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1.
J Environ Sci (China) ; 109: 161-170, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34607665

RESUMO

Decabrominated diphenyl ether (BDE-209) is generally utilized in multiple polymer materials as common brominated flame retardant. BDE-209 has been listed as persistent organic pollutants (POPs), which was considered to be reproductive toxin in the environment. But it still remains unclear about the effects of BDE-209 on DNA methylation and the induced-male reproductive toxicity. Due to the extensive epigenetic regulation in germ line development, we hypothesize that BDE-209 exposure impacts the statue of DNA methylation in spermatocytes in vitro. Therefore, the mouse GC-2spd (GC-2) cells were used for the genome wide DNA methylation analysis after treated with 32 µg/mL BDE-209 for 24 hr. The results showed that BDE-209 caused genomic methylation changes with 32,083 differentially methylated CpGs in GC-2 cells, including 16,164 (50.38%) hypermethylated and 15,919 (49.62%) hypomethylated sites. With integrated analysis of DNA methylation data and functional enrichment, we found that BDE-209 might affect the functional transcription in cell growth and sperm development by differential gene methylation. qRT-PCR validation demonstrated the involvement of p53-dependent DNA damage response in the GC-2 cells after BDE-209 exposure. In general, our findings indicated that BDE-209-induced genome wide methylation changes could be interrelated with reproductive dysfunction. This study might provide new insights into the mechanisms of male reproductive toxicity under the environmental exposure to BDE-209.


Assuntos
Metilação de DNA , Retardadores de Chama , Animais , Dano ao DNA , Epigênese Genética , Retardadores de Chama/toxicidade , Células Germinativas , Éteres Difenil Halogenados/toxicidade , Masculino , Camundongos
2.
J Hazard Mater ; 416: 126203, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492966

RESUMO

Increasing electrical and electronic waste have raised concerns about the potential toxicity of brominated flame retardants (BFRs) and heavy metals (HMs). However, few studies have focused on the combined effect of BFRs and HMs on microorganisms, especially denitrifying bacteria, which have an essential role in N cycles and N2O emission. Herein, we investigate the combined effect of tetrabromobisphenol A (TBBPA) and Cu on model denitrifying bacteria. A further 24.5% decline in N removal efficiency was observed when 0.05 mg/L Cu were added into a denitrifying system containing 0.75 mg/L TBBPA. Further study demonstrated that Cu heightened the toxicity of TBBPA to denitrification via following aspects: (1) Cu stimulated EPS secretion induced by TBBPA during denitrification, blocked the transmembrane transport of glucose, which caused insufficient carbon substrate for bacteria growth and electron provision; (2) Cu further suppressed key denitrifying enzymes' activity and down-regulated genes involving electron transport induced by TBBPA, led to the decrease of electron transport activity. Finally, the decrease of bacterial growth, insufficient electron donor, and lower electron transport activity caused the synergetic toxic effect of TBBPA and Cu on denitrification. Overall, the present study provides new insights into the combined effect of BFRs and HMs on microorganisms.


Assuntos
Retardadores de Chama , Bifenil Polibromatos , Cobre/toxicidade , Desnitrificação , Transporte de Elétrons , Elétrons , Retardadores de Chama/toxicidade , Bifenil Polibromatos/toxicidade
3.
Environ Sci Pollut Res Int ; 28(36): 49507-49528, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34378126

RESUMO

The ban and restriction of polychlorinated biphenyls (PCBs) and major brominated flame retardants (BFRs), including hexabromocyclododecane (HBCD) and polybrominated diphenyl ethers (PBDEs), due to their confirmed detrimental effects on wildlife and humans have paved the way for the wide application of organophosphate esters (OPEs). OPEs have been extensively used as alternative flame retardants, plasticizer, and antifoaming agents in various industrial and consumer products, which leads to an increase in production, usage, and discharge in the environment. We compile recent information on the production/usage and physicochemical properties of OPEs and discussed and compared the available sample treatment and analysis techniques of OPEs, including extraction, clean-up, and instrumental analysis. The occurrence of OPEs in sediment, aquatic biota, surface, and drinking water is documented. Toxicity, human exposure, and ecological risks of OPEs were summarized; toxicological data of several OPEs shows different adverse health effects on aquatic organisms and humans. Much attention was given to document evidence regarding the bioaccumulation and biomagnification potential of OPEs in aquatic organisms. Finally, identified research gaps and avenues for future studies are forwarded.


Assuntos
Monitoramento Ambiental , Retardadores de Chama , Bioacumulação , Ésteres , Retardadores de Chama/análise , Retardadores de Chama/toxicidade , Humanos , Organofosfatos/toxicidade
4.
Ecotoxicol Environ Saf ; 223: 112589, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34358932

RESUMO

In recent years, organophosphate ester flame retardants (OPFRs), which have been regarded as alternatives for brominated flame retardants (BFRs), have become widely used in building materials, textiles, and electric equipment. Elucidating the relationship between OPFRs and tumors holds great significance for the treatment and prevention of diseases. In this work, we found a new method for predicting the correlation between the interactive genes of OPFRs and tumors. Transcriptome profiles and OPFR information were obtained from The Cancer Genome Atlas and the Genotype-Tissue Expression, Comparative Toxicogenomics, and PharmMapper databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that interactive genes were mainly enriched in prostate cancer, steroid metabolic process, and steroid hormone regulation. Furthermore, protein-protein interaction network analysis revealed 33 biological hub genes. The operating characteristic curves and survival analysis showed the role of key genes in predicting the prognosis of prostate cancer. Gene target prediction and gene set variation analysis proved that OPFRs and their metabolites exert potential effects on prostate cancer. Colony formation assay showed that the cells with AR, mTOR and DDIT3 knockdown could remarkably mitigate the cell proliferation ability in both PC-3 and LNCap cells. Transwell assay demonstrated that the silencing of AR, mTOR and DDIT3 could significantly inhibit the cell invasion capacity of prostate cells. Triphenyl phosphate (TPP) significantly increase the cell proliferation ability and promote cell invasion capacity. AR, mTOR and DDIT3 in the PC-3 and LNCap cells were significantly upregulated with 10-6 M TPP treated.


Assuntos
Retardadores de Chama , Neoplasias da Próstata , Compreensão , Retardadores de Chama/toxicidade , Humanos , Masculino , Organofosfatos/toxicidade , Compostos Organofosforados , Neoplasias da Próstata/genética
5.
Environ Sci Pollut Res Int ; 28(39): 54466-54476, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34420170

RESUMO

Although some regulatory agencies have claimed that consumer exposures to tetrabromobisphenol A (TBBPA) are not likely to cause adverse health effects in humans or the environment, the safety of tetrabromobisphenol A (TBBPA) has been questioned. Here, we summarize the literature concerning in vivo and in vitro neurotoxicity of TBBPA over the past decades. Most laboratory rodent studies reported that gavage administration of TBBPA at doses below 1000 mg/kg/day generally exerted no or limited effects on neuropathology and locomotor behaviors, but increased anxiety and auditory impairments were observed in several studies. In fish and amphibians, waterborne exposure to TBBPA was generally reported to disrupt neurodevelopment and lead to neurobehavioral alterations. Moreover, in vitro studies support the observations that TBBPA could exert neurotoxic effects in vertebrates. Thus, we suggest that TBBPA could have adverse effects on the nervous system in vertebrates. Given rapid excretion and low availability of TBBPA in laboratory rodents following single gavage administration, we speculate that single-daily gavage could result in an underestimation of the neurotoxic effects of TBBPA in rodents. Thus, we propose to employ multiple-daily administration routes (such as dermal, inhalation, and drinking water), to further assess the neurotoxic effects of TBBPA in mammals.


Assuntos
Retardadores de Chama , Bifenil Polibromatos/toxicidade , Animais , Retardadores de Chama/toxicidade , Humanos
6.
Ecotoxicol Environ Saf ; 223: 112605, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34371453

RESUMO

The global phase-out has decreased the use of polybrominated diphenyl ethers (PBDEs), thereby, rapidly increasing the production and use of their important surrogates, organophosphorus flame retardants (OPFRs). Currently, OPFRs are often found at higher levels in the environments compared to PBDEs. Although the two typical OPFRs, tris (1,3-dichloroisopropyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP), have been frequently detected in marine environments with significant concentrations, their toxicity to marine organisms remains unknown. We used Oryzias melastigma to investigate and compare their developmental toxicity in marine organisms through two-generational chronic exposure. The results showed that TDCIPP and TPhP exposure shortened the body length and length of the pectoral fin of O. melastigma. Both TDCIPP and TPhP deformed the pectoral fins in the 1st fry and caused spinal curvature in adult fish. Therefore, these two chemicals may pose potential risks to marine fish and marine ecosystems. Further studies suggested that although these two chemicals caused similar developmental bone toxicity, they had different modes of modulating the expression of bone developmental genes such as, bmp4, bmp2 and runx2.


Assuntos
Retardadores de Chama , Oryzias , Animais , Ecossistema , Retardadores de Chama/toxicidade , Organofosfatos , Compostos Organofosforados
7.
Environ Pollut ; 285: 117527, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34380225

RESUMO

2-Ethylhexyl diphenyl phosphate (EHDPP) is a common flame retardant and environmental pollutant, exposing humans with endocrinal disrupting potentials. Its mutagenicity, especially following metabolism, remains unclear. In this study, molecular docking analysis indicated that EHDPP was a potential substrate for several human CYP enzymes except for CYP1A1. Among V79-derived cell lines genetically engineered for the expression of each CYP, EHDPP (6 h exposure/18 h recovery) did not induce micronuclei in the V79 or V79-derived cells expressing human CYP1A1, however, it was positive in V79-derived cell lines expressing human CYP2E1, 3A4, and 2B6. In a human hepatoma (HepG2) cell line, EHDPP (48 h exposure) moderately induced micronuclei, which was blocked by 1-aminobenzotriazole (ABT, 60 µM, inhibitor of CYPs); pretreating HepG2 cells with bisphenol AF, another organic pollutant as inducer of CYPs (0.1 µM for 16 h), significantly potentiated micronuclei formation by EHDPP, threshold being decreased from 10 to 1.25 µM. This effect was blocked by ABT, drastically reduced by ketoconazole (inhibiting CYP3A expression/activity), and moderately inhibited by trans-1,2-dichloroethylene (selective CYP2E1 inhibitor). Immunofluorescent centromere protein B staining indicated that EHDPP-induced micronuclei in V79-derived cell lines expressing human CYP2E1 and 3A4 were predominantly centromere-negative, and that in HepG2 cells pretreated with bisphenol AF (for inducing multiple CYPs) were purely centromere-negative. In bisphenol AF-pretreated HepG2 cells EHDPP potently induced DNA breaks, as indicated by the comet assay and Western blot analysis of γ-H2AX. In conclusion, our study suggests that EHDPP is potently clastogenic, following activation by several human CYP enzymes, CYP3A4 being a major one.


Assuntos
Retardadores de Chama , Mutagênicos , Animais , Compostos de Bifenilo , Linhagem Celular , Cricetinae , Cricetulus , Retardadores de Chama/toxicidade , Humanos , Simulação de Acoplamento Molecular , Fosfatos
8.
Environ Pollut ; 289: 117855, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34340181

RESUMO

A wide range of novel replacement flame retardants (nFRs) is consistently detected in increasing concentrations in the environment and human matrices. Evidence suggests that nFRs exposure may be associated with disruption of the endocrine system, which has been linked with the etiology of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). NAFLD is a multifactorial disease characterized by the uncontrolled accumulation of fats (lipids) in the hepatocytes and involves multiple-hit pathogenesis, including exposure to occupational and environmental chemicals such as organophosphate flame retardants (OPFRs). In the present study we aimed to investigate the potential mechanisms of the nFRs-induced hepatic steatosis in the human liver cells. In this study, we employed an in vitro bioassay toolbox to assess the key events (KEs) in the proposed adverse outcome pathways (AOP) (s) for hepatic steatosis. We examined nine nFRs using AOP- based in vitro assays measuring KEs such as lipid accumulation, mitochondrial dysfunction, gene expression, and in silico approach to identify the putative molecular initiating events (MIEs). Our findings suggest that several tested OPFRs induced lipid accumulation in human liver cell culture. Tricresyl phosphate (TMPP), triphenyl phosphate (TPHP), tris(1,3-dichloropropyl) phosphate (TDCIPP), and 2-ethylhexyl diphenyl phosphate (EHDPP) induced the highest lipid accumulation by altering the expression of genes encoding hepatic de novo lipogenesis and mitochondrial dysfunction depicted by decreased cellular ATP production. Available in vitro data from ToxCast and in silico molecular docking suggests that pregnane X receptor (PXR) and peroxisome proliferator-activated receptor gamma (PPARγ) could be the molecular targets for the tested nFRs. The study identifies several nFRs, such as TMPP and EHDPP, TPHP, and TDCIPP, as potential risk factor for NAFLD and advances our understanding of the mechanisms involved, demonstrating the utility of an AOP-based strategy for screening and prioritizing chemicals and elucidating the molecular mechanisms of toxicity.


Assuntos
Rotas de Resultados Adversos , Retardadores de Chama , Técnicas de Cultura de Células , Retardadores de Chama/toxicidade , Hepatócitos , Humanos , Simulação de Acoplamento Molecular , Organofosfatos
9.
Environ Health ; 20(1): 76, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193151

RESUMO

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are endocrine disrupting chemicals with widespread exposures across the U.S. given their abundance in consumer products. PFAS and PBDEs are associated with reproductive toxicity and adverse health outcomes, including certain cancers. PFAS and PBDEs may affect health through alternations in telomere length. In this study, we examined joint associations between prenatal exposure to PFAS, PBDEs, and maternal and newborn telomere length using mixture analyses, to characterize effects of cumulative environmental chemical exposures. METHODS: Study participants were enrolled in the Chemicals in Our Bodies (CIOB) study, a demographically diverse cohort of pregnant people and children in San Francisco, CA. Seven PFAS (ng/mL) and four PBDEs (ng/g lipid) were measured in second trimester maternal serum samples. Telomere length (T/S ratio) was measured in delivery cord blood of 292 newborns and 110 second trimester maternal whole blood samples. Quantile g-computation was used to assess the joint associations between groups of PFAS and PBDEs and newborn and maternal telomere length. Groups considered were: (1) all PFAS and PBDEs combined, (2) PFAS, and (3) PBDEs. Maternal and newborn telomere length were modeled as separate outcomes. RESULTS: T/S ratios in newborn cord and maternal whole blood were moderately correlated (Spearman ρ = 0.31). In mixtures analyses, a simultaneous one quartile increase in all PFAS and PBDEs was associated with a small increase in newborn (mean change per quartile increase = 0.03, 95% confidence interval [CI] = -0.03, 0.08) and maternal telomere length (mean change per quartile increase = 0.03 (95% CI = -0.03, 0.09). When restricted to maternal-fetal paired samples (N = 76), increasing all PFAS and PBDEs combined was associated with a strong, positive increase in newborn telomere length (mean change per quartile increase = 0.16, 95% CI = 0.03, 0.28). These associations were primarily driven by PFAS (mean change per quartile increase = 0.11 [95% CI = 0.01, 0.22]). No associations were observed with maternal telomere length among paired samples. CONCLUSIONS: Our findings suggest that PFAS and PBDEs may be positively associated with newborn telomere length.


Assuntos
Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Fluorcarbonetos/toxicidade , Éteres Difenil Halogenados/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Telômero/efeitos dos fármacos , Adulto , Monitoramento Biológico , Poluentes Ambientais/análise , Ácidos Graxos/análise , Ácidos Graxos/toxicidade , Feminino , Retardadores de Chama/análise , Fluorcarbonetos/análise , Éteres Difenil Halogenados/análise , Humanos , Recém-Nascido , Masculino , Exposição Materna , Troca Materno-Fetal , Gravidez , Ácidos Sulfônicos/análise , Ácidos Sulfônicos/toxicidade
10.
Sci Total Environ ; 793: 148596, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34328967

RESUMO

Tetrabromobisphenol A-TBBPA, a widely used brominated flame retardant detected in aquatic environments, is considered a potential endocrine disruptor-ED for its reproductive/developmental effects in vertebrates. In aquatic invertebrates, the modes of action of most EDs are largely unknown, due to partial knowledge of the mechanisms controlling neuroendocrine functions. In the marine bivalve Mytilus galloprovincialis, TBBPA has been previously shown to affect larval development in the 48 h larval toxicity assay at environmental concentrations. In this work, the effects of TBBPA were further investigated at different times post-fertilization. TBBPA, from 1 µg/L, affected shell biogenesis at 48 hours post fertilization-hpf, as shown by phenotypic and SEM analysis. The mechanisms of action of TBBPA were investigated at concentrations of the same order of magnitude as those found in highly polluted coastal areas (10 µg/L). At 28-32 hpf, TBBPA significantly affected deposition of both the organic matrix and CaCO3 in the shell. TBBPA also altered expression of shell-related genes from 24 to 48 hpf, in particular of tyrosinase, a key enzyme in shell matrix remodeling. At earlier stages (24 hpf), TBBPA affected the development of dopaminergic, serotoninergic and GABAergic systems, as shown by in situ hybridization-ISH and immunocytochemistry. These data contribute draw adverse outcome pathways-AOPs, where TBBPA affects the synthesis of neutrotransmitters involved in key events (neurodevelopment and shell biogenesis), resulting in phenotypic changes on individuals (delayed or arrested development) that might lead to detrimental consequences on populations.


Assuntos
Retardadores de Chama , Mytilus , Bifenil Polibromatos , Animais , Retardadores de Chama/toxicidade , Humanos , Larva , Bifenil Polibromatos/toxicidade
11.
Sci Total Environ ; 795: 148837, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34246143

RESUMO

Organophosphate flame retardants (OPFRs), as a substitute for brominated flame retardants (BFRs), are widely used in industrial production and life. The presence of OPFRs in the environment has an adverse effect on the ecological environment system. This review provides comprehensive data for the occurrence of OPFRs and their diester metabolites (OP diesters) in wastewater treatment plants, surface water, drinking water, sediment, soil, air and dust in the environment. In particular, the accumulation and metabolism of OPFRs in organisms and the types of metabolites and metabolic pathways are discussed for animals and plants. In addition, the toxicity of OP triesters and OP diesters in organisms is discussed. Although research on OPFRs has gradually increased in recent years, there are still many gaps to be filled, especially for metabolic and toxicity mechanisms that need in-depth study. This review also highlights the shortcomings of current research and provides suggestions for a basis for future research on OPFRs.


Assuntos
Retardadores de Chama , Animais , Poeira/análise , Meio Ambiente , Retardadores de Chama/análise , Retardadores de Chama/toxicidade , Organofosfatos/análise , Organofosfatos/toxicidade , Água
12.
J Hazard Mater ; 418: 126279, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329041

RESUMO

As alternatives to traditional brominated flame retardants, organophosphate flame retardants (OPFRs), especially for organophosphate esters (OPEs) -- the most widely used and investigated OPFRs, have raised people's concern on their environmental and health-related risks over the years. Considering their extensive environmental occurrence and potential adverse effects, precise estimation on the human body burden of OPEs will be conducive to the restrictions on the usage of these compounds scientifically. Biomonitoring research can provide precise information on human exposure to OPEs as it reveals the degree of external exposure from all exposure routes. Knowledge on biotransformation and metabolism of OPEs in the biosystems is of great significance for our understanding of the internal exposure to these compounds. In this study, the biological metabolic processes of nine OPEs prevalent in the environment, involving tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tripropyl phosphate (TPrP), tri-n-butyl phosphate (TnBP), tris(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPhP), 2-ethylhexyl diphenyl phosphate (EHDPP), and tricresyl phosphate (TCrP), are comprehensively reviewed. Specifically, the metabolic pathway, kinetics and mechanism of OPEs are depicted in detail. Under this context, the advances and limitations on biomonitoring of OPE metabolites in human urine are summarized. The requirements of specificity, quantitative stability, high detection frequency/concentration are needed for OPE metabolites to be considered and validated as biomarkers. Thus far, deeper elucidations on the metabolic processes and identification of biomarkers of OPEs are urgently required, given that some OPEs have no suitable biomarkers in human biomonitoring. For better assessment of the body burden of OPEs in humans, reliable and effective methodologies for urine sampling and estimation on internal exposure to OPEs need to be further developed in the future.


Assuntos
Ésteres , Retardadores de Chama , China , Monitoramento Ambiental , Retardadores de Chama/análise , Retardadores de Chama/toxicidade , Humanos , Organofosfatos/toxicidade
13.
Environ Toxicol Pharmacol ; 87: 103699, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34237467

RESUMO

Tris (2-chloroethyl) phosphate (TCEP) is an emerging aquatic environmental pollutant. In the present study, juvenile yellow catfish (Pelteobagrus fulvidraco) were exposed to environmentally relevant concentrations of TCEP for 30 days. The results showed that TCEP exposure decreased the survival rate (100 µg/L), body weight (10 and 100 µg/L) and specific growth rate (10 and 100 µg/L) of juvenile yellow catfish. Exposure to TCEP resulted in pronounced damages of gill structures. Gene transcription analysis showed that the antioxidant capacity of the liver and gills was affected; CYP1A1 might contribute to phase I metabolism of TCEP in the liver rather than CYP1B1; TCEP stress might increase the demand of ion transport in fish gill; TCEP could stimulate the immune response and might induce apoptosis via a p53-Bax pathway and caspase-dependent pathway in gills. Collectively, these findings provide new insights into the toxic effects of TCEP on fish.


Assuntos
Peixes-Gato , Retardadores de Chama/toxicidade , Organofosfatos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Peixes-Gato/genética , Peixes-Gato/crescimento & desenvolvimento , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Proteínas de Peixes/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Brânquias/patologia , Glutationa Transferase/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Osmorregulação/efeitos dos fármacos , Osmorregulação/genética , Oxirredutases/genética
14.
Chemosphere ; 284: 131250, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34225124

RESUMO

An emerging experimental framework suggests that endocrine-disrupting compounds are candidate obesogens. However, this potential effect has not yet been determined for Tricresyl phosphate (TCP), a mass-produced organophosphate flame retardant (OPFR) that has been exposed to human beings in many ways. Many OPFRs, including TCP, have been shown to activate pregnane X receptor (PXR), a nuclear receptor that regulates lipid metabolism. Accordingly, we found that TCP exposure caused lipid accumulation in HepG2 cells in this study. Therefore, to elucidate the role of PXR played in TCP metabolism and promotion of lipid accumulation, HepG2 cells were exposed to different concentrations (5 × 10-8 to 5 × 10-5 M) of TCP for 24 h. The enlarged hepatic lipid droplets and increased hepatic triglyceride contents were observed in HepG2 cells after TCP exposure for 24 h. This is the result of a confluence of lipogenesis increase and ß-oxidation suppression imposed by PXR activation which was verified by the up regulation of genes in fatty acid (FA) synthesis and the down regulation of genes in ß-oxidation. Surface plasmon resonance (SPR) analysis and molecular docking revealed favorable binding mode of TCP to PXR and the knockout of PXR gene with CRISPR/cpf1 system in HepG2 cells abolished TCP-induced triglyceride accumulation, thus underlying the crucial role of PXR in hepatic lipid metabolism resulting from OPFRs exposure. This study enhances our understanding of molecular mechanisms and associations of PXR in lipid metabolism disturbance induced by TCP and provides novel evidence regarding the lipotoxicity effect and potential metabolism pathway of OPFRs.


Assuntos
Retardadores de Chama , Receptores de Esteroides , Tritolil Fosfatos , Retardadores de Chama/toxicidade , Homeostase , Humanos , Simulação de Acoplamento Molecular , Receptor de Pregnano X/genética , Receptores de Esteroides/genética
15.
Toxicology ; 458: 152837, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34166751

RESUMO

Decabromodiphenyl ether (BDE209) has been widely used as a flame retardant in the past four decades, leading to human health consequences, especially neurological impairments. Our previous in vivo studies have suggested that developmental neurotoxicity in offspring may be the result of BDE209-induced placental type III iodothyronine deiodinase (Dio3) disturbance and consequent thyroid hormone (TH) instability. Dio3 is paternally imprinted gene, and its balanced expression is crucial in directing normal development and growth. In this study, we used placenta-derived cells to investigate how BDE209 affected Dio3 expression through interfering imprinting mechanisms in the delta-like homolog 1 (Dlk1)-Dio3 imprinted region. Gene chip analysis and RT-qPCR identified miR409-3p, miR410-5p, miR494-3p, miR668-3p and miR889-5p as potential candidates involved in Dio3 deregulation. The sodium bisulfite-clonal sequencing revealed the BDE209 affect methylation status of two differentially methylated regions (DMRs), intergenic-DMR (IG-DMR) and maternally expressed gene 3-DMR (MEG3-DMR). Our data indicate that placental Dio3 may be a potential molecular target for future study of BDE209 developmental toxicity. In particular, miRNAs, IG-DMR and MEG3-DMR in the Dlk1-Dio3 imprinted locus may be informative in directing studies in TH disturbance and developmental toxicity induced by in utero exposure to environmental persistent organic pollutants (POPs), and those candidate miRNAs may prove to be convenient and noninvasive biomarkers for future large-scale population studies.


Assuntos
Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Iodeto Peroxidase/efeitos dos fármacos , Proteínas de Membrana/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Hormônios Tireóideos/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , MicroRNAs/metabolismo , Gravidez , Transfecção
16.
Ecotoxicol Environ Saf ; 221: 112425, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34146984

RESUMO

The frequent detection of (2,3-dibromopropyl) phosphate (TDBPP) in environment has led to a consistent risk to organisms. However, little is known about the toxicity of TDBPP exclusive for its carcinogen. Mitochondrion that tightly relates to adverse outcomes once deteriorated is referred as a target of environmental pollutants. Here, we investigated the role of mitochondrial abnormality in development of cellular pathobiology especially lipid deposition when response to TDBPP in mitochondria-rich hepatocyte (AML12) at the same order of magnitude as the environmental concentrations (10-6 mol/L or below) via multiplexed quantitative high content analytic system. The present study claimed TDBPP shifted mitochondria from fusion morphology to fission phenotype charactering by less mitochondrial networks, larger mitochondrial areas and shorter branch length at 10-7 mol/L or above. This dynamic imbalance was triggered by high levels of fis and drp1 genes when treated with TDBPP. The deformation caused by TDBPP reciprocally influenced biogenesis through PGC1α and electron transport chains via ectopic expression of genes encoding for mitochondria complex I and III subunits. Accordingly, we observed high mitoROS level and low mitochondria membrane potential. Consequently, cells contained those abnormal mitochondria were predisposed to accumulating lipids after exposure to TDBPP. Here we showed that TDBPP deteriorated mitochondrial morphology and function, which may induce lipid generation. As for a banned while still emerged contaminant, our study also claimed further exploration on the non-carcinogenic toxicity of TDBPP.


Assuntos
Retardadores de Chama/toxicidade , Hepatócitos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Organofosfatos/toxicidade , Animais , Linhagem Celular , Hepatócitos/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/fisiologia , Espécies Reativas de Oxigênio/metabolismo
17.
Ecotoxicol Environ Saf ; 221: 112423, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34146985

RESUMO

Tetrabromodiphenyl ether (BDE-47) is widely used as commercial flame retardants that can be released into the environment and finally enter human body through the food chain. It has been identified to generate neurotoxicity, but little is known about auditory damage and the underlying mechanism following BDE-47 exposure. This study aimed to assess the cell viability with BDE-47 concentration ranging from 0 to 150 µM in mouse organ of Corti-derived cell lines (HEI-OC1). Aryl hydrocarbon receptor (AhR) as an environmental sensor, reactive oxygen species (ROS), NLRP3 inflammasome and p38 MAPK pathways were detected. Results: (1) BDE-47 inhibited the viability in a time- and dose-dependent way in HEI-OC1 cells. Cell cycle was arrested in G1 phase by BDE-47; (2) Elevated intracellular ROS, LDH levels and necrosis were found, which was alleviated by pretreatment with ROS scavenger N-acetylcysteine (NAC); (3) AhR plays an essential role in ligand-regulated transcription factor activation by exogenous environmental compounds. We found increased expression of AhR and decreased downstream targets of CYP 1A1 and CYP 1B1 in BDE-47-treated HEI-OC1 cells, which was reversed by the AhR antagonist CH-223191 for 2 h before BDE-47 exposure. No significant change was detected in CYP 2B; (4) Enhanced expressions of NLRP3 and caspase-1 were induced by BDE-47, with up-regulations of both pro-inflammatory factors for IL-1ß, IL-6 and TNF-α, and anti-inflammatory factors for IL-4, IL-10 and IL-13, but down-regulation for IL-1α; (5) Additionally, the p38 MAPK signaling pathway was activated with increased phosphorylation levels of MKK/3/6, p38 MAPK and NF-kB. Overall, our findings illustrate a role of AhR in ROS-induced necrosis of cochlear hair cells by BDE-47 exposure, in which NLRP3 inflammasome and p38 MAPK signaling pathways are activated. The current study first elucidates the sense of hearing damage induced by BDE-47, and cell-specific or mixture exposures in vivo or human studies are needed to confirm this association.


Assuntos
Retardadores de Chama/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Inflamassomos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Necrose/induzido quimicamente , Necrose/metabolismo , Necrose/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065337

RESUMO

Organophosphate flame retardants (OPFRs) are substances added to plastics, textiles, and furniture, and are used as alternatives to brominated flame retardants. As the use of OPFRs increases in the manufacturing industry, the concentration in the aquatic environment is also increasing. In this study, OPFRs introduced into a wastewater treatment plant (WWTP) were identified, and the toxicity of biotransformation molecules generated by the biological reaction was predicted. Tris(2-butoxyethyl) phosphate, tris(2-butoxyethyl) phosphate, and triphenyl phosphate were selected as research analytes. Chemicals were analyzed using high-resolution mass spectrometry, and toxicity was predicted according to the structure. As a result, tris(1-chloro-2-propyl) phosphate showed the highest concentration, and the removal rate of OPFRs in the WWTP was 0-57%. A total of 15 biotransformation products were produced by microorganisms in the WWTP. Most of the biotransformation products were predicted to be less toxic than the parent compound, but some were highly toxic. These biotransformation products, as well as OPFRs, could flow into the water from the WWTP and affect the aquatic ecosystem.


Assuntos
Biotransformação/fisiologia , Retardadores de Chama/toxicidade , Organofosfatos/química , Organofosfatos/toxicidade , Águas Residuárias/análise , Águas Residuárias/química , Ecossistema , Espectrometria de Massas/métodos , Compostos Organofosforados/química , Compostos Organofosforados/toxicidade , Purificação da Água/métodos
19.
Environ Pollut ; 285: 117471, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34082372

RESUMO

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP), an alternative to brominated flame retardants, might pose an exposure risk to humans and wild animals during fetal development. Our recent study suggested that short-term TDCIPP exposure during early development caused sex-dependent behavioral alteration in adults. In the present study, multigenerational neurodevelopmental toxicity upon early-life exposure of parental zebrafish was evaluated, and the possible underlying mechanisms were further explored. Specifically, after embryonic exposure (0-10 days post-fertilization, dpf) to TDCIPP (0, 0.01, 0.10, and 1.00 µM), zebrafish larvae were cultured in clean water until the sexually matured to produce progeny (F1). The results confirmed neurodevelopmental toxicity in F1 larvae characterized by changes of developmental endpoints, reduced thigmotaxis, as well as altered transcription of genes including myelin basic protein a (mbpa), growth associated protein (gap43) and synapsin IIa (syn2a). Sex-specific changes in thyroid hormones (THs) indicated the relationship of abnormal THs levels with previously reported neurotoxicity in adult females after early-life exposure to TDCIPP. Similar changing profiles of TH levels (increased T3 and decreased T4) in adult females and F1 eggs, but not in F1 larvae, suggested that the TH disruptions were primarily inherited from the maternal fish. Further results demonstrated hypermethylation of global DNA and key genes related to TH transport including transthyretin (ttr) and solute carrier family 16 member 2 (slc16a2), which might affect the transport of THs to target tissues, thus at least partially contributing to the neurodevelopmental toxicity in F1 larvae. Overall, our results confirmed that early-life TDCIPP exposure of parental fish could affect the early neurodevelopment of F1 offspring. The underlying mechanism could involve altered TH levels inherited from maternal zebrafish and epigenetic modifications in F1 larvae.


Assuntos
Retardadores de Chama , Simportadores , Poluentes Químicos da Água , Animais , Epigênese Genética , Feminino , Retardadores de Chama/toxicidade , Humanos , Larva/metabolismo , Masculino , Transportadores de Ácidos Monocarboxílicos , Compostos Organofosforados , Fosfatos/metabolismo , Hormônios Tireóideos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
20.
Environ Pollut ; 285: 117475, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087639

RESUMO

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.


Assuntos
Disruptores Endócrinos , Retardadores de Chama , Hidrocarbonetos Bromados , Bifenil Polibromatos , Animais , Poeira/análise , Retardadores de Chama/análise , Retardadores de Chama/toxicidade , Humanos , Hidrocarbonetos Bromados/análise , Hidrocarbonetos Bromados/toxicidade , Bifenil Polibromatos/análise , Solo
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