Polybrominated Diphenyl Ethers Exposure Research Articles

Exposure to an environmentally representative mixture of polybrominated diphenyl ethers (PBDEs) alters zebrafish neuromuscular development

Polybrominated diphenyl ethers (PBDEs) are a prevalent group of brominated flame retardants (BFRs) added to several products such as electronics, plastics, and textiles to reduce their flammability. They are reported as endocrine disruptors and neurodevelopmental toxicants that can accumulate in human and wildlife tissues, thus making their ability to leach out of products into the environment a great cause for concern. In this study, zebrafish (Danio rerio) embryos and larvae were exposed to a wide concentration range (1.5, 15, 150 and 300 pM) of a PBDE mixture from one to six days post-fertilization (dpf). Hatching rates, mortality and general morphology were assessed during the exposure period. A delay in hatching was observed at the two highest PBDEs concentrations and mortality rate increased at 6 dpf. By 4 dpf, larvae exposed to 150 pM and 300 pM PBDEs developed an upcurved phenotype. Analysis of motor behavior at 6 dpf revealed that PBDE exposure acutely reduced locomotion. To further analyze these motor deficits, we assessed the neural network density and motor neuron and neuromuscular junctions (NMJ) development by immunostaining and imaging. Acetylated α-tubulin staining revealed a significant loss of neurons in a dose-dependent manner. Synaptic vesicle protein 2 (SV2) and ⍺-bungarotoxin (⍺-BTX) staining revealed a similar pattern, with a significant loss of SV2 and nicotinic acetylcholine receptors, thus preventing the colocalization of presynaptic neurons with postsynaptic neurons. Consistent with these results, the presence of cleaved caspase-3 and acridine orange positive cells showed increased cell death in zebrafish larvae exposed to PBDEs. Our results suggest that exposure to PBDEs leads to deficits in the zebrafish neuromuscular system through neuron death, inducing morphological and motor deficiencies throughout their development. They provide valuable insight into the neurotoxic effects of PBDEs, further highlighting the relevance of the zebrafish model in toxicological studies.

Distribution of Polybrominated Diphenyl Ethers (PBDEs) in Placental Tissues of Maternal and Fetal Origin in Exposed Wistar Rats and Associations with Thyroid Hormone Levels.

In utero exposure to polybrominated diphenyl ethers (PBDEs) is linked to adverse pregnancy and fetal health outcomes, including altered thyroid hormone (TH) levels. Despite their phase out, PBDEs are still commonly detected in newborn cord blood. While PBDEs can cross the placenta, few studies have separately assessed PBDEs or THs in the maternal and fetal placental tissues. Additionally, no studies have separately assessed THs in these tissues across mid- and late gestation, during the onset of fetal TH synthesis. To address these gaps, we conducted a study with Wistar rats and examined PBDE accumulation in the maternal and fetal placenta. Pregnant dams were exposed daily to sesame oil vehicle, a low dose, or high dose PBDE mixture. At GD15 and 20, dams were sacrificed and placental tissues were collected. Tissues were analyzed for PBDEs, T3, rT3, and T4 using mass spectrometry. BDE-47, -99, -100, and -209 were frequently detected in both the fetal and maternal placenta. At GD15, higher concentrations of BDE-99, -100, and -209 were measured in the fetal placenta; however, this trend reversed by GD20, with higher maternal placental concentrations. Placental T3 and T4 were significantly impacted by exposure, tissue, and exposure x tissue at GD15, with significant reductions in both THs following low dose exposure in the maternal placenta. By GD20, maternal placental T3 was only significantly reduced in the high exposure groups and there was no effect on placental T4. Overall, these results highlight the rapid developmental changes that occur throughout gestation between the maternal and fetal placenta, and the differential impacts of gestational PBDE exposure on placental T3 and T4 across mid- and late-gestation.

Polybrominated diphenyl ethers in paired dust-breast milk samples: Levels, predictors of contamination, and health risk assessment for infants and mothers

An integrated study on the levels of 7 polybrominated diphenyl ethers (PBDEs) in house dust and breast milk samples from women (N = 30) living in these households was conducted. ∑PBDEs ranged from <LOD to 523 ng g−1 dust (median 4.9 ng g−1 dust), and from 0.16 to 6.3 ng g−1 lipid weight (lw) (median 0.49 ng g−1 lw), in house dust and breast milk samples, respectively. Statistically significant correlations were observed between the mass fractions of BDE-153 from breast milk, and BDE-47, BDE-99 and BDE-100 from house dust, congeners that all originate from the “penta” formulation, indicating its dominance as PBDE exposure source in the examined household dusts. The number of electronic and electrical devices, and age of the building were positive, and the number of upholstered furniture and household area were negative predictors of PBDE dust levels. Mothers age was negative predictor of the PBDE levels in breast milk, possibly due to dilution of PBDEs in total body fat accumulated over the years. The results of health risk assessment suggest that detected PBDE levels don’t pose non-carcinogenic risk to the study population.

Identification of serum metabolites associated with polybrominated diphenyl ethers (PBDEs) exposure in papillary thyroid carcinoma: a case–control study

As the most common endocrine cancer, thyroid cancer (TC) has sharply increased globally over the past three decades. The growing incidence of TC might be counted by genetics, radiation, iodine, autoimmune disease, and exposure to environmental endocrine–disrupting chemicals (EDCs). Polybrominated diphenyl ethers (PBDEs), being typical EDCs, have been widely utilized in plastics, electronics, furniture, and textiles as flame retardants since the 1980s, and research has indicated a significant correlation between their exposure and the risk of TC. Even so, PBDEs exposure impact on the metabolic signature for TC remains unexplored. In this study, eight congeners of PBDEs were determined in serum from 111 patents with papillary thyroid cancer (PTC) and 111 healthy participants based on case–control epidemiology using gas chromatography–atmospheric pressure chemical ionization–tandem mass spectrometry (GC-APCI–MS/MS). Based on the tertile distribution of total PBDEs concentrations in 59 participants, metabolomics analysis was further performed by ultra-high performance liquid chromatography coupled to hybrid quadrupole–Orbitrap MS. In the partial correlation analysis, the 29 identified metabolites were correlated with PBDEs exposure (P < 0.05). In addition, PBDEs disrupted the metabolism of glycerophospholipids, sphingolipids, taurine, and hypotaurine, indicating that neurotransmitters, oxidative stress, and inflammation are the vulnerable pathways affected in PTC. Furthermore, (±)-octopamine and 5-hydroxyindole, both of which modulate the actions of neurotransmitters, emerged as potential disturbed metabolite markers for TC following exposure to PBDEs. This study analyzed the impact of PBDEs on PTC in terms of the metabolic changes and further explored possible biomarkers, which helped us have a deep understanding of the possible mechanism of the effects of PBDEs on TC.

Maternal Exposure to Low-Dose BDE-47 Induced Weight Gain and Impaired Insulin Sensitivity in the Offspring.

Polybrominated diphenyl ethers (PBDEs), commonly used as synthetic flame retardants, are present in a variety of consumer products, including electronics, polyurethane foams, textiles, and building materials. Initial evidence from epidemiological and experimental studies suggests that maternal PBDE exposure may be associated with a higher BMI in children, with disturbance of energy metabolism and an increased risk of Type 2 diabetes. However, the causality between early exposure to real-life PBDE concentrations and increased weight as well as mechanisms underlying impaired metabolic pathways in the offspring remain elusive. Here, using a mouse model we examined the effect of maternal exposure to 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47), the most abundant congener in human samples, on offspring weight gain and energy homeostasis using a mouse model. Maternal exposure to BDE-47 at low dose resulted in weight gain in female offspring together with an impaired glucose and insulin tolerance in both female and male mice. In vitro and in vivo data suggest increased adipogenesis induced by BDE-47, possibly mediated by DNA hypermethylation. Furthermore, mRNA data suggest that neuronal dysregulation of energy homeostasis, driven via a disturbed leptin signaling may contribute to the observed weight gain as well as impaired insulin and glucose tolerance.

Mixture effects of prenatal exposure to polybrominated diphenyl ethers on urinary oxidative stress biomarkers in the Chemicals in Our Bodies Cohort.

Polybrominated diphenyl ethers (PBDEs) exposure is associated with preterm birth. Laboratory studies suggest that PBDEs lead to elevated oxidative stress, a known contributor to preterm birth in epidemiologic studies. We hypothesized that elevated levels of PBDEs would be associated with increased oxidative stress during human pregnancy. Participants in this analysis were enrolled in the Chemicals in Our Bodies cohort and resided in the San Francisco Bay Area (N=201). Four PBDEs (BDE-47, -99, -100, -153) were measured in second trimester serum. Urinary oxidative stress biomarkers were measured at two timepoints (second and third trimester) and included 8-isoprostane-prostaglandin-F2α [8-iso-PGF2α], 2,3-dinor-5,6-dihydro-8-iso-PGF2α, 2,3-dinor-8-iso-PGF2α, and prostaglandin-F2α [PGF2α]. Associations between individual PBDEs and oxidative stress biomarkers (averaged and trimester specific) were examined using linear regression. Quantile g-computation and Bayesian kernel machine regression (BKMR) were used to assess cumulative effects of PBDEs. Quantile g-computation showed that higher concentrations of PBDEs were associated with increasing 8-iso-PGF2α, 2,3-dinor-8-iso-PGF2α, and PGF2α. Associations were greatest in magnitude for second trimester levels of 2,3-dinor-8-iso-PGF2α (mean change per quartile increase=0.25, 95% confidence interval=0.09, 0.41). Associations were similar using BKMR and linear regression. Our findings suggest that oxidative stress may be a plausible biological pathway by which PBDE exposure might lead to preterm birth.

Alterations of gut microbiota and its metabolomics in children with 6PPDQ, PBDE, PCB, and metal(loid) exposure

The composition and metabolites of the gut microbiota can be altered by environmental pollutants. However, the effect of co-exposure to multiple pollutants on the human gut microbiota has not been sufficiently studied. In this study, gut microorganisms and their metabolites were compared between 33 children from Guiyu, an e-waste dismantling and recycling area, and 34 children from Haojiang, a healthy environment. The exposure level was assessed by estimating the daily intake (EDI) of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), 6PPD-quinone (6PPDQ), and metal(loid)s in kindergarten dust. Significant correlations were found between the EDIs of 6PPDQ, BDE28, PCB52, Ni, Cu, and the composition of gut microbiota and specific metabolites. The Bayesian kernel machine regression model showed negative correlations between the EDIs of five pollutants (6PPDQ, BDE28, PCB52, Ni, and Cu) and the composition of gut microbiota. The EDIs of these five pollutants were positively correlated with the levels of the metabolite 2,4-diaminobutyric acid, while negatively correlated with the levels of d-erythro-sphingosine and d-threitol. Our study suggests that exposure to 6PPDQ, BDE28, PCB52, Ni, and Cu in kindergarten dust is associated with alterations in the composition and metabolites of the gut microbiota. These alterations may be associated with children’s health.

Exposure to Polybrominated Diphenyl Ethers and Risk of All-Cause and Cause-Specific Mortality

Polybrominated diphenyl ethers (PBDEs) are an important group of persistent organic pollutants with endocrine-disrupting properties. However, prospective cohort studies regarding the association of PBDE exposure with long-term health outcomes, particularly mortality, are lacking. To examine the association of environmental exposure to PBDEs with risk of all-cause and cause-specific mortality. This nationally representative cohort study used data from the National Health and Nutrition Examination Survey 2003 to 2004 and linked mortality information through December 31, 2019. Adults aged 20 years or older with available data on PBDE measurements and mortality were included. Statistical analysis was performed from February 2022 to April 2023. PBDE analytes in serum samples were measured using solid phase extraction and isotope dilution gas chromatography high-resolution mass spectrometry. All-cause mortality, cancer mortality, and cardiovascular mortality. This study included 1100 participants (mean [SE] age, 42.9 [0.6] years; proportion [SE] female, 51.8% [1.6%]; proportion [SE] Hispanic, 12.9% [2.7%]; proportion [SE] non-Hispanic Black, 10.5% [1.6%]; proportion [SE] non-Hispanic White, 70.8% [3.7%]; proportion [SE] other race and ethnicity, 5.8% [1.1%]). During 16 162 person-years of follow-up (median [IQR] follow-up, 15.8 [15.2-16.3] years; maximum follow-up, 17 years), 199 deaths occurred. Participants with higher serum PBDE levels were at higher risk for death. After adjustment for age, sex, and race and ethnicity, lifestyle and socioeconomic factors, and body mass index, participants with the highest tertile of serum PBDE levels had an approximately 300% increased risk of cancer mortality (HR, 4.09 [95% CI, 1.71-9.79]) compared with those with the lowest tertile of serum PBDE levels. No significant association of PBDE exposure with all-cause mortality (HR, 1.43 [95% CI, 0.98-2.07]) or cardiovascular mortality (HR, 0.92 [95% CI, 0.41-2.08]) was observed. In this nationally representative cohort study, PBDE exposure was significantly associated with an increased risk of cancer mortality. Further studies are needed to replicate the findings and determine the underlying mechanisms.

Prenatal exposure to polybrominated diphenyl ether (PBDE) and child neurodevelopment: The role of breastfeeding duration

BackgroundPrenatal and early-life exposure to polybrominated diphenyl ethers (PBDEs) is associated with detrimental and irreversible neurodevelopmental health outcomes during childhood. Breastfeeding may be a child's largest sustained exposure to PBDE— potentially exacerbating their risk for adverse neurodevelopment outcomes. However, breastfeeding has also been associated with positive neurodevelopment. Our study investigates if breastfeeding mitigates or exacerbates the known adverse effects of prenatal exposure to PBDEs and child neurodevelopment. MethodsParticipants included 321 mother-infant dyads from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal birth cohort in California. PBDE concentrations were measured in maternal serum blood samples collected during pregnancy or at delivery. Using generalized estimated equations (GEE), we estimated associations of PBDE concentrations with children's attention, executive function, and cognitive scores assessed longitudinally between 7 and 12 years of age, stratified by duration of exclusive and complementary breastfeeding. ResultsWe observed that higher maternal prenatal PBDE concentrations were associated with poorer executive function among children who were complementary breastfed for a shorter duration compared to children breastfed for a longer duration; preservative errors (β for 10-fold increase in complementary breastfeeding <7 months = −6.6; 95 % Confidence Interval (CI): −11.4, −1.8; β ≥ 7 months = −5.1; 95 % CI: −10.2, 0.1) and global executive composition (β for 10-fold increase <7 months = 4.3; 95 % CI: 0.4, 8.2; β for 10-fold increase ≥7 months = 0.6; 95 % CI: −2.8, 3.9). ConclusionsProlonged breastfeeding does not exacerbate but may mitigate some previously observed negative associations of prenatal PBDE exposure and child neurodevelopment.

Polybrominated diphenyl ethers in dust, hair and urine: Exposure, excretion

Polybrominated diphenyl ethers (PBDEs) have been detected in various environmental media and human tissues. PBDEs concentrations in dust from college buildings and homes and in paired hair and urine samples from students were determined. This is of great significance to explore the accumulation and excretion patterns of PBDEs in the human body. The median PBDEs concentrations in the dust (College: 84.59 ng/g; Home: 170.32 ng/g) and hair (undergraduate: 6.16 ng/g; Home: 3.25 ng/g) samples were generally lower than were found in the majority of previous studies. The PBDEs concentrations in the hair and urine samples were subjected to principal component analysis, and the results combined with the PBDEs detection rates confirmed that hair is a useful non-invasive sampling medium for assessing PBDEs exposure and the risks posed. Body mass indices (BMIs) were used to divide students who had not been exposed to large amounts of PBDEs into groups. Body fat percentage is an important factor affecting the accumulation of PBDE in the human body. Environmental factors were found to affect the PBDEs concentrations in the hair and urine samples less for normal-weight students (BMI≤24) than overweight students (BMI>24). Short-term environmental changes to more readily affect the PBDEs concentrations in the tissues of the normal-weight than overweight students. PBDEs with seven or more bromine substituents were found not to be readily excreted in urine. Performing molecular docking simulations of the binding of isomers BDE-99 and BDE-100 to megalin. The binding energy was higher for BDE-100 and megalin than for BDE-99 and megalin, meaning BDE-99 would be more readily excreted than BDE-100.

Chemicals Used in Plastic Materials: An Estimate of the Attributable Disease Burden and Costs in the United States.

Chemicals used in plastics have been described to contribute to disease and disability, but attributable fractions have not been quantified to assess specific contributions. Without this information, interventions proposed as part of the Global Plastics Treaty cannot be evaluated for potential benefits. To accurately inform the tradeoffs involved in the ongoing reliance on plastic production as a source of economic productivity in the United States, we calculated the attributable disease burden and cost due to chemicals used in plastic materials in 2018. We first analyzed the existing literature to identify plastic-related fractions (PRF) of disease and disability for specific polybrominated diphenylethers (PBDE), phthalates, bisphenols, and polyfluoroalkyl substances and perfluoroalkyl substances (PFAS). We then updated previously published disease burden and cost estimates for these chemicals in the United States to 2018. By uniting these data, we computed estimates of attributable disease burden and costs due to plastics in the United States. We identified PRFs of 97.5% for bisphenol A (96.25-98.75% for sensitivity analysis), 98% (96%-99%) for di-2-ethylhexylphthalate, 100% (71%-100%) for butyl phthalates and benzyl phthalates, 98% (97%-99%) for PBDE-47, and 93% (16%-96%) for PFAS. In total, we estimate $249 billion (sensitivity analysis: $226 billion-$289 billion) in plastic-attributable disease burden in 2018. The majority of these costs arose as a result of PBDE exposure, though $66.7 billion ($64.7 billion-67.3 billion) was due to phthalate exposure and $22.4 billion was due to PFAS exposure (sensitivity analysis: $3.85-$60.1 billion). Plastics contribute substantially to disease and associated social costs in the United States, accounting for 1.22% of the gross domestic product. The costs of plastic pollution will continue to accumulate as long as exposures continue at current levels. Actions through the Global Plastics Treaty and other policy initiatives will reduce these costs in proportion to the actual reductions in chemical exposures achieved.

Ex vivo exposure to polybrominated diphenyl ether (PBDE) selectively affects the immune response in autistic children

Children on the autism spectrum have been shown to have immune dysregulation that often correlates with behavioral deficits. The role of the post-natal environment in this dysregulation is an area of active investigation. We examined the association between plasma levels of polybrominated diphenyl ether (PBDE) and immune cell function in age-matched autistic children and non-autistic controls. Plasma from children on the autism spectrum (n = 38) and typically developing controls (TD; n = 60) were analyzed for 14 major PBDE congeners. Cytokine/chemokine production was measured in peripheral blood mononuclear cell (PBMC) supernatants with and without ex vivo BDE-49 exposure. Total plasma concentration (∑PBDE14) and individual congener levels were also correlated with T cell function. ∑PBDE14 did not differ between diagnostic groups but correlated with reduced immune function in children on the autism spectrum. In autistic children, IL-2 and IFN-γ production was reduced in association with several individual BDE congeners, especially BDE-49 (p = 0.001). Furthermore, when PBMCs were exposed ex vivo to BDE-49, cells from autistic children produced elevated levels of IL-6, TNF-α, IL-1β, MIP-1α and MCP-1 (p < 0.05). Therefore, despite similar plasma levels of PBDE, these data suggest that PBMC function was differentially impacted in the context of several PBDE congeners in autistic children relative to TD children where increased body burden of PBDE significantly correlated with a suppressed immune response in autistic children but not TD controls. Further, acute ex vivo exposure of PBMCs to BDE-49 stimulates an elevated cytokine response in AU cases versus a depressed response in TD controls. These data suggest that exposure to the toxicant BDE-49 differentially impacts immune cell function in autistic children relative to TD children providing evidence for an underlying association between susceptibility to PBDE exposure and immune anomalies in children on the autism spectrum.

OR06-02 Placental Distribution Of Polybrominated Diphenyl Ethers (Pbdes) And Thyroid Hormones Across Gestation In PBDE-exposed Wistar Rats

Abstract Disclosure: S. Gaballah: None. B. Horman: None. G. St Armour: None. K. Hoffman: None. H.B. Patisaul: None. H. Stapleton: None. In utero exposure to polybrominated diphenyl ethers (PBDEs) has been linked to adverse pregnancy and fetal health outcomes, including altered thyroid hormone (TH) levels. Despite their phase out, PBDEs are still measured in newborn cord blood. While evidence suggests that PBDEs can cross the placental barrier, few studies have assessed differences in PBDE or TH accumulation in the maternally and fetally-derived placental tissue layers or studied fetal sex-differences. To address these gaps, we conducted a controlled exposure study in Wistar rats (n=8 per treatment and gestational day (GD)). From GD2, pregnant dams were exposed daily to sesame oil vehicle, a low dose, or high dose mixture of 10 PBDEs. The low dose represents the 95th percentile of PBDEs measured in U.S. house dust, and the high dose is ∼20X higher. At GD15 and GD20, dams were sacrificed and placental tissues were micro-dissected into maternally and fetally-derived layers. Tissues were analyzed for PBDEs and for T3, rT3, and T4 using mass spectrometry. BDEs 47, 99, 100, and 209 were frequently detected in the fetal and maternal tissues. Higher concentrations of BDEs 99, 100, and 209 were measured in the fetal placenta on GD 15; however, this trend flipped at GD20, with higher maternal concentrations of BDEs 47, 99, and 209. This shift appears to be related to changes in the mass of the maternal and fetal layers during gestation and not to different partioning processes. Only BDE 99 was significantly different between the two layers, in both sexes. At both timepoints, T3 levels were several-fold higher in maternal tissues than fetal, but T3 decreased in maternal tissues by GD20. No sex differences were observed. In general, we observed a significant difference in maternal and fetal T3 levels at GD15 and GD20 in control, low, and high dose-exposed animals. At GD15, there was a significant difference between maternal and fetal female placental T4 levels (p=0.0237) and a suggestive difference in males (p=0.081) in the high dose group, as well as a significant effect of sex between the fetal tissues in the low dose group (p=0.0044). T4 was only detected in the fetal side at GD20, with no significant effects of treatment or sex. These results highlight the rapid developmental changes throughout gestation between the maternal and fetal placenta. Overall, these data highlight that PBDE accumulation in Wistar rats changes across gestation, causing disruption of TH levels in maternal and fetal tissues, and that sex-specific differences may be contributing to differential accumulation patterns in male and female-associated placentas. Coupled with rapid morphological changes in the fetal and maternal layers during placental growth, in utero PBDE exposure may result in adverse impacts on placental TH regulation and fetal health. Presentation: Thursday, June 15, 2023

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.

Photosynthetic response mechanism to polybrominated diphenyl ether exposure in Chlorella pyrenoidosa

Polybrominated diphenyl ether (PBDE) contamination is common in aquatic environments and can severely damage aquatic organisms. However, there is a lack of information on the response and self-adaptation mechanisms of these organisms. Chlorella pyrenoidosa was treated with 2,2′,4,4′-tetrabromodiphenyl ether (BDE47), causing significant growth inhibition, pigment reduction, oxidative stress, and chloroplast atrophy. Photosynthetic damage contributed to inhibition, as indicated by Fv/Fm, Chl a fluorescence induction, photosynthetic oxygen evolution activity, and photosystem subunit stoichiometry. Here, Chl a fluorescence induction and quinone electron acceptor (QA−) reoxidation kinetics showed that the PSII donor and acceptor sides were insensitive to BDE47. Quantitative analyses of D1 and PsaD proteins illustrated that PSII and PSI complexes were the main primary targets of photosynthesis inhibition by BDE47. Significant modulation of PSII complex might have been caused by the potential binding of BDE47 on D1 protein, and molecular docking was performed to investigate this. Increased activation of antioxidant defense systems and photosystem repair as a function of exposure time indicated a positive resistance to BDE47. After a 5-day exposure, 23 % of BDE47 was metabolized. Our findings suggest that C. pyrenoidosa has potential as a bioremediator for wastewater-borne PBDEs and can improve our understanding of ecological risks to microalgae.

Proteomic analyses of primary human villous trophoblasts exposed to flame retardant BDE-47 using SWATH-MS

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants and recognized developmental toxicants that are detectable in placental tissues. Higher levels of in utero PBDE exposure have been associated with an increased risk of adverse birth outcomes. During pregnancy, cytotrophoblasts (CTBs) from the placenta play critical roles in the formation of the maternal-fetal interface via uterine invasion and vascular remodeling. The differentiation of these cells towards an invasive phenotype is crucial for proper placental development. We previously have shown that BDE-47 can impact CTB viability and hinder the ability of these cells to migrate and invade. To expand on potential toxicological mechanisms, we utilized quantitative proteomic approaches to identify changes in the global proteome of mid-gestation primary human CTBs after exposure to BDE-47. Using sequential window acquisition of all theoretical fragment-ion spectra (SWATH), we identified 3024 proteins in our CTB model of differentiation/invasion. Over 200 proteins were impacted as a function of BDE-47 exposure (1 μM and 5 μM) across the treatment period (15, 24, and 39 h). The differentially expressed molecules displayed time- and concentration-dependent changes in expression and were enriched in pathways associated with aggregatory and adhesive processes. Network analysis identified CYFIP1, a molecule previously unexplored in a placental context, to be dysregulated at BDE-47 concentrations previously seen to impact CTB migration/invasion. Our SWATH-MS dataset thus demonstrates BDE-47 impacts the global proteome of differentiating CTBs and serves as a valuable resource for further understanding of the relationship between environmental chemical exposures and placental development and function. Availability of data and materialRaw chromatograms are deposited on the MassIVE proteomic database (https://massive.ucsd.edu) under accession number MSV000087870. Normalized relative abundances are also available as Table S1.

Maternal PBDE exposure disrupts gut microbiome and promotes hepatic proinflammatory signaling in humanized PXR-transgenic mouse offspring over time.

Developmental exposure to the persistent environmental pollutant, polybrominated diphenyl ethers (PBDEs), is associated with increased diabetes prevalence. The microbial tryptophan metabolite, indole-3-propionic acid (IPA), is associated with reduced risk of type 2 diabetes and lower-grade inflammation and is a pregnane X receptor (PXR) activator. To explore the role of IPA in modifying the PBDE developmental toxicity, we orally exposed humanized PXR-transgenic (hPXR-TG) mouse dams to vehicle, 0.1 mg/kg/day DE-71 (an industrial PBDE mixture), DE-71+IPA (20 mg/kg/day), or IPA, from 4 weeks preconception to the end of lactation. Pups were weaned at 21 days of age and IPA supplementation continued in the corresponding treatment groups. Tissues were collected at various ages until 6 months of age (n = 5 per group). In general, the effect of maternal DE-71 exposure on the gut microbiome of pups was amplified over time. The regulation of hepatic cytokines and prototypical xenobiotic-sensing transcription factor target genes by DE-71 and IPA was age- and sex-dependent, where DE-71-mediated mRNA increased selected cytokines (Il10, Il12p40, Il1β [both sexes], and [males]). The hepatic mRNA of the aryl hydrocarbon receptor (AhR) target gene Cyp1a2 was increased by maternal DE-71 and DE-71+IPA exposure at postnatal day 21 but intestinal Cyp1a1 was not altered by any of the exposures and ages. Maternal DE-71 exposure persistently increased serum indole, a known AhR ligand, in age- and sex-dependent manner. In conclusion, maternal DE-71 exposure produced a proinflammatory signature along the gut-liver axis, including gut dysbiosis, dysregulated tryptophan microbial metabolism, attenuated PXR signaling, and elevated AhR signaling in postweaned hPXR-TG pups over time, which was partially corrected by IPA supplementation.

Probiotic Therapy with Lactobacillus reuteri Rescues Social and Emotional Recognition Behavior in an Environmental Mouse Model of Autism

Introduction: Polybrominated diphenyl ethers (PBDEs) are neuroendocrine disrupting chemicals with adverse neurodevelopmental effects in children. Our group has previously shown that PBDEs produce autistic-like traits in developmentally exposed mice offspring (Kozlova et al. 2022 Arch Tox; PMID: 34687351). Our pilot data suggests that PBDEs reduce hypothalamic oxytocin expression. Moreover, PBDEs are well established disruptors of thyroid hormones. Lactobacillus reuteri (LR) is a beneficial probiotic that can increase oxytocin and thyroid hormones in other ASD mouse models. Therefore, we hypothesized that LR can restore PBDE-induced deficits in social behavior. Methods: C57BL/6N dams were dosed with a commercial mixture of PBDE congeners, DE-71, at 0.1 mg/kg/d (DE-71), or corn oil vehicle control (VEH/CON) for 10 wk (preconception: 4 wk; gestation: 3 wk; lactation: 3 wk). Dams were gavaged with L. reuteri (LR) ATCC 6475 (gift of Biogaia, Sweeden) at 10 8 CFU/mL. Cohort 1 pups (C1-LR) received LR via dam until weaning (PND 21). Cohort 2 pups (C2-LR) continued to receive gavage of LR post-weaning, daily, through 6 mo of age. Results: PCR analysis showed increased gene expression of fecal LR 6475 in feces collected from LR offspring and dams confirming efficacy of maternal LR supplementation. Compared to VEH/CON neither DE-71 nor LR disrupted normal maternal behavior. In offspring, DE-71 produced deficient short- (SRT, 30 min retention) and long-term social recognition memory (SRMT, 24 h retention) in adult females (short- and long-term) and adult males (short-term). LR normalized these deficits. The social recognition deficit was not present at PND 11 as measured on a maternal attachment homing test. On an emotional recognition test DE-71 exposed male and female offspring did not prefer investigation of stimulus mice subjected to 15 min restraint stress vs neutral conditions (normalized with LR). In a marble burying test, compared to VEH/CON, DE-71 exposed offspring showed abnormally elevated scores, which were normalized by LR treatment only in females. Developmental benchmarks that are likely affected by the TH-disruptive effects of DE-71 showed complex interactions between DE-71 and LR. LR normalized delayed (vs VEH/CON) incisor eruption in DE-71 females and improved latency of righting reflex in DE-71 males. LR normalized DE-71-induced hyperactivity on an open field test in females. Ongoing studies are focused on exploring possible mechanisms underlying the normalization provided by LR. However, our early data suggest a potential role of 1) OXT confirmed by increased plasma OXT in DE-71 male (C1-LR) mice and normalized with LR, and 2) maternal THs since LR supplementation elevated plasma T4 in DE-71 pregnant dams. Conclusions: These results suggest that maternal LR treatment during developmental PBDE exposure provides normalization of autistic-like features in a sex-dependent manner. This work is supported by a Danone North America Gut Microbiome, Yogurt and Probiotics Fellowship Grant and a University of California President's Pre-Professoriate Fellowship to E.V.K. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Environmental signature and health risk assessment of polybrominated diphenyl ethers (PBDEs) emitted from a landfill fire in Santiago de Chile

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in building materials, electronics, furnishings, vehicles, airplanes, plastics, polyurethane foams, and textiles for many years. Currently, the primary commercial mixtures, penta-, octa-, and deca-BDE, are globally restricted. Still, products containing PBDEs are expected to impact waste management and the environment for many years. In January 2016, an open fire in the Santa Marta landfill close to Santiago de Chile affected the city and surroundings. The fire caused several acute health effects and an increase in emergency hospitalizations. We measured PBDE levels in the areas affected by the fire in the air (gaseous and particulate) and soil, and PBDE emissions were estimated using a dispersion model. The results showed an increase in PBDE concentrations by a factor of 2–4 one day after the start of the fire. However, PBDE concentrations measured after the fire in PM10 and the gas phase were considered low compared to other regions. Interestingly, PBDEs’ patterns differed across the sites; however, BDE209 was the dominant congener for all environmental matrices. A preliminary risk assessment was conducted using the daily exposure dose (DED) by air inhalation estimation. The results showed low DED values for adults and children and suggested no direct health risk due to PBDE exposure. This study brings new data useful for future solid waste management initiatives in the country.

Serum polybrominated diphenyl ether exposure and influence factors in blood donors of Wuxi adults from 2013 to 2016

Polybrominated diphenyl ethers (PBDEs) have been used as brominated flame retardants worldwide and are correlated with extensive environmental pollution and human health concerns. This study is aimed at analyzing the concentrations of PBDEs and at evaluating their temporal trends among a population of blood donors (n = 33) over a 4-year period. A total of 132 serum samples were used for PBDE detection. Nine PBDE congeners were quantified in serum samples by gas chromatography with mass spectrometry (GC-MS). The median concentrations of Σ9PBDEs in each year were 33.46, 29.75, 30.85, and 35.02ng/g lipid, respectively. Most of the PBDE congeners showed a downward trend from 2013 to 2014 and then increased after 2014. No correlations between age and PBDE congener concentrations were observed, while concentrations of each congener and Σ9PBDE were nearly always lower in females than in males, especially in BDE-66, BDE-153, BDE-183, BDE-190, and Σ9PBDE. We also found that the intake of fish, fruit, and eggs in the daily diet was related to the exposure level of PBDEs. Our results suggest that, as deca-BDE is still produced and used in China, diet is an important exposure pathway for PBDEs, and follow-up studies will be required to improve our understanding of the behaviors of PBDE isomers in humans and the exposure levels.