studies have shown that environmental contaminants, such as polybrominated diphenyl ethers (PBDEs) could be playing a role. Exposure to PBDEs have been shown to lower circulating free T4 and T3 in animal studies and their metabolites can be inhibitors of deiodinase enzymes. However, no studies to date have investigated potential changes in TH levels in paired maternal serum, placenta, and fetal tissues following exposure to PBDEs during development. Although it is well known that the rat fetus relies on maternal synthesis and delivery of TH until gestational day (GD) 18, it is unclear how levels of TH fluctuate in paired maternal serum, placenta and fetus prior to GD 18 and if there are any sex differences. In this study, pregnant Wistar rats were dosed daily from GD 6 to 15 with a mixture of PBDEs ranging in concentration from 5.3 - 30.4 ug/kg/day. After 10 days, two fetuses per sex per treatment, their paired micro-dissected placenta (isolated fetal and maternal placental tissue) and dam serum were collected. The tissues were extracted, purified and quantified for TH’s (T4, T3, rT3) and PBDE’s. We also examined gene expression of TH transporters in the fetal portion of the placenta using qPCR. Circulating T3 levels in the dosed dams were lower relative to controls, but not significantly different (p=0.1). However, we detected a significant increase in T3 levels in the maternal placental tissues of the dosed dams relative to controls (p=0.037), suggesting the tissue sampled has a significant impact on the direction of TH disruption. Furthermore, we found that the sex of the fetus influenced the levels of T3 in the fetal placental tissues (increased levels of T3 from female fetuses, decreased levels from male fetuses). Preliminary data on TH levels in the fetus thus far suggest changes in TH levels are influenced by both sex and exposure. For example, rT3 levels were lower in females compared to males (p<0.001) and was not influenced by exposure. T3 was also lower in females compared to males (p<0.001) and was significantly reduced by exposure to PBDEs (p=0.027). Furthermore, we observed an upregulation in gene expression for TH transporter MCT8 in the fetal portion of the placenta in males relative to females. Lastly, we also observed significant differences in TH levels based on GD, with levels decreasing from GD 12-15 (p<0.001). This study suggests that even though there are no significant effects of dose on maternal TH levels, there is significant disruption of TH homeostasis in the placenta as well as the fetus.

Two PBDEs exposure inducing feeding depression and disorder of digestive and antioxidative system of Daphnia magna

2,2′,4,4′-tetrabrominated diphenyl ether (BDE-47) and 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99) are two typical polybrominated diphenyl ethers (PBDEs), and studies have proven that these PBDs can disrupt the behaviors and physical function of aquatic organisms. However, little is known about the compositional impacts of BDE-47/BDE-99 compound pollution on the feeding behavior of Daphnia magna. In this study, a response surface methodology (RSM) was introduced into the combined toxicity assessment of BDE-47 and BDE-99 on the feeding depression of D. magna. Low concentrations of BDE-47 (9.2 μg/L) and BDE-99 (5.4 μg/L) had no effect on the feeding behavior of D. magna; nevertheless, the feeding depression was strengthened, and a concentration-dependent effect was observed with increasing concentrations of BDE-47 and BDE-99. The results of RSM indicated that the mixture of BDE-47 and BDE-99 can enhance their toxicity on the feeding behavior of D. magna. Moreover, real-time PCR (qPCR) analysis showed that the down-regulation of α-amylase (AMS) appeared in most of the exposed D. magna. However, there were significant different in the gene expression of trypsin, superoxide dismutase (SOD) and catalase (CAT) between the exposure and control groups. The change in the enzyme activity of AMS, trypsin, SOD and CAT implied that BDE-47 and BDE-99 cause damage to the digestive and antioxidative systems of D. magna. Correlation analysis indicated that a significant positive correlation existed between the gene expression and enzyme activity of SOD and CAT. Our results contribute to the understanding of toxicity caused by BDE-47/BDE-99 compound pollution in D. magna and help to improve traditional toxicity assessment methods for aquatic environments.