Effects Of Polybrominated Diphenyl Ethers Research Articles

Associations of serum persistent organic pollutant concentrations with incident diabetes in midlife women: The Study of Women’s Health Across the Nation Multi-Pollutant Study

BackgroundOrganochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that can negatively impact metabolic health through pathways including endocrine disruption. Few studies have evaluated diabetes risk associated with PBDEs. Little is known about the joint effect of exposure to POP mixtures on diabetes risk. ObjectivesWe investigated the relationship between POPs, individually and as mixtures, and diabetes development over 18 years (1999–2016) in midlife women. MethodsWe measured lipid-standardized serum concentrations of 34 PCBs, 19 OCPs, and 14 PBDEs in 1040 midlife women aged 45–56 years from the Study of Women’s Health Across the Nation. We tested the association between POPs measured in 1999/2000 and incident diabetes using Cox proportional hazards models. We evaluated diabetes risk associated with the overall POP mixture using Quantile-Based G-Computation (QBGC). ResultsFor most mixture components, single pollutant and mixtures analyses indicated null associations with diabetes risk, however results were inconsistent. After adjustment, hazard ratios (HRs) of developing diabetes (95% CI) associated with upper exposure tertiles (T2/T3) compared with the first tertile (T1), were 1.7 (1.0, 2.8) at T2 and 1.5 (0.84, 2.7) at T3 for hexachlorobenzene and 1.9 (1.1, 3.3) at T2 and 1.6 (0.88, 2.9) at T3 for PCB 123. A doubling of PBDE 47 was associated with 1.11 (1.00, 1.24) times the risk of T2D. QBGC identified no association for the overall joint effect of the POP mixture on diabetes (HR = 1.04 [0.53, 2.07]). ConclusionExposure to a mixture of PCBs, OCPs, and PBDEs was not associated with incident diabetes in midlife U.S. women, although some individual POPs demonstrated significant yet inconsistent associations with diabetes. Non-linear and non-monotonic dose-response dynamics deserve further exploration. More research is needed on the diabetogenic effects of PBDEs.

Associations of serum persistent organic pollutant concentrations with incident diabetes in midlife women: the Study of Women’s Health Across the Nation Multi-Pollutant Study

BackgroundOrganochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that can negatively impact metabolic health through pathways including endocrine disruption. Few studies have evaluated diabetes risk associated with PBDEs. Little is known about the joint effect of exposure to POP mixtures on diabetes risk. ObjectivesWe investigated the relationship between POPs, individually and as mixtures, and diabetes development over 18 years (1999-2016) in midlife women MethodsWe measured lipid-standardized serum concentrations of 34 PCBs, 19 OCPs, and 14 PBDEs in 1,040 midlife women aged 45-56 years from the Study of Women’s Health Across the Nation. We tested the association between POPs measured in 1999/2000 and incident diabetes using Cox proportional hazards models. We evaluated diabetes risk associated with the overall POP mixture using Quantile-Based G-Computation (QBGC). ResultsFor most mixture components, single pollutant and mixtures analyses indicated null associations with diabetes risk, however results were inconsistent. After adjustment, hazard ratios (HRs) of developing diabetes (95% CI) associated with upper exposure tertiles (T2/T3) compared with the first tertile (T1), were 1.7 (1.0, 2.8) at T2 and 1.5 (0.84, 2.7) at T3 for hexachlorobenzene and 1.9 (1.1, 3.3) at T2 and 1.6 (0.88, 2.9) at T3 for PCB 123. A doubling of PBDE 47 was associated with 1.11 (1.00, 1.24) times the risk of T2D. QBGC identified no association for the overall joint effect of the POP mixture on diabetes (HR=1.04 [0.53, 2.07]). ConclusionExposure to a mixture of PCBs, OCPs, and PBDEs was not associated with incident diabetes in midlife U.S. women, although some individual POPs demonstrated significant yet inconsistent associations with diabetes. Non-linear and non-monotonic dose-response dynamics deserve further exploration. More research is needed on the diabetogenic effects of PBDEs.

Study on the Biomolecular Competitive Mechanism of Polybrominated Diphenyl Ethers and Their Derivatives on Thyroid Hormones.

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants. PBDEs and their derivatives, hydroxylated PBDEs (OH-PBDEs), can bind to hormone receptors and impact hormone secretion, transportation, and metabolism, leading to endocrine disruption and the development of various diseases. They have particularly strong interference effects on thyroid hormones. This study used decabromodiphenyl ether (BDE-209); 2,2',4,4'-tetrabromodiphenyl ether (BDE-47); and 6-OH-BDE-47 as representative compounds of PBDEs and their derivatives, OH-PBDEs. A fluorescence probe, fluorescein-isothiocyanate-L-thyroxine (FITC-T4, F-T4), specific for binding to transthyretin (TTR), a thyroid transport protein, was prepared. The binding capacity of PBDEs and their derivatives, OH-PBDEs, to TTR was quantitatively measured using fluorescence spectroscopy. The principle of quenching the fluorescence intensity of F-T4 after binding to TTR was used to analyze the competitive interaction between the probe and BDE-209, BDE-47, and 6-OH-BDE-47, thereby evaluating the toxic effects of PBDEs and their derivatives on the thyroid system. Additionally, AutoDock molecular docking software (1.5.6) was used to further analyze the interference mechanism of OH-PBDEs on T4. The results of the study are as follows: (1) Different types of PBDEs and OH-PBDEs exhibit varying degrees of interference with T4. Both the degree of bromination and hydroxylation affect their ability to competitively bind to TTR. Higher bromination and hydroxylation degrees result in stronger competitive substitution. (2) The competitive substitution ability of the same disruptor varies at different concentrations. Higher concentrations lead to stronger substitution ability, but there is a threshold beyond which the substitution ability no longer increases. (3) When OH-PBDEs have four or more bromine atoms and exhibit the most structural similarity to T4, their binding affinity to TTR is stronger than that of T4.

Higher HDL-C levels attenuated the association of plasma polybrominated diphenyl ethers with prediabetes and type 2 diabetes mellitus in rural Chinese adults

BackgroundPlasma polybrominated diphenyl ethers (PBDE) were used as flame retardants widely, however, epidemiological evidence for the association between PBDEs and type 2 diabetes mellitus (T2DM) is inconsistent. Moreover, the combined effects of PBDEs and blood lipid indicators on impaired fasting glucose (IFG) and T2DM remains largely unknown in rural areas lacking good waste recycling infrastructure. MethodsIn this study, a total of 2607 subjects aged 18–79 years were included from the Henan Rural Cohort. Generalized linear and logistic regression models were applied to evaluate the associations of various PBDE pollutants on IFG and T2DM. Quantile g-computation regression and PBDE pollution score created by the adaptive elastic net were applied to evaluate the impact of PBDEs mixtures on IFG and T2DM. Interaction effects of individual PBDE pollutants and blood lipid indicators on IFG and T2DM were assessed by using Interaction plots. ResultsThe geometric mean concentrations (detection rates) were 0.09 ng/mL (100.0%), 0.12 ng/mL (97.8%), 0.22 ng/mL (94.7%), 0.16 ng/mL (99.2%) and 0.28 ng/mL (100.0%) for PBDE-28, PBDE-47, PBDE-99, and PBDE-153 respectively. However, PBDE-28, PBDE-99, PBDE-100, and ΣPBDEs were positively associated with IFG (odds ratios (ORs) (95% confidence intervals (CIs)): 1.14 (1.06, 1.23), 1.16 (1.04, 1.29), 1.25 (1.14, 1.37), and 1.27 (1.08, 1.50)). Similarly, PBDE-28, PBDE-47, PBDE-99, PBDE-100, and ΣPBDEs were positively associated with T2DM (ORs (95% CIs): 1.30 (1.10, 1.54), 1.13 (1.06, 1.22), 1.27 (1.13, 1.43), 1.27 (1.15, 1.40), and 1.30 (1.10, 1.54)). Moreover, five PBDE mixtures or jointly as PBDE pollution score, were significantly associated with an increased risk of T2DM (P < 0.05 for all). In addition, the harmful effect of PBDE exposure on T2DM was decreased with accompanying high‐density lipoprotein cholesterol (HDL-C) levels increased. ConclusionsOur findings highlight the importance of managing PBDEs contamination and suggest that HDL-C may be a novel way to prevent T2DM.

2,2′,4,4′-tetrabromodiphenyl ether causes depigmentation in zebrafish larvae via a light-mediated pathway

Polybrominated diphenyl ethers (PBDEs) are organic pollutants widely detected in various environmental media due to their high persistence and bioaccumulation. PBDE-induced visual impairment and neurotoxicity were previously demonstrated using zebrafish (Danio rerio) models, and recent research reported the phenotypic depigmentation effect of PBDEs at high concentrations on zebrafish, but whether those effects are still present at environment-relevant levels is still unclear. Herein, we performed both phenotypic examination and mechanism investigation in zebrafish embryos (48 hpf) and larvae (5 dpf) about their pigmentation status when exposing to PBDE congener BDE-47 (2,2′,4,4′-tetrabrominated diphenyl ether) at levels from 0.25 to 25 μg/L. Results showed that low-level BDE-47 can restrain the relative melanin abundance of zebrafish larvae to 70.47% (p < 0.05) and 61.54% (p < 0.01) respectively under 2.5 and 25 μg/L BDE-47 compared with control, and the thickness of retinal pigment epithelium (RPE) remarkably reduced from 571.4 nm to 350.3 nm (p < 0.001) under 25 μg/L BDE-47 exposure. We also observed disrupted expressions of melanin synthesis genes and disorganized mitfa differentiation patterns based on Tg(mifta:EGFP), as well as visual impairment resulting from thinner RPE. Considering both processes of visual development and melanin synthesis are highly sensitive to ambient light conditions, we prolonged the light regime of maintaining zebrafish larvae from 14 hours light versus 10 hours dark (14L:10D) to 18 hours light versus 6 hours dark (18L:6D). Lengthening photoperiod successfully rescued the fluorescent level of mitfa in zebrafish epidermis and most gene expressions associated with melanin synthesis under 25 μg/L BDE-47 exposure to the normal level. In conclusion, our work reported the effects of low-level PBDEs on melanin production using zebrafish embryos and larvae, and identified the potential role of a light-mediated pathway in the neurotoxic mechanism of PBDEs.

The crosstalk effects of polybrominated diphenyl ethers on the retinoic acid and thyroid hormone signaling pathway

The toxicological and pathological influences of polybrominated diphenyl ethers (PBDEs) on the animal central nervous system have attracted worldwide attention. However, their mechanism of action has not been completely elucidated. Given that retinoic acid (RA) and thyroid hormone (TH) signaling pathway are closely related to neurodevelopment, the crosstalk between the two signaling pathways at the levels of metabolite conversion, gene expression and ligand-receptor interaction after exposure to two representative PBDE congeners (BDE-47 and BDE-209) using zebrafish larvae, dual reporter gene assay, and docking simulation was studied. Our results clarified that BDE-47 could disrupt the transport and metabolism of retinoids, induce changes in expression of key genes, bind with the seven nuclear receptors, and activate RA signaling pathway. BDE-47 exhibited more effects on the indicators of the two signaling pathways than BDE-209. Furthermore, BDE-47 may disrupt TH signaling pathway by disrupting RA signaling pathway, indicating that RA signal is priorly influenced than TH signal. This work offered a new perspective to elucidate TH signal disruption mechanism induced by PBDEs from RA signaling pathway, which is of great significance to elucidate the health effects of PBDEs.

Evaluation of BDE-47-induced neurodevelopmental toxicity in zebrafish embryos.

There are growing concerns about the neurodevelopmental toxicity of polybrominated diphenyl ethers (PBDEs), but the toxicological phenotypes and mechanisms are not well elucidated. Here, zebrafish (Danio rerio) were exposed to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from 4 to 72 h post-fertilization (hpf). The results showed that BDE-47 stimulated the production of dopamine and 5-hydroxytryptamine, but inhibited expression of Nestin, GFAP, Gap43, and PSD95 in 24 hpf embryos. Importantly, we unraveled the inhibitory effects of BDE-47 on neural crest-derived melanocyte differentiation and melanin syntheses process, evidenced by disrupted expression of wnt1, wnt3, sox10, mitfa, tyrp1a, tyrp1b, tryp2, and oca2 gene in 72 hpf embryos and decreased tyrosinase activities in embryos at 48 and 72 hpf. The transcriptional activities of myosin VAa, kif5ba, rab27a, mlpha, and cdc42 genes, which are associated with intracellular transport process, were also disturbed during zebrafish development. Ultimately, these alterations led to fast spontaneous movement and melanin accumulation deficit in zebrafish embryos upon BDE-47 exposure. Our results provide an important extension for understanding the neurodevelopmental effects of PBDEs and facilitate the comprehensive evaluation of neurotoxicity in embryos.

BDE-47 Induces Immunotoxicity in RAW264.7 Macrophages through the Reactive Oxygen Species-Mediated Mitochondrial Apoptotic Pathway

Polybrominated diphenyl ethers (PBDEs) are classic and emerging pollutants that are potentially harmful to the human immune system. Research on their immunotoxicity and mechanisms suggests that they play an important role in the resulting pernicious effects of PBDEs. 2,2',4,4'-Tetrabrominated biphenyl ether (BDE-47) is the most biotoxic PBDE congener, and, in this study, we evaluated its toxicity toward RAW264.7 cells of mouse macrophages. The results show that exposure to BDE-47 led to a significant decrease in cell viability and a prominent increase in apoptosis. A decrease in mitochondrial membrane potential (MMP) and an increase in cytochrome C release and caspase cascade activation thus demonstrate that cell apoptosis induced by BDE-47 occurs via the mitochondrial pathway. In addition, BDE-47 inhibits phagocytosis in RAW264.7 cells, changes the related immune factor index, and causes immune function damage. Furthermore, we discovered a significant increase in the level of cellular reactive oxygen species (ROS), and the regulation of genes linked to oxidative stress was also demonstrated using transcriptome sequencing. The degree of apoptosis and immune function impairment caused by BDE-47 could be reversed after treatment with the antioxidant NAC and, conversely, exacerbated by treatment with the ROS-inducer BSO. These findings indicate that oxidative damage caused by BDE-47 is a critical event that leads to mitochondrial apoptosis in RAW264.7 macrophages, ultimately resulting in the suppression of immune function.

Contrasting responses of bacterial community to 4,4′-dibromodiphenyl ether (BDE-15) contamination in soil microcosms at different temperatures

Polybrominated diphenyl ethers (PBDEs) are biodegradable organic pollutants and pose potential risks to microorganisms exposed to the contamination, which are also affected by a variety of factors, such as temperature, in real environmental settings. A better understanding of the microbial community responses to PBDEs at different temperatures has practical significance for assessing ecological risks or possible degraders of these widely used flame retardants. In this study, soil microcosms spiked with or without 100 mg kg−1 4,4′-dibromodiphenyl ether (BDE-15) were established and incubated at four different temperatures (4 °C, 20 °C, 37 °C, and varying ambient temperature) for up to 180 days. Concentration and carbon isotope analyses were used to verify the transformation of BDE-15. Bacterial communities were monitored during the incubation to evaluate the community succession under the PBDE stress. The results showed the majority of added BDE-15 remained after the incubation period, with limited degradation occurred at all four temperatures. Temperature significantly shaped the richness, diversity, composition and co-occurrence network of soil bacterial community, while the impacts of PBDE on soil bacteria were temperature dependent. When incubated at 4 °C, BDE-15 substantially reduced the network complexity and changed the ratio of negative to positive interactions between taxa (nodes), highlighting the PBDE-associated risks at low temperature. At higher temperatures, BDE-15 had negligible influence on the community characteristics and network. Random forest model identified distinct taxa that might be related to PBDE degradation at different incubation temperatures. These findings demonstrate contrasting bacterial community effects of PBDE at different temperatures, thus attention should be paid to the ecological impacts of soil pollution under real environmental conditions.

Developmental exposure to indoor flame retardants and hypothalamic molecular signatures: Sex-dependent reprogramming of lipid homeostasis.

Polybrominated diphenyl ethers (PBDEs) are a class of flame-retardant organohalogen pollutants that act as endocrine/neuroendocrine disrupting chemicals (EDCs). In humans, exposure to brominated flame retardants (BFR) or other environmentally persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and novel organophosphate flame retardants has been associated with increasing trends of diabetes and metabolic disease. However, the effects of PBDEs on metabolic processes and their associated sex-dependent features are poorly understood. The metabolic-disrupting effects of perinatal exposure to industrial penta-PBDE mixture, DE-71, on male and female progeny of C57BL/6N mouse dams were examined in adulthood. Dams were exposed to environmentally relevant doses of PBDEs daily for 10 weeks (p.o.): 0.1 (L-DE-71) and 0.4 mg/kg/d (H-DE-71) and offspring parameters were compared to corn oil vehicle controls (VEH/CON). The following lipid metabolism indices were measured: plasma cholesterol, triglycerides, adiponectin, leptin, and liver lipids. L-DE-71 female offspring were particularly affected, showing hypercholesterolemia, elevated liver lipids and fasting plasma leptin as compared to same-sex VEH/CON, while L- and H-DE-71 male F1 only showed reduced plasma adiponectin. Using the quantitative Folch method, we found that mean liver lipid content was significantly elevated in L-DE-71 female offspring compared to controls. Oil Red O staining revealed fatty liver in female offspring and dams. General measures of adiposity, body weight, white and brown adipose tissue (BAT), and lean and fat mass were weighed or measured using EchoMRI. DE-71 did not produce abnormal adiposity, but decreased BAT depots in L-DE-71 females and males relative to same-sex VEH/CON. To begin to address potential central mechanisms of deregulated lipid metabolism, we used RT-qPCR to quantitate expression of hypothalamic genes in energy-regulating circuits that control lipid homeostasis. Both doses of DE-71 sex-dependently downregulated hypothalamic expression of Lepr, Stat3, Mc4r, Agrp, Gshr in female offspring while H-DE-71 downregulated Npy in exposed females relative to VEH/CON. In contrast, exposed male offspring displayed upregulated Stat3 and Mc4r. Intestinal barrier integrity was measured using FITC-dextran since it can lead to systemic inflammation that leads to liver damage and metabolic disease, but was not affected by DE-71 exposure. These findings indicate that maternal transfer of PBDEs disproportionately endangers female offspring to lipid metabolic reprogramming that may exaggerate risk for adult metabolic disease.

Associations between polybrominated diphenyl ethers (PBDEs) levels in adipose tissues and blood lipids in women of Shantou, China

Animal studies have indicated that exposure to polybrominated diphenyl ethers (PBDEs) during development can permanently affect blood/liver lipid balance. However, no epidemiological study has assessed the relationship between PBDEs in adipose tissues and blood lipid metabolism. In this study, we explored the associations between PBDEs levels in female adipose tissues and lipid profiles. We recruited 150 female patients undergoing plastic surgery from hospital in Shantou, China, collected their characteristics, clinical information, and adipose tissue samples. Fourteen PBDE congeners in adipose tissues were analyzed by gas chromatography-mass spectrometry (GC-MS). Multiple linear and logistic regression models were used to explore the relationships between PBDEs and lipid profiles, while restricted cubic spline (RCS) regression and Bayesian kernel machine regression (BKMR) models were used to evaluate the nonlinearity of mixtures. Median levels of ΣPBDEs and dominant congeners BDE-153, -209, and −183 in adipose tissues were 73.91, 26.12, 14.10 and 9.01 ng/g lipid, respectively. In the multiple linear model, BDE-153 and BDE-209 were negatively associated with triglycerides (TG), similarly for BDE-190 and total cholesterol (TC). While in the adjusted logistic models, BDE-138 was negatively associated with TC (OR = 0.76, 95%CI: 0.58, 0.99) and total lipids (TL) (OR = 0.76, 95%CI: 0.58, 0.99). Diastolic blood pressure was positively correlated with BDE-28 and BDE-71 (P < 0.05). Furthermore, a non-linear relationship was observed in BDE-138 and blood lipid levels using a RCS model (Pnonlinearity<0.05). BKMR analysis indicated that with the cumulative levels across PBDEs increased, the health risks of hypertriglyceridemia gradually rebounded, and the health risks of hypercholesterolemia and high total lipid gradually rebounded and then declined, but without statistical significance. PBDEs pollution was still prevalent in Shantou city, and several PBDE congeners were significant risk factors for dyslipidemia and blood pressure alteration. There exist deleterious effects of PBDEs and blood lipids.

Metabolomics insights into the prenatal exposure effects of polybrominated diphenyl ethers on neonatal birth outcomes.

Effects of polybrominated diphenyl ethers (PBDEs) on neonatal birth outcomes vary across previous studies, and the related mechanism investigation remains poorly understood, especially at the metabolic level. To evaluate the associations between prenatal PBDEs exposure and neonatal birth outcomes including gestational age, neonatal weight, birth length, head circumference (HC), Apgar score at 1 min (Apgar1) and 5 min, and further reveal the underlying metabolic disorders in a population-based birth cohort study. Gas chromatography-triple quadrupole tandem mass spectrometry (GC-MS/MS) based targeted method and GC-MS based untargeted method were respectively conducted to obtain PBDE levels and metabolic profiles of 200 placental tissue samples from a typical e-waste recycling area (Guiyu) and reference area (Haojiang) in China. Spearman correlation and regression analyses were applied to assess the associations between the placental PBDE levels and birth outcomes. Metabolome-wide association studies and the meet-in-the-middle approach were employed to explore disruptions linking PBDE exposures and the corresponding adverse birth outcomes. Eight out of 27 PBDE congeners were detected in placenta with more than 50% frequency in at least one district and significantly higher in Guiyu than those in Haojiang. The lower HC and Apgar1 had significant associations with PBDE exposures after adjustment for potential confounders. A total of 66, 16 and 14 metabolites were significantly correlated with PBDE exposures, HC and Apgar1, respectively. 4 and 12 PBDE-related metabolites were significantly associated with the risks of decreasing neonatal HC and Apgar1. The disrupted metabolites were mainly involved in the pentose phosphate pathway, ascorbate metabolism, threonine metabolism, butanoate metabolism, lipid metabolism, and arginine biosynthesis. In this birth cohort, higher placental PBDE levels were significantly associated with the lower HC and Apgar1. The associations might be modified by multiple metabolic disturbances through increasing oxidative stress, mediating neurotoxicity, maternal gut microbiota dysbiosis and vasodilatation regulation.

Exposure to Polybrominated Diphenyl Ether Flame Retardants Causes Deoxyribonucleic Acid Damage in Human Thyroid Cells In Vitro

IntroductionThe incidence of papillary thyroid cancer (PTC) in the United States has tripled in the past 30 y. Polybrominated diphenyl ethers (PBDEs) are flame retardants that were ubiquitously used over that time period, and exposure to PBDEs has been associated with PTC prevalence. They are potential carcinogens via their induction of reactive oxygen species (ROS) formation and resultant deoxyribonucleic acid (DNA) damage. We sought to determine the effects of PBDE and tris(2-chloroethyl) phosphate (TCEP), another flame retardant implicated in PTC incidence, on thyrocytes in vitro and measure PBDE levels in human thyroid tissue to determine their carcinogenic potential. MethodsNthy-Ori, an immortalized benign human thyroid follicular cell line was used as a model of normal human thyroid. MTT assays were used to measure cell viability after exposure to PBDEs and TCEP. ROS levels and double-stranded and single-stranded DNA breaks were measured to determine genotoxicity. DNA damage response protein levels were measured with immunoblotting. ResultsExposure to 20μM PBDE or TCEP for 48 h had minimal effects on thyrocyte viability. There was no significant increase in intracellular ROS up to 6 h following PBDE or TCEP exposure in thyrocytes; however, cells exposed to PBDE 47 showed evidence of DNA single-stranded and double-stranded breaks. There was a dose-dependent increase in γH2AX levels following exposure to PBDEs 47 and 209 in Nthy-Ori cells but not with TCEP treatment. ConclusionsPBDE 47 and 209 demonstrated genotoxicity but not cytotoxicity in follicular thyrocytes in vitro. Therefore, PBDE 47 and 209 may be carcinogenic in human thyroid cells.

PBDEs Found in House Dust Impact Human Lung Epithelial Cell Homeostasis.

The toxicity of eight polybrominated diphenyl ethers (PBDEs) congeners detected in environmental and biological samples (BDE-28, -47, -99, -100, -153, -154, -183, and -209) was evaluated on the epithelial lung cells. Exposure to these PBDEs increased membrane disruption and a release of lactate dehydrogenase, accompanied by oxidative stress in cells through the formation of reactive oxygen species (ROS) and a decrease in mitochondrial membrane potential. Interestingly, some of the tested PBDEs increased apoptotic markers as well. For several congeners, the observed toxicity was time dependent, meaning that even smaller concentrations of these compounds will have negative effects over time. Such time-dependent toxicity was also confirmed for cell treatment with a real house dust sample extract. This could be indicative with regard to the constant exposure to a mixture of PBDE congeners through different pathways in the organism and thereby presenting a risk for human health. As such, our findings point to the importance of further studies on the negative effects of PBDEs to understand their mechanism of action in detail.

Triiodothyronine or Antioxidants Block the Inhibitory Effects of BDE-47 and BDE-49 on Axonal Growth in Rat Hippocampal Neuron-Glia Co-Cultures.

We previously demonstrated that polybrominated diphenyl ethers (PBDEs) inhibit the growth of axons in primary rat hippocampal neurons. Here, we test the hypothesis that PBDE effects on axonal morphogenesis are mediated by thyroid hormone and/or reactive oxygen species (ROS)-dependent mechanisms. Axonal growth and ROS were quantified in primary neuronal-glial co-cultures dissociated from neonatal rat hippocampi exposed to nM concentrations of BDE-47 or BDE-49 in the absence or presence of triiodothyronine (T3; 3–30 nM), N-acetyl-cysteine (NAC; 100 µM), or α-tocopherol (100 µM). Co-exposure to T3 or either antioxidant prevented inhibition of axonal growth in hippocampal cultures exposed to BDE-47 or BDE-49. T3 supplementation in cultures not exposed to PBDEs did not alter axonal growth. T3 did, however, prevent PBDE-induced ROS generation and alterations in mitochondrial metabolism. Collectively, our data indicate that PBDEs inhibit axonal growth via ROS-dependent mechanisms, and that T3 protects axonal growth by inhibiting PBDE-induced ROS. These observations suggest that co-exposure to endocrine disruptors that decrease TH signaling in the brain may increase vulnerability to the adverse effects of developmental PBDE exposure on axonal morphogenesis.

The Effects of Dietary Polybrominated Diphenyl Ether Exposure and Rearing Temperature on Tadpole Growth, Development, and Their Underlying Processes.

Depression of growth rate due to polybrominated diphenyl ethers (PBDEs) has been documented in birds, mammals, amphibians, and fish at single temperatures. However, the underlying energetic mechanism for this effect and how it might change in relation to changing environmental temperature remain unstudied. We used a simple energy budget to address hypotheses regarding effects of PBDEs on tadpole (Lithobates pipiens) growth: that reductions in growth are linked to increased respiratory costs, reductions in digestive performance, differences in body composition, reductions in food intake, or a combination of these factors. From 18 days postfertilization (dpf) until 42 dpf, tadpoles were exposed dietarily to a pentabromodiphenyl ether mixture (DE-71TM ) at a concentration of 100 ng DE-71/g wet mass under a rearing temperature of either 22 or 27 °C. After 20 days of PBDE exposure, total PBDEs in tadpoles averaged 148.4 ng/g wet mass, with no differences by rearing temperature and approximately 50% higher than in their diet; controls not fed PBDE had levels <1 ng/g. Exposure to PBDE resulted in reductions in body length, mass, and development compared to controls, independent of rearing temperature; PBDE had no effect on measures of body composition, dry matter digestibility, or oxygen consumption. A simple energy budget using data from the present study revealed that a 10% decrease in feeding rate could explain the lower mass gain of tadpoles exposed to PBDE. Growth depression by PBDE could be due to (1) direct inhibition of growth processes by PBDE that indirectly decreases total energy demand and food intake, and (2) direct inhibition of food intake. Future studies to disentangle these possible pathways of PBDE effects are warranted. Environ Toxicol Chem 2021;40:3181-3192. © 2021 SETAC.

Polybrominated Diphenyl Ether Quinone Exposure Induces Atherosclerosis Progression via CD36-Mediated Lipid Accumulation, NLRP3 Inflammasome Activation, and Pyroptosis.

Polybrominated diphenyl ethers (PBDEs) are used worldwide in brominated flame retardants. Although due to the forbiddance of their application, PBDEs continuously exist in the environment due to their persistence. Therefore, it is important to expand the understanding of their potential toxicities and human risks. The underlying cardiovascular toxicological mechanisms of PBDEs are still largely unknown. Our previous studies indicated that PBDE quinone-type metabolite (PBDEQ) exposure causes reactive oxygen species (ROS)-driven cytotoxicity and various types of programmed cell death. Here, we first reported PBDEQ exposure induces atherosclerosis progression in bone marrow-derived macrophages (BMDMs) isolated from wild-type C57BL/6 or CD36-/- mice and J774A.1 macrophage models. First, we found that PBDEQ exposure induced lipid accumulation in oxidized low-density lipid (Ox-LDL)-treated J774A.1 macrophages. Consistently, in J774A.1 macrophages, PBDEQ exposure resulted in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis. CD36, a scavenger receptor responsible for the mediation of Ox-LDL uptake, was upregulated upon PBDEQ treatment. On the contrary, genetic knockout of CD36 or CD36 silencing by small interfering RNA efficiently attenuates PBDEQ-promoted lipid accumulation in BMDMs and J774A.1 macrophages. These findings highlight the effect of CD36 on the cardiovascular toxicity of PBDEs, which provides a better understanding of the pro-atherosclerosis effect of PBDEs.

Association between prenatal exposure to polybrominated diphenyl ethers and anogenital distance in girls at ages 0-4 years.

Anogenital distance (AGD) is a sensitive marker for the effect of in utero hormonal disturbance. However, studies on the associations between prenatal exposure to polybrominated diphenyl ethers (PBDEs), a group of endocrine disruptors, and AGD are limited. We examined the associations between prenatal PBDE exposure and AGD in girls at ages 0-4 years in the Shanghai-Minhang Birth Cohort Study. We measured PBDE in cord plasma collected from 148 girls at birth. Of them, two AGD metrics (AGDAC: from the anterior surface of the clitoral hood to the center of the anus; AGDAF: from the posterior end of the fourchette to the center of the anus) were measured in 142, 114, 104 and 120 of girls at birth, 6, 12, and 48 months of age, respectively. Linear regression models and linear mixed models were used to evaluate the associations between PBDE exposure and AGD at ages 0-4 years. We found positive associations of PBDE exposure with AGDAF and AGDAC in linear regression models, although some associations only reached significance at 6 and 48 months of age. For AGDAF, the associations were statistically significant for BDE-47, -99, and -100 at 6 months of age (β=2.34, 95% CI (0.21, 4.48) for BDE-47; β=2.21, 95% CI (0.05, 4.36) for BDE-99; β=2.12, 95% CI (0.01, 4.23) for BDE-100), and for BDE-99 and -100 at 48 months of age (β=4.49, 95% CI (1.27, 7.71) for BDE-99; β=5.04, 95% CI (1.87, 8.22) for BDE-100), while statistically significant associations with AGDAC were only observed for BDE-99, -100, -153, and ∑5PBDEs at 48 months of age (β=7.62, 95% CI (2.59, 12.64) for BDE-99; β=7.04, 95% CI (2.01, 12.07) for BDE-100; β=5.41, 95% CI (0.45, 10.38) for BDE-153; β=5.05mm, 95% CI (0.09, 10.01 for ∑5PBDEs). A consistent pattern of positive associations between prenatal exposure to PBDEs and AGD was also observed in linear mixed models. The finding provided further insights into the adverse effects of PBDEs on reproductive development at low dose exposure.

Polybrominated diphenyl ethers in serum from residents living in a brominated flame retardant production area: Occurrence, influencing factors, and relationships with thyroid and liver function.

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants (FRs) in China for decades, even after they were identified as persistent organic pollutants. In this study, serum samples were collected from 172 adults without occupational exposure who were residents of a well-known FR production region (Laizhou Bay, north China), and PBDE congeners were measured to assess their occurrence, congener profile and influencing factors in serum. Moreover, the relationships between serum concentrations of PBDEs and thyroid/liver function indicators were analyzed to evaluate whether human exposure to PBDEs would lead to thyroid/liver injury. All 8PBDE congeners were detected at higher frequencies and serum concentrations than those found in general populations. The median levels of ∑PBDEs, BDE-209 and ∑3-7PBDEs (sum of tri-to hepta-BDEs) were 64.5, 56.9 and 7.2ng/g lw (lipid weight), respectively, which indicated that deca-BDE was the primarily produced PBDE in Laizhou Bay and that the lower brominated BDEs were still ubiquitous in the environment. Gender was a primary influencing factor for some BDE congeners in serum; their levels in female serum samples were significantly lower than those in male serum samples. Serum PBDE levels showed a downward trend with increased body mass index (BMI), which might reflect the increasing serum lipid contents. Serum levels of some BDE congeners were significantly positively correlated with certain thyroid hormones and antibodies, including free triiodothyronine (fT3), total triiodothyronine (tT3), total thyroxine (tT4) and thyroid peroxidase antibody (TPO-Ab). Levels of some congeners were significantly negatively correlated with some types of serum lipid, including cholesterol (CHOL), low density lipoprotein (LDL) and total triglyceride (TG). Other than serum lipids, only two liver function indicators, total protein (TP) and direct bilirubin (DBIL), were significantly correlated with certain BDE congeners (BDE-100 and BDE-154). Our results provide new evidence on the thyroid-disrupting and hepatotoxic effects of PBDEs.

Plasma polybrominated diphenyl ethers, urinary heavy metals and the risk of thyroid cancer: A case-control study in China.

The incidence of thyroid cancer (TC) has increased rapidly worldwide in recent years. Exposure to endocrine disruptors can affect thyroid hormones and is probably carcinogenic to humans. The effects of polybrominated diphenyl ethers (PBDEs), some heavy metals (Cd, Pb, As and Hg) on risk of TC have been rarely reported. Hence, we aimed to examine the associations of TC risk with exposure to PBDEs and four heavy metals. This case-control study involved 308TC cases and 308 age- and sex-matched controls. Plasma PBDEs concentrations were determined by gas chromatograph-mass spectrometry. Concentrations of heavy metals concentrations in urine specimens were detected by graphite furnace atomic absorption spectrometry or inductively coupled plasma optical emission spectrometry. Conditional logistic regression models were used to explore associations of PBDEs and 4 heavy metals exposures with TC risk. A joint-effect interaction term was inserted into the logistic regression models to assess the multiplicative interaction effects of PBDEs-heavy metals on TC risk. Some PBDE congeners (BDE-028, -047,-099,-183,-209) were positively correlated with TC risk. As and Hg were also associated with the increased TC risk. Compared with low exposure levels, participants with high exposure levels of As and Hg were 5.35 and 2.98 times more likely to have TC, respectively. Co-exposure to BDE-209 and Pb had a negative interaction effect on TC risk. Some PBDE congeners (e.g. BDE-028, -047,-209) and Hg had a significant positive interaction effect on the risk of TC. The joint exposure of BDE-183 and Hg showed a negative interaction effect on TC risk, but the corresponding OR value was still statistically significant. Exposure to PBDEs, As and Hg may be associated with TC development. Joint exposure to PBDEs and Pb or Hg has interaction effects on TC risk. Further prospective research with large sample is required to confirm these findings.