Polybrominated Diphenyl Ethers Exposure Research Articles

Infants' Neurodevelopmental Effects of PM2.5 and Persistent Organohalogen Pollutants Exposure in Southern Taiwan

ABSTRACT Several studies have stated the harmful effects of PM2.5 to population health, including disruption of neurological development. However, the mechanism behind the neurodevelopmental effects of ambient PM2.5 and postnatal PBDEs and OCPs exposure is still unknown. Our goal was to determine influence of breastmilk residues, polybrominated diphenyl ethers (PBDEs) and organochlorine pesticides (OCPs), to the infants’ neurodevelopment with respect to high and low PM2.5 exposure areas. The participants were recruited from high PM2.5 exposure areas (n = 32) and low PM2.5 exposure areas (n = 23) of southern Taiwan. The extracted 14 PBDEs and 20 OCPs compounds were analyzed using gas chromatography coupled with mass spectrometer. The infants, aging from 8-12 months, were examined by Bayley Scales of Infants and Toddlers Development, Third Edition (Bayley-III) for neurodevelopment. Results showed that high PM2.5 exposure caused reduced head circumference and had significant effects on the motor skill and social emotional development. For breastmilk PBDEs, a positive correlation between BDE-196 and social emotion, after multivariate analysis with adjustment of confounders, was observed while BDE-99, 196, 197, and 207 showed higher magnitudes in low PM2.5 areas than in high PM2.5 areas. For OCPs, only γ- hexachlorcyclohexanes (γ-HCH) presented the significant difference between high and low PM2.5 exposure areas. Most breastmilk OCPs residues, including 4,4’-dichlorodiphenyltrichloroethane (4,4’-DDT), γ-HCH, endrin, and heptachlor epoxide showed negative impact on the Bayley-III scores after multivariate analysis. In conclusion, infants’ neurodevelopment was significantly correlated with the location of PM2.5 exposure and breastmilk intake of certain PBDEs and OCPs. Breastmilk OCPs might obviously affect infants’ neurodevelopment more compared to breastmilk PBDEs based on our finding. Moreover, this study further employs awareness about viable effects of PM2.5 in infants’ neurodevelopment.

1010: Polybrominated diphenyl ethers (PBDE) exposed placental and fetal membrane show differential protein expression in exosomes

Flame retardant chemical polybrominated diphenyl ethers (PBDE) exposure is associated with spontaneous preterm birth (PTB). We have shown that PBDE causes fetal membrane senescence and injury to placental cells. To determine if PBDE exposure and cellular level changes are reflected in exososomes released from these tissues, fetal membrane and placental explants were exposed to PBDE congener 99 and profiled their exosomal protein cargo Human fetal membrane and placenta explants from term, not in labor cesarean sections were exposed to PBDE-99, one of the harmful congeners, 25 μM for 48 hours. Exosomes were isolated from media by differential centrifugation followed by size exclusion chromatography. Exososome characterization was done by cryoelectron microscopy (morphology), nanoparticle tracking analysis (size and quantity), western blot (markers) and mass spectroscopy (cargo proteins). Differentially expressed proteins were analyzed by Ingenuity Pathway Analysis (IPA) to identify specific pathways. Membrane and placental explant exosomes shared similar characteristics and markers (Fig 1C, Table I). Compared to respective controls PBDE-99 exposed FM derived exosomes showed acute phase inflammatory response whereas inflammatory pathways were not dominant in placental exosomes (Fig 1D). PBDE exposure indicated FM cell necrosis that was not evident in placenta. Placenta had more immune cell activities than FM (Fig 1 D). Environmental pollutant PBDE-99 did not produce any characteristic changes in exosomes derived from FM or placenta. However, exosome cargo reflected varying pathologic effects by PBDE on FM and placenta. FM appears to be more susceptible to the deleterious effects of PBDE-99 compared to placenta.

Childhood polybrominated diphenyl ether (PBDE) serum concentration and reading ability at ages 5 and 8 years: The HOME Study

BackgroundPolybrominated diphenyl ethers (PBDEs) exist extensively in the environment and human beings. PBDE concentrations are higher in children than adults. A previous study found that prenatal PBDE exposure was associated with decreased reading skills in children; however, evidence is limited on the potential impact of childhood exposure to PBDEs. The study examined the association between childhood PBDE exposures and reading ability in children at ages 5 and 8 years. MethodsThe study included 230 children from an ongoing prospective pregnancy and birth cohort study, the Health Outcomes and Measures of Environment (HOME) Study, conducted in Cincinnati, Ohio. Children's serum concentrations of eleven PBDE congeners were measured at 1, 2, 3, 5, and 8 years. The Woodcock-Johnson Tests of Achievement - III and the Wide Range Achievement Test - 4 were administered to assess children's reading skills at ages 5 and 8 years, respectively. We used multiple informant models to examine the associations between repeated measures of PBDEs and reading scores at ages 5 and 8 years. We also estimated the βs and 95% CIs of the association of PBDE measure at each age by including interaction terms between PBDE concentrations and child age in the models. ResultsAll childhood BDE-153 concentrations were inversely associated with reading scores at 5 and 8 years, but associations were not statistically significant after covariate adjustment. For example, a 10-fold increase in BDE-153 concentrations at ages 3 and 5 years was associated with a −5.0 (95% confidence interval (CI): −11.0, 1.0) and −5.5 (95% CI: −12.5, 1.4) point change in Basic Reading score at age 5 years, respectively. Similarly, the estimates for Brief Reading score at age 5 years were −4.5 (95% CI: −10.5, 1.5) and −5.2 (95% CI: −12.2, 1.7) point changes, respectively. Serum concentration of BDE-47, -99, -100, and Sum4PBDEs (sum of BDE-47, 99, 100, and 153) at every age were inversely associated with reading scores at ages 5 and 8 years in unadjusted analyses. While the adjusted estimates were much attenuated and became non-significant, the direction of most of the associations was not altered. ConclusionOur study has shown a suggestive but non-significant trend of inverse associations between childhood PBDE serum concentrations, particularly BDE-153, and children's reading skills. Future studies with a larger sample size are needed to examine these associations.

Polybrominated diphenyl ethers perturb axonal growth and actin distribution

We investigated toxicological effects of two of the most common polybrominated diphenyl ether (PBDE) flame retardants, BDE-47 and BDE-209, in model PC12 cell line under two environmentally relevant exposure conditions: long term exposure to microgram-per-liter levels of PBDEs and acute exposure to high concentrations of PBDEs. Cells treated under both long term and acute exposure conditions showed significantly perturbed cell growth and differentiation. Importantly, even when the cells were exposed to microgram-per-liter concentration of PBDEs over an extended period, both the fraction of differentiated cells and the axonal growth were affected. The calcium release assay showed that PBDEs perturbed intracellular calcium release in a concentration dependent manner, indicating that intracellular Ca++ homeostasis and signaling was involved in the neurotoxicity. More interestingly, depending on PBDE concentration and exposure conditions, cytoskeleton F-actin distribution was altered. BIBECHANA 16 (2019) 64-78

Distribution and bioaccumulation of POPs and mercury in the Ga-Selati River (South Africa) and the rivers Gudbrandsdalslågen and Rena (Norway)

Biomagnification of Hg and persistent organic pollutants (POPs: polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs)) in aquatic food chains can lead to high pollutant concentrations in top predators, including humans. Despite this threat to human health, research concerning bioaccumulation is still underrepresented in the southern hemisphere and in (sub)arctic and (sub)tropical areas, emphasizing the need for research in these locations. In this study, samples of water, sediment and aquatic biota were analyzed to determine concentrations of POPs and total mercury (THg) in the Ga-Selati river (South Africa) and two rivers Rena and Gudbrandsdalslågen in Norway. Trophic magnification factors (TMFs) were determined to evaluate and compare the biomagnification and the threat to human health due to consumption of the fish was assessed.Concentrations of POPs in sediment and biota samples were generally low except for relatively high concentrations of ∑DDX (dichlorodiphenyltrichloroethane and metabolites) in aquatic biota from the Ga-Selati river (ranging from 1.9 to 133 ng/g ww in invertebrates and 1.9 to 5643 ng/g ww in fish). Dissolved THg concentrations were high in the Ga-Selati river (ranging from 0.009 to 0.036 μg/l) but THg concentrations in sediment and biota were low in studied rivers compared to other studies. Biomagnification occurred for THg, several DDT-metabolites and PCB compounds, TN and CN. Biomagnification of p,p′-DDT and THg differed significantly between the two countries, supporting existing patterns found in literature, although more data is needed to attribute these differences to climatic or other factors. Concentrations in fish from the rivers Ga-Selati and Rena were under the threshold levels reported for THg and POPs, but caution should be taken when consuming Northern pike (Esox Lucius) from the subarctic river Gudbrandsdalslågen, to avoid harmful effects due to both elevated THg and PBDE exposure.

Measurement of legacy and emerging flame retardants in indoor dust from a rural village (Kopawa) in Nepal: Implication for source apportionment and health risk assessment

Under the Stockholm Convention, signatory countries are obliged to direct source inventories, find current sources, and provide ecological monitoring evidence to guarantee that the encompassing levels of persistent organic pollutants (POPs) are declining. However, such monitoring of different types of POPs are to a great degree constrained in most developing countries including Nepal and are primarily confined to suspected source area/ densely populated regions. In this study, 9 polybrominated diphenyl ethers (PBDEs), 2 dechlorane plus (DPs), 6 novel brominated flame retardants (NBFRs) and 8 organophosphate ester flame retardants (OPFRs) were investigated in indoor dust from a rural area (Kopawa) in Nepal in order to evaluate their occurrence/level, profile, spatial distribution and their sources. Additionally, health risk exposure was estimated to anticipate the possible health risk to the local population. The results showed that OPFRs was the most abundant FR measured in the dust. The concentration of ∑8OPFRs was about 2, 3 and 4 orders of magnitude higher than the ∑6NBFRs, ∑9PBDEs, and ∑2DPs, respectively. Tris (methylphenyl) phosphate (TMPP) and Tris (2-ethylhexyl) phosphate (TEHP) were the most abundant OPFRs analyzed in the dust; while decabromodiphenyl ethane (DBDPE) exceeded among NBFRs. Likewise, 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenylether (BDE-209) was the most identified chemical among PBDEs. The total organic carbon (TOC) content in dust was significantly and positively connected with octa-BDEs (Rho = 0.615, p < 0.01), BTBPE (Rho = 0.733, p < 0.01), TPHP (Rho = 0.621, p < 0.01), TEHP (Rho = 0.560, p < 0.01) and TMPPs (Rho = 0.550, p < 0.01), while black carbon (BC) was either weakly related or not related, suggesting little or no impact of BC in the distribution of FRs. Principal component analysis indicated the contribution from commercial penta-, octa- and deca-BDEs formulation, the adhesive substance, food packaging and paints, and degradation of BDE-209 as the essential sources of FRs. Health risk exposure estimates showed that dermal absorption via dust as the primary route of FRs intake. The estimated daily exposure of PBDEs, NBFRs and OPFRs were 2–10 orders of magnitude lower than their corresponding reference dose (RfD), suggesting insignificant risk. However, other routes such as inhalation and dietary intake might still be significant in the case of Kopawa which should be tested in future.

Evaluating the Use of Silicone Wristbands To Measure Personal Exposure to Brominated Flame Retardants.

Biomarkers remain the gold standard for assessing chemical exposure. However, silicone wristbands may provide some added benefits for characterizing personal exposures compared to single biomarker measurements, such as decreased costs, noninvasive sampling, and increased ease of analysis. Previously, we validated their use in characterizing exposure to organophosphate flame retardants (PFRs). However, it is unclear whether these results would extend to chemicals like polybrominated diphenyl ethers (PBDEs), which biomagnify and have longer half-lives than PFRs in the body. This study sought to determine if accumulation of PBDEs on wristbands was correlated to serum biomarkers. Adult participants ( n = 30) provided serum samples and wore wristbands for 7 days. PBDEs and 6 novel brominated flame retardants (BFRs) were measured on wristbands, and serum samples were analyzed for PBDE biomarkers. Like most PBDE congeners, 5 of 6 novel BFRs were frequently detected on wristbands (≥90% of bands). In particular, decabromodiphenyl ethane (DBDPE) was detected in all wristbands in this study and was significantly correlated with BDE-209, suggesting a similar source and exposure pathway. Wristband levels of BDE-47, -99, -100, and -153 were significantly and positively associated with respective serum biomarkers ( rs = 0.39-0.57, p < 0.05). This study demonstrates that silicone wristbands can accurately detect personal PBDE exposures.

Relationship between Polybrominated Diphenyl Ether (PBDE) Levels in Maternal Serum and Fetal Tissues during Mid-Gestation of Pregnancy and Associations with Placental Biomarkers of Growth and Development

Polybrominated diphenyl ether (PBDE) compounds are flame retardant chemicals with adverse effects on brain development, which may be mediated by placental effects. Pharmacokinetic factors may lead to disproportionate exposure in the developing fetus, yet the maternal-fetal relationship is not well understood. We examined whether PBDE concentrations vary between mother and fetus during early-to-mid pregnancy and identified placental biomarkers of PBDE exposure that may influence placental growth and function using statistical methods that account for left censored PBDE data. We calculated correlations between levels of 19 PBDE congeners across three biological matrices (maternal serum, placenta tissue, and fetal liver) in 130 maternal-fetal units. We conducted an exploratory analysis in a subset of samples to identify biomarkers of PBDE exposures that may influence placental development and function. Detection frequency was highest for BDE-47 (&amp;gt; 93% across matrices). Congener BDE-28 was more highly detected in placental and fetal liver tissues than maternal serum (&amp;gt; 60% compared to &amp;lt; 20%). PBDE levels were similar or higher in maternal compared to placental and fetal tissues before and after lipid adjustment for most congeners. The median BDE-47 concentration in serum was 0.24 ng/g (95% CI: 0.22, 0.28), more than twice as high as the placental value of 0.10 ng/g (95% CI: 0.09, 0.12). The difference was more pronounced after lipid adjustment, with 35.5 ng/g lipid BDE-47 found in serum compared to 10.8 ng/g in the placenta. Lipid-adjusted BDE-28, -99, and -153 levels were ~ two times higher in the placenta and fetal liver. Biomarker changes were observed in a subset of 12 placental tissues. Prenatal PBDE exposures are correlated with maternal levels. Molecular biomarkers related to placental development and function may be informative measures of PBDE exposure in future studies.

Distribution of Polybrominated Diphenyl Ethers (PBDEs) in Newfoundland Diet: Possible Connection to Hypothyroidism

Newfoundland sits directly in the Gulf of St. Lawrence and receives drainage from the Great Lakes watershed and the St. Lawrence River, both of which are contaminated with polybrominated diphenyl ethers (PBDEs) from anthropogenic sources. PBDEs have been inversely associated with thyroid hormones, and can also bioaccumulate in species to higher trophic levels. Seafood consumption is consistently found to be one of the main pathways for PBDE exposure in humans. The objective of this study is to explore if there may be a risk of human exposure to PBDEs from local seafood consumption in Newfoundland (NL).Liver samples from turbot (Scophthalmus maximus) and cod (Gadus morhua) were collected off the coasts of NL, and analyzed by gas chromatography/mass spectrometry for PBDE congeners. Residents in Burin (south coast) and New-Wes-Valley (northeast coast) completed a seafood consumption survey and gave blood samples to be tested for thyroid hormone levels ad PBDE concentrations. BDEs-28, 47, 99, 156, 209, and methoxylated polybrominated diphenyl ethers 47 (MeO-BDE-47) and 68 (MeO-BDE-68) were detected in fish liver tissue from all sampling locations around NL. Concentrations of &amp;#8721;PBDEs (5.52-11.75 ng/g) did not differ in concentration coastwise or by species. Results from the seafood consumption survey and human blood samples will be available for the conference.PBDE concentrations in fish liver do not differ by species or location, therefore there may be PBDEs in the Labrador current and from the St. Lawrence River affecting the marine food chain around NL.This study is the first to document PBDE contamination in the Newfoundland coastal waters and population, and adds to past research on health effects of PBDE contamination from the St. Lawrence River. This research will help inform policy development of chemicals use and regulation in Canada, and increase research into environmental contamination and public health.

Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Permanently Alters Blood-Liver Balance of Lipids in Male Mice.

Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives starting 1965 and were recently withdrawn from commerce in North America and Europe. Approximately 1/5 of the total U.S. population were born when environmental concentrations of PBDE plateaued at their maximum. Accumulating evidence suggests that developmental exposures to PBDE may result in long-lasting programming of liver metabolism. In this study, CD-1 mice were exposed prenatally or neonatally to 1 mg/kg body weight of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), and changes in liver histology, transcriptome, and liver-blood balance of triglycerides were analyzed in 10 months old male offspring. In both exposure groups, long-term reprogramming of lipid metabolism was observed, including increased liver triglycerides and decreased blood triglycerides, and altered expression of metabolic genes in the liver. Significant upregulation of lipid influx transporter Cd36 2.3- and 5.7-fold in pre- and neonatal exposure groups, respectively was identified as a potential mechanism of blood/liver imbalance of triglycerides. Analysis of our and previously published all-genome gene expression data identified changes in expression of ribosomal protein genes as a transcriptomic signature of PBDE exposure. Further comparison of our new data and published data demonstrate that low doses (0.2 mg/kg body weight) of PBDE induce long-lasting up-regulation of ribosomal genes, suppression of Cd36 in liver and increase circulating triglycerides in blood, while moderated doses (≥1 mg/kg body weight) produce opposite long-lasting effects. To conclude, this study shows that an environmentally relevant developmental exposures to BDE-47 permanently alter lipid uptake and accumulation in the liver, with low and moderate doses having opposite effect on liver transcriptomics and triglyceride balance. Similar effects of pre- and neonatal exposures point at hepatocyte maturation as a sensitive window of the liver metabolism programming. These results suggest that PBDE exposure may be an important factor increasing risks of cardio-vascular disease and non-alcoholic fatty liver disease via modulation of liver/blood balance of lipids. The translational relevance of these findings for human remain to be studied.

Genomic Profiling of BDE-47 Effects on Human Placental Cytotrophoblasts.

Despite gradual legislative efforts to phase out flame retardants (FRs) from the marketplace, polybrominated diphenyl ethers (PBDEs) are still widely detected in human maternal and fetal tissues, eg, placenta, due to their continued global application in consumer goods and inherent biological persistence. Recent studies in rodents and human placental cell lines suggest that PBDEs directly cause placental toxicity. During pregnancy, trophoblasts play key roles in uterine invasion, vascular remodeling, and anchoring of the placenta-fetal unit to the mother. Thus, to study the potential consequences of PBDE exposures on human placental development, we used an in vitro model: primary villous cytotrophoblasts (CTBs). Following exposures, the endpoints that were evaluated included cytotoxicity, function (migration, invasion), the transcriptome, and the methylome. In a concentration-dependent manner, common PBDE congeners, BDE-47 and -99, significantly reduced cell viability and increased death. Upon exposures to sub-cytotoxic concentrations (≤ 5 µM), we observed BDE-47 accumulation in CTBs with limited evidence of metabolism. At a functional level, BDE-47 hindered the ability of CTBs to migrate and invade. Transcriptomic analyses of BDE-47 effects suggested concentration-dependent changes in gene expression, involving stress pathways, eg, inflammation and lipid/cholesterol metabolism as well as processes underlying trophoblast fate, eg, differentiation, migration, and vascular morphogenesis. In parallel assessments, BDE-47 induced low-level global increases in methylation of CpG islands, including a subset that were proximal to genes with roles in cell adhesion/migration. Thus, using a primary human CTB model, we showed that PBDEs induced alterations at cellular and molecular levels, which could adversely impact placental development.

Effects of Organophosphate Ester Flame Retardants on Endochondral Ossification in Ex Vivo Murine Limb Bud Cultures.

Phasing out the usage of polybrominated diphenyl ether (PBDE) flame retardants (FRs) in consumer products led to their widespread replacement with organophosphate ester (OPE) FRs, despite scarce safety data. PBDE exposures were associated with the suppression of endochondral ossification but little is known about the effects of OPEs on bones. Here, we used a novel ex vivo murine limb bud culture system to compare the effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) with those of several OPEs. Gestation day 13 embryos were collected from transgenic CD1 mice expressing fluorescent markers for the major stages of endochondral ossification: COL2A1-ECFP (chondrogenesis), COL10A1-mCherry (early osteogenesis), and COL1A1-YFP (late osteogenesis). Limbs were excised and cultured for 6 days in the presence of vehicle, BDE-47, or an OPE FR: triphenyl phosphate (TPHP), tert-butylphenyl diphenyl phosphate (BPDP), tris(methylphenyl) phosphate (TMPP), or isopropylated triphenyl phosphate (IPPP). BDE-47 (50 μM) decreased the extent of chondrogenesis in the digits and COL1A1-YFP expression in the radius and ulna relative to control. In comparison, concentrations of ≥1 μM of all 4 OPEs limited chondrogenesis; osteogenesis (both COL10A1-mCherry and COL1A1-YFP fluorescence) was markedly inhibited at concentrations ≥3 μM. The expression of Sox9, the master regulator of chondrogenesis, was altered by BDE-47, TPHP, and BPDP. BDE-47 exposure had minimal impact on the expression of Runx2 and Sp7, which drive osteogenesis, whereas TPHP and BPDP both suppressed the expression of these transcription factors. These data suggest that OPE FRs may be more detrimental to bone formation than their brominated predecessors.

Effects of Polybrominated Diphenyl Ethers on Child Cognitive, Behavioral, and Motor Development.

Polybrominated Diphenyl Ether (PBDE) flame retardants are environmental chemicals that cross the placenta during pregnancy and have shown evidence of neurotoxicity. As the in utero period is a sensitive developmental window, such exposure may result in adverse childhood outcomes. Associations between in utero PBDE exposure and neurodevelopment are found in animal models and increasingly in human population studies. Here, we review the epidemiological evidence of the association between prenatal exposure to PBDEs and motor, cognitive, and behavioral development in infants and children. Published work suggests a negative association between PBDE concentrations and neurodevelopment despite varying PBDE congeners measured, bio-specimen matrix used, timing of the biological sampling, geographic location of study population, specific developmental tests used, age of children at time of testing, and statistical methodologies. This review includes 16 published studies that measured PBDE exposure in maternal blood during pregnancy or in cord blood at delivery and performed validated motor, cognitive, and/or behavioral testing at one or more time during childhood. We evaluate possible mediation through PBDE-induced perturbations in thyroid function and effect measure modification by child sex. While the majority of studies support an adverse association between PBDEs and neurodevelopment, additional research is required to understand the mechanism of action, possibly through the perturbations in thyroid function either in the pregnant woman or in the child, and the role of biologically relevant effect modifiers such as sex.

Regulation of protein-coding gene and long noncoding RNA pairs in liver of conventional and germ-free mice following oral PBDE exposure.

Gut microbiome communicates with the host liver to modify hepatic xenobiotic biotransformation and nutrient homeostasis. Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants that are detected in fatty food, household dust, and human breast milk at worrisome levels. Recently, long noncoding RNAs (lncRNAs) have been recognized as novel biomarkers for toxicological responses and may regulate the transcriptional/translational output of protein-coding genes (PCGs). However, very little is known regarding to what extent the interactions between PBDEs and gut microbiome modulate hepatic lncRNAs and PCGs, and what critical signaling pathways are impacted at the transcriptomic scale. In this study, we performed RNA-Seq in livers of nine-week-old male conventional (CV) and germ-free (GF) mice orally exposed to the most prevalent PBDE congeners BDE-47 and BDE-99 (100 μmol/kg once daily for 4-days; vehicle: corn oil, 10 ml/kg), and unveiled key molecular pathways and PCG-lncRNA pairs targeted by PBDE-gut microbiome interactions. Lack of gut microbiome profoundly altered the PBDE-mediated transcriptomic response in liver, with the most prominent effect observed in BDE-99-exposed GF mice. The top pathways up-regulated by PBDEs were related to xenobiotic metabolism, whereas the top pathways down-regulated by PBDEs were in lipid metabolism and protein synthesis in both enterotypes. Genomic annotation of the differentially regulated lncRNAs revealed that majority of these lncRNAs overlapped with introns and 3’-UTRs of PCGs. Lack of gut microbiome profoundly increased the percentage of PBDE-regulated lncRNAs mapped to the 3’-UTRs of PCGs, suggesting the potential involvement of lncRNAs in increasing the translational efficiency of PCGs by preventing miRNA-3’-UTR binding, as a compensatory mechanism following toxic exposure to PBDEs. Pathway analysis of PCGs paired with lncRNAs revealed that in CV mice, BDE-47 regulated nucleic acid and retinol metabolism, as well as circadian rhythm; whereas BDE-99 regulated fatty acid metabolism. In GF mice, BDE-47 differentially regulated 19 lncRNA-PCG pairs that were associated with glutathione conjugation and transcriptional regulation. In contrast, BDE-99 up-regulated the xenobiotic-metabolizing Cyp3a genes, but down-regulated the fatty acid-metabolizing Cyp4 genes. Taken together, the present study reveals common and unique lncRNAs and PCG targets of PBDEs in mouse liver, and is among the first to show that lack of gut microbiome sensitizes the liver to toxic exposure of BDE-99 but not BDE-47. Therefore, lncRNAs may serve as specific biomarkers that differentiate various PBDE congeners as well as environmental chemical-mediated dysbiosis. Coordinate regulation of PCG-lncRNA pairs may serve as a more efficient molecular mechanism to combat against xenobiotic insult, and especially during dysbiosis-induced increase in the internal dose of toxicants.

Association of In Utero Exposure to Polybrominated Diphenyl Ethers With the Risk of Hypospadias

Polybrominated diphenyl ethers (PBDEs) are added to many consumer products as flame retardants, and their endocrine-disrupting properties are a growing health concern in pregnancy. To investigate whether in utero PBDE exposure as measured in maternal hair is associated with increased risk for hypospadias. In this case-control study, the setting was the urology clinic of a tertiary pediatric hospital between January 3, 2011, and April 1, 2013. Participants were children diagnosed as having hypospadias and their mothers and a control group of children without hypospadias and their mothers. Dates of data analysis were September 3, 2017, to December 28, 2017. Gestational exposure to 8 PBDEs as measured in the 3-cm segment closest to the skull of maternal hair by gas chromatography-mass spectroscopy as a proxy for in utero exposure. The mothers resided in the same household for the duration of their pregnancy. Difference in total maternal hair PBDE levels between the hypospadias and control groups. Total PBDE levels were significantly higher among mothers of infants with hypospadias (n = 152) (total PBDE level, 51.4 pg/mg; interquartile range, 35.8-78.5 pg/mg) than among controls (n = 64) (total PBDE level, 35.8 pg/mg; interquartile range, 18.1-69.9 pg/mg) (P = .02). Of the 152 women with sufficient hair samples for analysis in the case group, 89 completed a questionnaire and were included in a multivariable analysis, and of the 64 women with sufficient hair samples for analysis in the control group, 54 completed a questionnaire and were included in a multivariable analysis. Adjusting for potential confounders, hypospadias was associated with a relative 48.2% (95% CI, 23.2%-65.4%) higher maternal level of total PBDE levels in the multivariable analysis. In this analysis, mothers of children with hypospadias were exposed during pregnancy to significantly higher levels of PBDEs. The results of this study suggest that level of exposure to PBDEs during gestation may have a role in the etiology of hypospadias.

Dietary exposure to a binary mixture of polybrominated diphenyl ethers alters innate immunity and disease susceptibility in juvenile Chinook salmon (Oncorhynchus tshawytscha)

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in consumer products and are now found in the aquatic environment. The presence of PBDEs puts the health and survival of aquatic species at risk due to the various toxic effects associated with exposure to these compounds. The effects of a binary dietary mixture of PBDEs on innate immunity and disease susceptibility of juvenile Chinook salmon (Oncorhynchus tshawytscha) were examined in the present study. Salmon were fed roughly 1:1 mixtures of two environmentally predominant PBDE congeners, BDE-47 and BDE-99. The six resulting whole body total PBDE concentrations ranged from less than the limit of quantification to 184 ng/g, wet weight (ww). The innate immune system was assessed by using two in vitro macrophage function assays. Specifically, assays that examined the ability of head kidney macrophages to: (1) engulf sheep red blood cells (SRBCs); and (2) produce a respiratory burst, as determined by the production of a reactive oxygen species, superoxide anion. Macrophages from salmon fed the BDE-47/99 mixture diets engulfed more SRBCs and produced greater superoxide anion than salmon fed the control diet. An increase in macrophage function was observed in fish with whole body total PBDE concentrations ranging from 2.81 ng/g, ww to 184 ng/g, ww. The mechanism for this increase in macrophage function due to PBDE exposure is currently unknown, but may be due to the ability of PBDEs to act as an endocrine receptor agonist and/or antagonist. Salmon exposed to the BDE-47/99 mixture diets were also challenged with the pathogenic bacteria, Vibrio (Listonella) anguillarum to determine disease susceptibility. Kaplan-Meier survival curves of fish exposed to the BDE-47/99 mixture and control diets were significantly different. The Cox proportional hazard risk ratios of disease-induced mortality in juvenile Chinook salmon with whole body concentrations of total PBDEs of 10.9, 36.8, and 184 ng/g, ww were significantly greater than the fish fed the control diet by 1.56, 1.83 and 1.50 times, respectively. Not all concentrations of the binary mixture diets had significant hazard ratios relative to the control diet, due to a non-monotonic concentration response curve. The mixture of PBDE congeners resulted in interactive effects that were generally non-additive and dependent upon the congener concentrations and metric examined. Consequently, predicting the interactive effects in juvenile Chinook salmon exposed to mixtures of PBDE congeners on innate immunity and disease susceptibility cannot be readily determined from the adverse effects of individual PBDE congeners.

Waterborne exposure to low concentrations of BDE-47 impedes early vascular development in zebrafish embryos/larvae

Polybrominated diphenyl ethers (PBDEs) are persistent flame retardants ubiquitously existing in various environment matrices. In spite of a recent reduction in use according to the phase-out policy, high levels of PBDEs are still found in both environmental and biological samples due to their persistent property and large-scale production over a long history. Developmental toxicity is a major health concern of PBDEs. However, the impact of PBDE exposure on vascular development remains poorly understood. In this study, we investigated the effect of low concentrations of 2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47), a predominant PBDE congener, in environmental matrices and biota, on early vascular development using zebrafish. Zebrafish embryos were continuously exposed to waterborne BDE-47 at 0.06, 0.2, 0.6 μM starting from 2 h post-fertilization (hpf). Fluorescent images of vasculatures in Tg(kdrl:eGFP) zebrafish were acquired using a confocal microscope. The results indicated that BDE-47 exposure had no effect on hatching rate, survival, body weight, body length or heart rate in the early stage within 72 hpf, whereas zebrafish exposed to BDE-47 exhibited impairments in the growth of multiple types of blood vessels. The percentage of completed intersegmental vessels (ISV) at 30 hpf decreased in embryos treated with BDE-47 in a dose-dependent fashion. BDE-47 exposure led to a slight decrease in the growth of common cardinal vein (CCV), while dramatically hindered CCV remodeling process reflected by the larger CCV area and wider ventral diameter. BDE-47 exposure significantly reduced sub-intestinal vessels (SIV) area as well as the vascularized yolk area in zebrafish larvae at 72 hpf. In addition, the expression of genes related to vascular growth and remodeling was markedly suppressed in BDE-47-exposed zebrafish. These findings demonstrate the adverse effects of BDE-47 on early vascular development, and confirm the vascular toxicity of PBDEs in vivo. The results indicate that developing vasculature in zebrafish is sensitive to BDE-47 exposure, and may serve as a powerful tool for the assessment of early exposure to PBDEs.

A nested case-control study of the association between exposure to polybrominated diphenyl ethers and the risk of gestational diabetes mellitus

BackgroundGestational diabetes mellitus (GDM) is rapidly increasing worldwide. Exposure to endocrine-disrupting chemicals such as polybrominated diphenyl ethers (PBDEs) is thought to be a contributor to GDM, independent of diet and physical activity. ObjectiveThe prospective association between PBDEs body burden in early pregnancy and GDM risk was investigated. MethodsA nested case-control study of 439 pregnant women was conducted between 2013 and 2015 in Beijing, China. Seven predominant PBDE congeners were measured in first trimester maternal serum by gas chromatography-high resolution mass spectrometry. Pregnant women were screened for GDM at 24–28 weeks of gestation using the oral glucose tolerance test. GDM was defined based on the diagnostic criteria set by China Ministry of Health. Conditional logistic and linear regression were used to estimate the association between PBDEs exposure and GDM risk, and PBDEs exposure and glucose level, respectively. ResultsA total of 77 (17.5%) women developed GDM in this study. Median concentrations of PBDEs were higher in women with GDM. Analyses parameterizing PBDE concentrations as continuous variables suggested significant associations between BDE-153, -154, -183 and GDM risk with an estimated odds ratio of 4.04 (95%CI: 1.92, 8.52), 1.88 (95%CI: 1.15, 3.09) and 1.91 (95%CI: 1.31, 2.08), respectively. In the quartile analyses, a significant increase in the odds ratio of GDM was associated with the highest levels of BDE-153 (OR = 3.42 95%CI: 1.49, 7.89) and BDE-183 (OR = 3.70, 95%CI: 1.58, 8.65), whereas, BDE-154 demonstrated an inverted U-shaped association with GDM. In addition, BDE-153 and -154 were significantly positively associated with fasting glucose, and both 1 h and 2 h glucose level (p < 0.05). ConclusionsThese results suggest that exposure to PBDEs disturbs maternal glucose homeostasis and increases the risk of GDM. These findings should be replicated in future studies with a larger population and wider range of exposure.

Multiple-life-stage probabilistic risk assessment for the exposure of Chinese population to PBDEs and risk managements

Studies assessing body burden of polybrominated diphenyl ethers (PBDEs) exposure have been conducted in the United States and Europe. However, the long-term assessment that is associated with multimedia exposure of PBDEs for the Chinese population is not available. The current study estimated the health risks using large PBDEs data to quantify the contributions of various media from different regions and distinguished the most vulnerable periods in life. We summarized media-specific (soil, dust, outdoor and indoor air, human milk and food) concentration of PBDEs in China from 2005 to 2016. Probabilistic risk assessment was adopted to estimate the health risks of infants, toddlers, children, teenagers and adults through ingestion, inhalation and dermal absorption. Monte Carlo simulation and sensitivity analysis were performed to quantify risk estimates uncertainties. E-waste areas had the highest PBDEs concentration, which was at least an order of magnitude higher than in other areas. BDE209 was the primary congener, accounting for 38–99% of the estimated daily intake. The dominant exposure pathway for infants was dietary intake through human milk, whereas dust ingestion was a higher contributing factor for toddlers, children, teenagers and adults. The 95th percentile of hazard index for infants and toddlers from e-waste areas of Guangdong and Zhejiang provinces exceeded one. Our estimates also suggested that infants may have the highest body burdens of PBDEs compared to other age groups. Sensitivity analyses indicated that PBDEs concentrations and ingestion rates contributed to major variances in the risk model. In this study, e-waste was found as a significant source of PBDEs, and PBDEs-containing e-waste are likely to be a threat to human health especially during early period of life. Risk strategies for better managing environmental PBDEs-exposure and human health are needed, due to the high intake of PBDEs and their persistence in the environment.

Embryo-larval BDE-47 exposure causes decreased pathogen resistance in adult male fathead minnows (Pimephales promelas)

Exposures to polybrominated diphenyl ethers (PBDEs) have been shown to alter immune function in adult organisms across a variety of taxa. However, few if any studies have investigated the long-term consequences of early life stage PBDE exposures on immune function in fish. This study sought to determine the effects of early life stage BDE-47 exposure on pathogen resistance in the fathead minnow (Pimephales promelas) following an extended depuration period (≥180 d). Minnows were exposed to BDE-47 via a combination of maternal transfer and diet through 34 days post fertilization (dpf), raised to adulthood (>215 dpf) on a clean diet, then subjected to pathogen resistance trials. Early life stage exposures to BDE-47 did not affect the ability of females to survive from Yersinia ruckeri infection. However, the survival of BDE-47 exposed males was significantly reduced relative to controls, indicating that developmental exposures to BDE-47 altered male immunity. Because BDE-47 is a known thyroid hormone disruptor and thyroid hormone disruptors have the potential to adversely impact immune development and function, metrics indicative of thyroid disruption were evaluated, as were immune parameters known to be altered in response to thyroid disruption. BDE-47 exposed minnows exhibited signs of thyroid disruption (i.e., reduced growth); however, no alterations were observed in immune parameters known to be influenced by thyroid hormones (i.e., thymus size, expression of genes associated with lymphoid development) suggesting that the observed alterations in immunocompetence may occur through alternative mechanisms. Regardless of the mechanisms responsible, the results of this study demonstrate the potential for early life stage PBDE exposures to adversely impact immunity and illustrate that the immunological consequences of PBDE exposures are sex dependent.