High-fat diet exacerbates 1-Bromopropane-induced loss of dopaminergic neurons in the substantia nigra of mice through mitochondrial damage associated necroptotic pathway.

In recent years, accumulating evidence supports that occupational exposure to solvents is associated with an increased incidence of Parkinson's disease (PD) among workers. The neurotoxic effects of 1-bromopropane (1-BP), a widely used new-type solvent, are well-established, yet data on its relationship with the etiology of PD remain limited. Simultaneously, high-fat consumption in modern society is recognized as a significant risk factor for PD. However, whether there is a synergistic effect between a high-fat diet and 1-BP exposure remains unclear. In this study, adult C57BL/6 mice were fed either a chow or a high-fat diet for 18 weeks prior to 12-week 1-BP treatment. Subsequent neurobehavioral and neuropathological examinations were conducted to assess the effects of 1-BP exposure on parkinsonian pathology. The results demonstrated that 1-BP exposure produced obvious neurobehavioral abnormalities and dopaminergic degeneration in the nigral region of mice. Importantly, a high-fat diet further exacerbated the impact of 1-BP on motor and cognitive abnormalities in mice. Mechanistic investigation revealed that mitochondrial damage and mtDNA release induced by 1-BP and high-fat diet activate NLRP3 and cGAS-STING pathway- mediated neuroinflammatory response, and ultimately lead to necroptosis of dopaminergic neurons. In summary, our study unveils a potential link between chronic 1-BP exposure and PD-like pathology with motor and no-motor defects in experimental animals, and long-term high-fat diet can further promote 1-BP neurotoxicity, which underscores the pivotal role of environmental factors in the etiology of PD.

Association between brominated flame retardants and risk of endocrine-related cancer: A systematic review and meta-analysis.

BACKGROUND: The incidence of endocrine-related cancer, which includes tumors in major endocrine glands such as the breast, thyroid, pituitary, and prostate, has been increasing year by year. Various studies have indicated that brominated flame retardants (BFRs) are neurotoxic, endocrine-toxic, reproductive-toxic, and even carcinogenic. However, the epidemiological relationship between BFR exposure and endocrine-related cancer risk remains unclear. METHODS: We searched the PubMed, Google Scholar, and Web of Science databases for articles evaluating the association between BFR exposure and endocrine-related cancer risk. The odds ratio (OR) and its corresponding 95% confidence interval (95% CI) were used to assess the association. Statistical heterogeneity among studies was assessed with the Q-test and I2 statistics. Begg's test was performed to evaluate the publication bias. RESULTS: We collected 15 studies, including 6 nested case-control and 9 case-control studies, with 3468 cases and 4187 controls. These studies assessed the risk of breast cancer, thyroid cancer, and endocrine-related cancers in relation to BFR levels. Our findings indicate a significant association between BFR exposure in adipose tissue and an increased risk of breast cancer. However, this association was not observed for thyroid cancer. Generally, BFR exposure appears to elevate the risk of endocrine-related cancers, with a notable increase in risk linked to higher levels of BDE-28, a specific polybrominated diphenyl ether congener. CONCLUSIONS: In conclusion, although this meta-analysis has several limitations, our results suggest that BFR exposure is a significant risk factor for breast cancer, and low-brominated BDE-28 exposure could significantly increase the risk of endocrine-related cancers. Further research is essential to clarify the potential causal relationships between BFRs and endocrine-related cancers, and their carcinogenic mechanisms.

Bioaccumulation and Male Reproductive Toxicity of the New Brominated Flame Retardant Tetrabromobisphenol A-Bis(2,3-dibromo-2-methylpropyl ether) in Comparison with Hexabromocyclododecane.

Tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) (TBBPA-DBMPE) has come into use as an alternative to hexabromocyclododecane (HBCD), but it is unclear whether TBBPA-DBMPE has less hazard than HBCD. Here, we compared the bioaccumulation and male reproductive toxicity between TBBPA-DBMPE and HBCD in mice following long-term oral exposure after birth. We found that the concentrations of TBBPA-DBMPE in livers significantly increased with time, exhibiting a bioaccumulation potency not substantially different from HBCD. Lactational exposure to 1000 µg/kg/d TBBPA-DBMPE as well as 50 µg/kg/d HBCD inhibited testis development in suckling pups, and extended exposure up to adulthood resulted in significant molecular and cellular alterations in testes, with slighter effects of 50 µg/kg/d TBBPA-DBMPE. When exposure was extended to 8 month age, severe reproductive impairments including reduced sperm count, increased abnormal sperm, and subfertility occurred in all treated animals, although 50 µg/kg/d TBBPA-DBMPE exerted lower effects than 50 µg/kg/d HBCD. Altogether, all data led us to conclude that TBBPA-DBMPE exerted weaker male reproductive toxicity than HBCD at the same doses but exhibited bioaccumulation potential roughly equivalent to HBCD. Our study fills the data gap regarding the bioaccumulation and toxicity of TBBPA-DBMPE and raises concerns about its use as an alternative to HBCD.

Hexabromocyclododecane-induced reproductive toxicity in Brachionus plicatilis: Impacts and assessment.

Hexabromocyclododecane (HBCD), third-generation brominated flame retardants (BRFs), has aroused worldwide concern because of its wide application and potentially negative impacts on marine ecosystems, but an information gap still exists regarding marine low-trophic organisms. Brachionus plicatilis, the model marine zooplankton, was used in the present study, and its reproductive responses were used as the endpoint to indicate HBCD-induced toxicity. HBCD was suggested to be extremely highly toxic compounds regarding the 96 h-LC50 of 0.58 mg L-1. The sublethal exposure of HBCD injured the reproduction of B. plicatilis: The total number of offspring per female and the key population index calculated from the life table, including the intrinsic rate of population increase (rm) and net reproductive rate (R0), were significantly influenced in a concentration-dependent manner. The reproductive process was also altered, as indicated by the first spawning time, first hatching time and oocyst development time. At the same time, individual survival and growth (body length) were also negatively affected by HBCD. Reactive oxygen species (ROS) were suggested to be responsible for reproductive toxicity mainly because the total ROS contents as well as the main components of •OH and H2O2 greatly increased and resulted in the oxidative imbalance that presented as malondialdehyde (MDA) elevation. Simultaneous activation of the glutathione antioxidant system was accompanied by the apoptosis marker enzymes Caspase-3 and 9, as well as the correlation between ROS content, physiological alteration and cell apoptosis, providing further evidence for this. The integrated biomarker response (IBR) and adverse outcome pathway (AOP) showed that HBCD had a significant toxic effect on B. plicatilis near the concentration range of 96 h-LC50. The establishment of this concentration range will provide a reliable reference for future environmental concentration warning of HBCD in marine.

The brominated flame retardant tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) as well as hexabromocyclododecane lead to lipid disorders in mice.

The brominated flame retardant tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) (TBBPA-DBMPE) is a recommended substitute for hexabromocyclododecane (HBCD), a banned persistent organic pollutant, yet its potential toxicities remains largely unexplored. Here, we investigated the effects of a long-term exposure to TBBPA-DBMPE at nominal doses of 50 and 1000 µg/kg/d on lipid homeostasis in CD-1 mice, in comparison with 50 µg/kg/d HBCD as a positive control. Male pups received chemical treatments through maternal administration via drinking water from postnatal day 0-21, followed by direct administration through drinking water after weaning. On the 23rd week after treatment, the oral lipid tolerance test revealed that low-dose TBBPA-DBMPE as well as HBCD affected lipid tolerance, although the fasting serum triglyceride (TG) levels were not altered. When chemical treatment was extended to the 32nd week, TBBPA-DBMPE-treated animals displayed adipocyte hypertrophy in both white adipose tissue (eWAT) and brown adipose tissue (BAT) and hepatic steatosis, which was largely consistent with the effects of HBCD. These findings indicate that like HBCD, TBBPA-DBMPE led to increased lipid load in mice. Interestingly, we also observed intestinal histological changes, coupled with increased expression of lipid absorption-related genes in both HBCD and TBBPA-DBMPE treatments, suggesting increased lipid absorption. This was supported by in vitro findings that both HBCD and TBBPA-DBMPE promoted lipid accumulation in IEC-6 cells under the stress of oleic acid for 6 h, implying that altered lipid absorption by the intestine may partly contributed to increased lipid load in mice. Overall, the effects of 50 µg/kg/d TBBPA-DBMPE in terms of some parameters were comparable with 50 µg/kg/d HBCD, suggesting that TBBPA-DBMPE may not be an ideal substitute of HBCD.

Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

The epigenetic hallmark of early-life α-hexabromocyclododecane exposure: From cerebellar 6-mA levels to locomotor performance in adulthood.

There is a growing evidence that methylation at the N6 position of adenine (6-mA), whose modulation occurs primarily during development, would be a reliable epigenetic marker in eukaryotic organisms. The present study raises the question as to whether early-life exposure to α-hexabromocyclododecane (α-HBCDD), a brominated flame retardant, may trigger modifications in 6-mA epigenetic hallmarks in the brain during the development which, in turn could affect the offspring behaviour in adulthood. Pregnant Wistar rats were split into two groups: control and α-HBCDD (66 ng/kg/per os, G0-PND14). At PND1, α-HBCDD levels were assessed in brain and liver by LC-MS/MS. At PND14, DNA was isolated from the offspring's cerebellum. DNA methylation was measured by 6-mA-specific immunoprecipitation and Illumina® sequencing (MEDIP-Seq). Locomotor activity was finally evaluated at PND120. In our early-life exposure model, we confirmed that α-HBCDD can cross the placental barrier and be detected in pups at birth. An obvious post-exposure phenotype with locomotor deficits was observed when the rats reached adulthood. This was accompanied by sex-specific over-methylation of genes involved in the insulin signaling pathway, MAPK signaling pathway as well as serotonergic and GABAergic synapses, potentially altering the normal process of neurodevelopment with consequent motor impairments crystalized at adulthood.

Mechanisms of cell death induced by hexabromocyclododecane (HBCD) involves apoptosis, autophagy, and ER stress.

Hexabromocyclododecane (HBCD), was a widely utilized brominated flame retardant, commonly found in a wide range of household products. The pervasiveness of HBCD has identified the presence of this chemical in foods and in human tissues. Therefore, HBCD has been identified as a chemical of concern. The aim was to investigate the degree of cytotoxicity of HBCD in a range of cell lines derived from different tissues, (including hematopoietic, nerve, liver, and kidney-derived cells) with a view of determining any differential cell type effects. In addition, this study also investigated the mechanism(s) by which HBCD could cause cell death. The results showed that HCBD was considerably more toxic to leukocyte-derived (RBL2H3) and neuronal-derived (SHSY-5Y) cells with LC50 values of 1.5 and 6.1 µM, respectively, compared to cells derived from liver (HepG2) and kidney (Cos-7), which had LC50 values of 28.5 and 17.5 µM, respectively. A detailed investigation of the mechanism(s) of cell death showed that HBCD caused, at least in part, Ca2+ -dependent cell death, caspase-activated apoptosis, and autophagy, but there was little evidence for either necrosis or necroptosis occurring. Furthermore, it was shown that HBCD can also induce the ER stress response which is a known trigger of both apoptosis and autophagy and therefore this could be one of the crucial events by which cell death is initiated. As each of these cell death mechanisms was investigated in at least two different cell lines and no differences were identified, it is likely that the mode of action is not cell-type specific.

Carcinogenicity and testicular toxicity of 2-bromopropane in a 26-week inhalation study using the rasH2 mouse model.

2-Bromopropane (2-BP) is a colorless liquid at room temperature and is used in closed systems in factories, mainly as an intermediate for medicines, pesticides, and other chemicals. However, the carcinogenicity of 2-BP is still unknown. The CByB6F1-Tg(HRAS)2Jic (rasH2) transgenic mouse model has been established as an alternative to long-term studies (1.5 years-lifetime) to detect carcinogenicity in as short a time as six months. We performed a 26-week inhalation exposure study of 2-BP using the rasH2 mouse model. Male and female rasH2 mice were exposed to 0, 67, 200, or 600 ppm of 2-BP for 6 h/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. The results showed a concentration-dependent increase in lung tumor development in male and female rasH2 mice exposed by inhalation to 2-BP, which was significant by Peto's and Poly-3 trend tests. Furthermore, in male rasH2 mice, 2-BP was found to be a testicular toxin. This study is the first to demonstrate that 2-BP is carcinogenic in male and female mice and a testicular toxin in male mice using the rasH2 mouse model.

Maternal Transfer and Apical and Physiological Effects of Dietary Hexabromocyclododecane Exposure in Parental Fathead Minnows (Pimephales promelas).

Hexabromocyclododecane (HBCD) is a persistent organic pollutant that has been characterized as an endocrine disruptor, undergoes maternal transfer, and hinders development and growth in oviparous organisms. The present study examined the apical effects of dietary HBCD (11.5, 36.4, 106 mg/kg, wet wt) on adult fathead minnow exposed for 49 days and the subsequent accumulation and maternal transfer kinetics in adult tissue and eggs, respectively. Exposed adults displayed a significant increase in egg production in the medium treatment group, but no other significant effects were noted. Maternal transfer of dietary HBCD had a similar egg-to-muscle ratios (EMR) in the low and medium treatment groups (1.65 and 1.27 [wet wt], respectively). However, the high treatment group deviated from other treatments with an EMR of 4.2 (wet wt), potentially due to differences in total lipid content in food and/or reaching diffusion/lipid saturation limits in adult tissue, resulting in lower accumulation in the adult muscle tissue. A positive correlation was observed between egg HBCD concentration and time of exposure, which indicates that maternal transfer of HBCD is of concern in fish, and further studies should be conducted to fully elucidate the potential adverse effects that may be observed in the early life stage of oviparous organisms. Environ Toxicol Chem 2023;42:143-153. © 2022 SETAC.

An updated review on environmental occurrence, scientific assessment and removal of brominated flame retardants by engineered nanomaterials.

Due to the extensive manufacturing and use of brominated flame retardants (BFRs), they are known to be hazardous, bioaccumulative, and recalcitrant pollutants in various environmental matrices. BFRs make flame-resistant items for industrial purposes (textiles, electronics, and plastics equipment) that are disposed of in massive amounts and leak off in various environmental matrices. The consumption of plastic items has expanded tremendously during the COVID-19 pandemic which has resulted into the increasing load of solid waste on land and water. Some BFRs, such as polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDs), are no longer utilized or manufactured owing to their negative impacts, which promotes the utilization of new BFRs as alternatives. BFRs have been discovered worldwide in soil, sludge, water, and other contamination sources. Various approaches such as photocatalysis-based oxidation/reduction, adsorption, and heat treatment have been found to eradicate BFRs from the environment. Nanomaterials with unique properties are one of the most successful methodologies for removing BFRs via photocatalysis. These methods have been praised for being low-cost, quick, and highly efficient. Engineered nanoparticles degraded BFRs when exposed to light and either convert them into safer metabolites or completely mineralize. Scientific assessment of research taking place in this area during the past five years has been discussed. This review offers comprehensive details on environmental occurrence, toxicity, and removal of BFRs from various sources. Degradation pathways and different removal strategies related to data have also been presented. An attempt has also been made to highlight the research gaps prevailing in the current research area.

Biomarkers of exposure and effect in the serum and urine of rats or workers exposed to 1-bromopropane.

Extensively used in several industries in China as a cleaning agent, 1-bromopropane (1-BP) has significant adverse effects on the central nervous system. However, neither its mechanism of action nor sensitive biomarkers related to it have been determined thus far. In this study, animal experiments and occupational surveys were performed to explore the typical exposure and effect biomarkers of neurotoxicity induced by 1-BP. Male Wistar rats were exposed to 0, 500, or 1000 ppm of 1-BP followed by pathological and biomarker analyses. An epidemiological survey was conducted on 71 workers each from 1-BP exposed and control groups. Serum and urine samples were collected for biomarker testing. cNSE represents neuron-specific enolase (NSE) in the cerebral cortex, where as sNSE represents NSE in the serum; similar terminology applies to S-100ß, and cyclooxygenase-2 (COX-2). In rats exposed to 1000 ppm 1-BP, pathological changes were observed in Purkinje cells, lumbar gray matter, and tibiofibular nerve, while levels of cNSE, cS-100ß, cCOX-2, sS-100ß, and sCOX-2 were significantly elevated at different time checkpoints. In the 500 ppm group, cCOX-2, sNSE, and sCOX-2 levels were significantly elevated at different time checkpoints. 1-BP and N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys) were detected in rat urine, and there was a correlation between the level of sNSE or sCOX-2 and AcPrCys in the 500 ppm group. In the occupational epidemiological study, a significant correlation between AcPrCys and exposure concentration was also detected. The findings of this study indicated that AcPrCys was a sensitive exposure biomarker of 1-BP in rats as well as occupational populations.

Insight into phototransformation mechanism and toxicity evolution of novel and legacy brominated flame retardants in water: A comparative analysis.

The novel brominated flame retardants (NBFRs) have become widespread as a consequence of the prohibition on the use of polybrominated diphenyl ethers (PBDEs). However, the transformation mechanism and potential environmental risk are largely unclear. In this study, we have explored the phototransformation behavior of the most abundant NBFRs, 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) in water under ultraviolet (UV) irradiation. Meanwhile, the legacy 2,2',4,4',6,6'-hexabromodiphenyl ether (BDE155) with similar structure was investigated contrastively. Results show that novel BTBPE is more persistent than legacy BDE155, with nearly four times slower photodegradation rate constants (0.0120 min-1and 0.0447 min-1, respectively). 18 products are identified in the phototransformation of BTBPE. Different from the only debrominated products formed in legacy BDE155 transformation, the ether bond cleavage photoproducts (e.g. bromophenols) are also identified in novel BTBPE transformation. Compound-specific stable isotope analysis (CSIA) confirms the phototransformation mechanism is mainly via debromination accompanying with the breaking of ether bond. Computational toxicity assessment implies that transformation products of BTBPE still have the high kidney risks. Especially the bromophenols formed via the ether bond cleavage could significantly increase the health effects on skin irritation. This study emphasizes the importance of understanding the photolytic behavior and potential risks of novel NBFRs and other structurally similar analogues.

Integrated assessment of endocrine disrupting potential of four novel brominated flame retardants.

Novel brominated flame retardants (NBFRs) have emerged as alternatives to the legacy BFRs due to BFRs' persistence, bioaccumulation and evidence of adverse health effects. The increasing production of NBFRs has led to the frequent detection in environmental media and even in organisms. Thus the potential health risks of these novel NBFRs need to be taken into account. Herein, the endocrine disrupting effects of the four NBFRs (α/ß-TBCO, PBEB, EHTBB and BEHTBP) were evaluated by constructing an estrogen receptor (ERα), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) mediated dual-luciferase reporter gene assays on the CHO cells, in combination with steroid experiments on the H295R cells and molecular docking. The results revealed that α/ß-TBCO, PBEB and EHTBB induced anti-estrogenic activity at certain concentrations while none of the four NBFRs was agonistic to ERα. For reporter gene assay, only PBEB exhibited GR antagonistic effects. Notably, none of the four NBFRs possess neither agonistic nor antagonistic activity of MR. The molecular docking results were generally consistent with the reporter gene assay, which showed the different binding affinities between NBFRs and the receptors. For steroidogenesis, α/ß-TBCO, PBEB, and EHTBB all upregulated genes encoding for steroid synthesis enzymes, including 17ßHSD, CYP11B1 and CYP17. Altogether, the data clarified that NBFRs may pose risks of endocrine disruption.

Impact of brominated flame retardants on lipid metabolism: An in vitro approach.

Brominated flame retardants (BFRs) are chemicals employed to lower the flammability of several objects. These endocrine disruptor chemicals are lipophilic and persistent in the environment. Due to these characteristics some have been restricted or banned by the European Union, and replaced by several new chemicals, the novel BFRs (NBFRs). BFRs are widely detected in human samples, such as adipose tissue and some were linked with altered thyroid hormone levels, liver toxicity, diabetes and metabolic syndrome in humans. However, the disturbance in lipid metabolism caused by BFRs with emphases to NBFRs remains poorly understood. In this study, we used a pre-adipocyte (3T3-L1) cell line and a hepatocyte (HepG2) cell line to investigate the possible lipid metabolism disruption caused by four BFRs: hexabromobenzene (HBB), pentabromotoluene (PBT), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) and hexabromocyclododecane (HBCD). For that purpose, proliferation and Oil Red O assays, as well as, medium fatty acids profile evaluation using Gas chromatography and RNA extraction for quantitative RT-PCR assays were performed. We detected a significant reduction in the proliferation of preadipocytes and an increased lipid accumulation during differentiation caused by HBB. This BFR also lead to a significant increased expression of IL-1ß and decreased expression of PGC-1α and adiponectin. Nevertheless, PBT, TBB and HBCD show to increase lipid accumulation in hepatocytes. PBT also display a significant increase of PPARγ gene expression. Lipid accumulation in the cells can occur by diverse mechanisms depending on the BFR. These results highlight the importance of endocrine disruptor compounds in obesity etiopathogeny.

Health toxicity effects of brominated flame retardants: From environmental to human exposure.

Hexabromocyclododecane (HBCD) and Tetrabromobisphenol A (TBBP-A) are brominated flame retardants widely used in variety of industrial and consumer products (e.g., automobiles, electronics, furniture, textiles and plastics) to reduce flammability. HBCD and TBBPA can also contaminate the environment, mainly water, dust, air and soil, from which human exposure occurs. This constant exposure has raised some concerns against human health. These compounds can act as endocrine disruptors, a property that gives them the ability to interfere with hormonal function and quantity, when HBCD and TBBPA bind target tissues in the body. Studies in human and animals suggest a correlation between HBCD and TBBPA exposure and adverse health outcomes, namely thyroid disorders, neurobehavior and development disorders, reproductive health, immunological, oncological and cardiovascular diseases. However, in humans these effects are still poorly understood, once only a few data evaluated the human health effects. Thus, the purpose of this review is to present the toxicity effects of HBCD and TBBPA and how these compounds affect the environment and health, resorting to data and knowledge of 255 published papers from 1979 to 2020.

Kinetics, pathways and toxicity of hexabromocyclododecane biodegradation: Isolation of the novel bacterium Citrobacter sp. Y3.

This research investigated the biodegradation kinetics, pathways and ecological risk of hexabromocyclododecane (HBCD) by a novel bacterium Citrobacter sp. Y3. Results showed the biodegradation followed a first-order model. The specific degradation rate constant of HBCD were obviously higher in batch experiments with combined carbon sources (k: 0.156-0.290 d-1) than those using HBCD as the sole carbon source (k: 0.055 d-1). Correspondingly, the degradation half-life became much shorter (T1/2: 2.39-4.44 d vs T1/2: 13.7 d). HBCD could be degraded through dehydrobromination and dehalohydroxylation, of which six possible degradation products were detected. To evaluate the ecological risk of HBCD biodegradation products, acute toxicity tests were assessed for the first time. The acute toxicity decreased slowly during treatment for 3-5 d and then decreased sharply. In general, treatment by Strain Y3 is not only a biodegradation process but also a detoxification process, thus it shows potential for bioremediation of HBCD contaminated sites.

The brominated flame retardants TBECH and DPTE alter prostate growth, histology and gene expression patterns in the mouse.

The brominated flame retardants (BFRs), 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) bind to the androgen receptor (AR). in vitro bioassays have shown that TBECH is a potent androgen agonist while DPTE is a potent AR antagonist. Both TBECH and DPTE alter gene expression associated with AR regulation. However, it remains to be determined if TBECH and DPTE can affect the prostate. For this reason, we exposed CD1 mice to a 1:1 mixture of TBECH diastereomers α and ß, a 1:1 mixture of γ and δ, and to DPTE, and tested their effects on prostate growth, histology and gene expression profiles. Castrated mice were used to study the androgenic effects of TBECHαß and TBECHγδ while the antagonistic effects of DPTE were studied in non-castrated mice. We observed that testosterone and TBECHγδ increased body and prostate weights while TBECHαß affected neither of them; and that DPTE had no effect on body weight but reduced prostate weight drastically. Histomorphometric analysis of the prostate revealed epithelial and glandular alterations in the TBECHγδ group comparable to those in testosterone group while alterations in the TBECHαß group were less pronounced. DPTE displayed androgen antagonist activity reminiscent of castration. The transcription profile of the prostate was altered by castration and exposure to testosterone and to TBECHγδ reversed several of these changes. Testosterone and TBECHγδ also regulated the expression of several androgen responsive genes implicated in prostate growth and cancer. While DPTE resulted in a drastic reduction in prostate weight, it only affected a small number of genes. The results indicate that TBECHγδ and DPTE are of high human health concern as they may contribute to changes in prostate growth, histology and function.

Per- and polyfluoroalkyl mixtures toxicity assessment "Proof-of-Concept" illustration for the hazard index approach.

The 2018 ATSDR mixture framework recommends three approaches including the hazard index (HI) for environmental mixture toxicity assessment. Per- and polyfluoroalkyls (PFAS) are found in our environment and general populations. Recent experimental mixture toxicity studies of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and an assessment of 17 PFAS indicate the use of additivity for their joint toxicity assessment. The aim of this investigation was to detail the stepwise procedures and examine the extent and use of the HI approach for PFAS mixture assessment. Using estimated general public lifetime exposures (high, medium, and low), binary mixtures of PFOS and PFOA yielded, respectively, hazard indices (HIs) of 30.67, 8.33, and 3.63 for developmental toxicity; 10.67, 5.04, and 2.34 for immunological toxicity; 3.57, 1.68, and 0.78 for endocrine toxicity; 4.51, 1.73, and 0.79 for hepatic toxicity; and 15.08, 2.29, and 0.88 for reproductive toxicity. A heterogeneous mixture of PFOA, PFAS, dioxin (CDD), and polybrominated compounds (PBDE) for high exposure scenario yielded HIs of 30.99 for developmental, 10.77 for immunological, 3.64 for endocrine, 4.61 for hepatic, and 17.36 for reproductive effects. The HI values are used as a screening tool; the potential concern for exposures rises as HI values increase. For HI values >1, a follow-up including further analysis of specific exposures, use of internal dosimetry, and uncertainty factors is conducted before recommending appropriate actions. The HI approach appears suitable to address present-day PFAS public health concerns for initial assessment of multiple health effects, until further insights are gained into their mechanistic toxicology.The findings and conclusions in this article are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.