RESUMO
Decabromodiphenyl ether (BDE-209) and Sodium nitrite (SN) coexist in the processing meat and fish foods, but there is no research considering them together. The present study aimed to investigate the binary mixture's toxicity of BDE-209 and SN and explore the protective effect of hesperidin (Hsp) on the combined toxicity. Results showed that compared with the impact of BDE-209 or SN alone, the binary mixture had a synergistic toxic effect on impairing the viability of HepG2 cells, accompanied by oxidative stress, Ca2+ accumulation, mitochondrial dysfunction. The increase of γ-H2AX fluorescent foci and micronuclei number also indicated its genotoxicity. Pretreatment of Hsp could significantly alleviate the above damage caused by the binary combination. These findings revealed the toxicological interaction of BDE-209 and SN and highlighted that food containing abundant natural flavonoids, as hesperidin, could reduce this toxicological risk.
Assuntos
Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Hesperidina/farmacologia , Nitrito de Sódio/toxicidade , Cálcio/metabolismo , Sinergismo Farmacológico , Retardadores de Chama/administração & dosagem , Éteres Difenil Halogenados/administração & dosagem , Células Hep G2 , Humanos , Técnicas In Vitro , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Testes de Mutagenicidade , Estresse Oxidativo/efeitos dos fármacos , Nitrito de Sódio/administração & dosagemRESUMO
4-Bromodiphenyl ether (BDE3) is a photodegradation product of higher polybrominated diphenyl ether flame retardants and is known as an endocrine disruptor. However, it is unclear whether and how BDE3 affects the development of fetal testes. This study aimed to investigate the effect of in utero exposure to BDE3 on fetal testicular development in rats. From gestational day (GD) 12-21, BDE3 (0, 50, 100, and 200 mg/kg) was daily gavaged to female pregnant Sprague Dawley rats. BDE3 significantly reduced serum testosterone levels of male pups starting at 50 mg/kg. BDE3 reduced fetal Leydig cell number at a dose of 200 mg/kg without affecting fetal Leydig cell cluster frequency and Sertoli cell number. In addition, BDE3 down-regulated the expression of fetal Leydig cell genes (Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3) and their proteins at 100 and/or 200 mg/kg. RNA-seq analysis showed that genes responsive to cAMP (Ass1, Gpd1, Rpl13a) were down-regulated and hypoxia-related genes (Egln3 and P4ha1) were up-regulated at 200 mg/kg. In utero exposure to BDE3 can promote autophagy and apoptosis of fetal Leydig cells via increasing the levels of Beclin1, LC3-II, BAX, and by decreasing the levels of p62 and BCL2. In conclusion, in utero exposure to BDE3 blocks the development of fetal rat testes.
Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Testículo/efeitos dos fármacos , Testículo/embriologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Feto/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Éteres Difenil Halogenados/administração & dosagem , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , TranscriptomaRESUMO
Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants, commonly used as flame retardants in a wide variety of products. In the last years, the concentration of PBDEs is increasing in the environment, turning human exposure more common. Since the diet is the primary source of human exposure, several surveys evaluate the levels of PBDEs in foods to estimate the dietary intake and the hazard index (HI). However, this data is limited in Brazil. Thus, this study aims to determine the level of seven PBDE congeners (BDE-28, 47, 99, 100, 153, 154, 183) in Brazilian food of animal origin. The total concentration of PBDE (∑PBDE) determined in the food samples were 2.29 (0.92-4.85) ng/g wet weight (ww), 1.98 (1.23-3.12) ng/g ww, 1.91 (1.23-3.12) ng/g ww, and 4.42 (1.26-8.42) ng/g ww in eggs, fish, seafood, and milk, respectively. BDE-47 was the most abundant compound. Based on consumer habits and the found levels of PBDEs in Brazilian food, we estimated the daily intake of ∑PBDEs as 3.25 (0.02-2.19) ng/kg bw per day. Surprisingly, the PBDE levels in milk samples were higher than those found in reported studies in other countries, and the consumption of milk products give a higher relative contribution to PBDEs exposure. The HI was <1. A complete risk assessment of the human exposure to PBDEs most likely could be evaluated considering all commercial PBDEs congeners and other exposure sources of these contaminants.
Assuntos
Ovos/análise , Poluentes Ambientais/toxicidade , Éteres Difenil Halogenados/toxicidade , Leite/química , Alimentos Marinhos/análise , Animais , Brasil , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/química , Peixes , Análise de Alimentos , Contaminação de Alimentos , Éteres Difenil Halogenados/administração & dosagem , Éteres Difenil Halogenados/química , HumanosRESUMO
As a typical persistent organic pollutant, decabromodiphenyl ether (BDE-209) is associated with various health risks, especially on immune system, which is sensitive to environmental pollutants. In addition, there is a problem of multi-index estimation and lack of comprehensive evaluation in immune toxicity study. In this study, the immunotoxicity of BDE-209 was systematically estimated from the aspects of immunopathology, humoral immunity, cellular immunity and non-specific immunity, etc., and integrated biomarker responses (IBR) combined with principal component analysis was applied to comprehensively evaluate the immunotoxicity of BDE-209 and its self-recovery after discontinuation. Results showed that BDE-209 exposure could cause immunotoxicity. This response seems to depend on (1) atrophying immune organs (thymus and spleen), hepatomegaly accompanied by increasing aspartate aminotransferase and oxidative stress;(2) changing humoral (immunoglobulins) and cellular (lymphocyte proliferation and cytokine secretion) immunity indices; (3) altering related expressions of genes, and further leading to imbalance of Th1/Th2 (Th, helper T cell). Integrated biomarker responses (IBR) companied with principal component analysis selected five biomarkers (mRNA expression of GATA-3, malondialdehyde level in thymus, count of white blood cell, serum IgG and lipopolysaccharide-induced splenic lymphocyte proliferation) to clarify the immunotoxicity induced by BDE-209. Furthermore, IBR combined with factorial analysis revealed that the effect of BDE-209 could be dose-dependently reduced after withdrawal of BDE-209. Overall results suggested that BDE-209 has immunotoxicity on adult Balb/c mice, whereas this immunotoxicity could be reduced by the self-regulation of organisms to some extent.
Assuntos
Éteres Difenil Halogenados/toxicidade , Imunidade Humoral/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Baço/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/metabolismo , Esquema de Medicação , Contagem de Eritrócitos , Feminino , Retardadores de Chama/administração & dosagem , Retardadores de Chama/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Éteres Difenil Halogenados/administração & dosagem , Imunoglobulinas/metabolismo , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Baço/metabolismoRESUMO
2,2',4,4'-Tetrabromodiphenyl ether (BDE47), a flame retardant, is extensively distributed in the food chain. However, whether BDE47 affects Leydig cell development during prepuberty remains unclear. BDE47 was daily gavaged to 21-day-old Sprague-Dawley male rats with 0 (corn oil), 0.1, 0.2, and 0.4 mg/kg for 14 days. BDE47 did not affect the body weight or testis weight of rats. It significantly increased serum testosterone level at 0.4 mg/kg, but decreased luteinizing hormone (LH) level without affecting estradiol level. BDE47 induced Leydig cell hyperplasia (the number of CYP11A1-positive Leydig cells increased), and up-regulated the expression of Scarb1, Star, Hsd11b1, Pcna, and Ccnd1 in the testis. BDE47 significantly reduced p53 and p21 levels but increased CCND1 level. It also markedly increased the phosphorylation of AKT1, AKT2, ERK1/2, and CREB. BDE47 significantly up-regulated the expression of Scarb1, Star, and Hsd11b1 and stimulated androgen production by immature Leydig cells from rats under basal, LH, and 8Br-cAMP stimulated conditions at 100 nM in vitro. In conclusion, BDE47 increased Leydig cell number and up-regulated the expression of Scarb1 and Star, thereby leading to increased testosterone synthesis.
Assuntos
Éteres Difenil Halogenados/toxicidade , Células Intersticiais do Testículo/fisiologia , Maturidade Sexual/fisiologia , Células-Tronco/efeitos dos fármacos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Células Cultivadas , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Relação Dose-Resposta a Droga , Hormônio Foliculoestimulante , Regulação da Expressão Gênica/efeitos dos fármacos , Éteres Difenil Halogenados/administração & dosagem , Éteres Difenil Halogenados/química , Hormônio Luteinizante , Masculino , Estrutura Molecular , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismoRESUMO
Polybrominated diphenyl ethers (PBDEs) were formally used as flame-retardants and are chemically stable, lipophlic persistent organic pollutants which are known to bioaccumulate in humans. Although its toxicities are well characterized, little is known about the changes in transcriptional regulation caused by PBDE exposure. Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of transcriptional and translational processes. It is hypothesized that lncRNAs can regulate nearby protein-coding genes (PCGs) and changes in the transcription of lncRNAs may act in cis to perturb gene expression of its neighboring PCGs. The goals of this study were to 1) characterize PCGs and lncRNAs that are differentially regulated from exposure to PBDEs; 2) identify PCG-lncRNA pairs through genome annotation and predictive binding tools; and 3) determine enriched canonical pathways caused by differentially expressed lncRNA-PCGs pairs. HepaRG cells, which are human-derived hepatic cells that accurately represent gene expression profiles of human liver tissue, were exposed to BDE-47 and BDE-99 at a dose of 25 µM for 24 hours. Differentially expressed lncRNA-PCG pairs were identified through DESeq2 and HOMER; significant canonical pathways were determined through Ingenuity Pathway Analysis (IPA). LncTar was used to predict the binding of 19 lncRNA-PCG pairs with known roles in drug-processing pathways. Genome annotation revealed that the majority of the differentially expressed lncRNAs map to PCG introns. PBDEs regulated overlapping pathways with PXR and CAR such as protein ubiqutination pathway and peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (PPARα-RXRα) activation but also regulate distinctive pathways involved in intermediary metabolism. PBDEs uniquely down-regulated GDP-L-fucose biosynthesis, suggesting its role in modifying important pathways involved in intermediary metabolism such as carbohydrate and lipid metabolism. In conclusion, we provide strong evidence that PBDEs regulate both PCGs and lncRNAs in a PXR/CAR ligand-dependent and independent manner.
Assuntos
Retardadores de Chama/farmacologia , Perfilação da Expressão Gênica/métodos , Éteres Difenil Halogenados/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , RNA Longo não Codificante/metabolismo , Metabolismo dos Carboidratos , Linhagem Celular , Receptor Constitutivo de Androstano , Retardadores de Chama/administração & dosagem , Regulação da Expressão Gênica , Éteres Difenil Halogenados/administração & dosagem , Humanos , Íntrons/genética , Metabolismo dos Lipídeos , PPAR alfa/metabolismo , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptor X Retinoide alfa/metabolismoRESUMO
Flame retardants are detected in the environment worldwide, and thus pose great risks to human health. The potential effects of these chemicals on the development of the central nervous system, have recently raised public concern. In this study, to explore the toxicity of these chemicals during the early developmental stages of the human central nervous system, we induced human embryonic stem cells to differentiate into neural ectoderm in the presence of five halogenated flame retardants, BDE-47, BDE-209, TBBPA, TBBPS and TCBPA, individually or in combination. We identified a set of neural development-related biological processes that responded to these chemicals, by analyzing the whole transcriptional changes. We confirmed the RNA-seq results by qRT-PCR and found that transcription factors crucial for neural development, such as ZIC1, ZIC3, HES3, IGFBP3 and DLX5, were dysregulated by those chemicals. In addition, the five flame retardants might also influence axon growth/guidance and neuron transmission-related processes, by dysregulating genes including CNTN2, SLIT1, LRRC4C, RELN, CBLN1, CHRNB4 and GDF7. Furthermore, the chemical treatments seemed to interfere with the WNT and AHR signaling pathways. Overall, our findings revealed that BDE-209 had similar toxicity as BDE-47, whereas TBBPS and TCBPA might not be safe alternatives to TBBPA. Interestingly, we observed no obvious synergistic effects when we mixed those five flame retardants together.
Assuntos
Clorofenóis/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/toxicidade , Sistema Nervoso/embriologia , Bifenil Polibromatos/toxicidade , Clorofenóis/administração & dosagem , Sinergismo Farmacológico , Retardadores de Chama/administração & dosagem , Imunofluorescência , Éteres Difenil Halogenados/administração & dosagem , Humanos , Sistema Nervoso/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Proteína Reelina , Toxicogenética/métodosRESUMO
Emerging evidence suggests environmental contaminant exposures during critical windows of development may contribute to the increasing prevalence of obesity. It has been shown that early life polybrominated diphenyl ethers exposures have critical impacts on child weight trajectories, however, little is known about their maternal mechanisms responsible for offspring obesity development. In this study, we investigated the effects of perigestational low-dose 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) exposure on maternal metabolome, and its possible link to adult offspring bodyweight changes. Female Sprague-Dawley rats were exposed to daily doses of 0.1, or 1â¯mg/kg BDE-47 from 10 days prior to conception until offspring were weaned on postnatal day 21, and then a gas chromatography-mass spectrometry based metabolomics analysis was used to uncover the global metabolic response in dams. The pups continued to grow into adulthood for measurements of bodyweight. Perigestational BDE-47 exposure caused increased adult bodyweight in male but not in female offspring and dams. Metabolomics revealed significant changes in maternal serum metabolites that clearly distinguish BDE-47 from control rats. These differentially expressed metabolites were primarily implicated in amino acid, lipid, carbohydrate, and energy metabolisms, which was confirmed by pathway analysis. Importantly, most of these identified metabolites were decreased, a state similar to maternal malnutrition that can predispose adult male offspring to weight increase and adiposity in a postnatal environment with abundant calories. Collectively, our data suggest that perigestational exposure to low-dose BDE-47 produces altered maternal serum metabolome, which may be an additional contributing factor to weight gain in adult male offspring.
Assuntos
Peso Corporal/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Exposição Materna/efeitos adversos , Metaboloma/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/toxicidade , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Éteres Difenil Halogenados/administração & dosagem , Lactação , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Aumento de Peso/efeitos dos fármacosRESUMO
Polybrominated diphenyl ethers (PBDEs) are persistent environmental toxicants associated with increased risk for metabolic syndrome. Intermediary metabolism is influenced by the intestinal microbiome. To test the hypothesis that PBDEs reduce host-beneficial intermediary metabolites in an intestinal microbiome-dependent manner, 9-week old male conventional (CV) and germ-free (GF) C57BL/6 mice were orally gavaged once daily with vehicle, BDE-47, or BDE-99 (100 µmol/kg) for 4 days. Intestinal microbiome (16S rDNA sequencing), liver transcriptome (RNA-Seq), and intermediary metabolites in serum, liver, as well as small and large intestinal contents (SIC and LIC; LC-MS) were examined. Changes in intermediary metabolite abundances in serum, liver, and SIC, were observed under basal conditions (CV vs. GF mice) and by PBDE exposure. PBDEs altered the largest number of metabolites in the LIC; most were regulated by PBDEs in GF conditions. Importantly, intestinal microbiome was necessary for PBDE-mediated decreases in branched-chain and aromatic amino acid metabolites, including 3-indolepropionic acid, a tryptophan metabolite recently shown to be protective against inflammation and diabetes. Gene-metabolite networks revealed a positive association between the hepatic glycan synthesis gene α-1,6-mannosyltransferase (Alg12) mRNA and mannose, which are important for protein glycosylation. Glycome changes have been observed in patients with metabolic syndrome. In LIC of CV mice, 23 bacterial taxa were regulated by PBDEs. Correlations of certain taxa with distinct serum metabolites further highlight a modulatory role of the microbiome in mediating PBDE effects. In summary, PBDEs impact intermediary metabolism in an intestinal microbiome-dependent manner, suggesting that dysbiosis may contribute to PBDE-mediated toxicities that include metabolic syndrome.
Assuntos
Disbiose/induzido quimicamente , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Síndrome Metabólica/microbiologia , Administração Oral , Animais , Modelos Animais de Doenças , Disbiose/microbiologia , Poluentes Ambientais/administração & dosagem , Microbioma Gastrointestinal/fisiologia , Vida Livre de Germes , Glicosilação/efeitos dos fármacos , Éteres Difenil Halogenados/administração & dosagem , Humanos , Hidroxilação , Intestino Grosso/metabolismo , Intestino Grosso/microbiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Manose/metabolismo , Manosiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Deca-bromodiphenyl ether (BDE-209) regulates various aspects of spermatogenesis and male fertility through its effect on estrogen receptor α (ERα), but the underlying mechanism remains unclear. Because molecular mechanisms such as remodeling of the blood-testis barrier (BTB) play crucial roles in spermatogenesis, we investigated the disruptive effects of ERα agonists on the BTB in spermatogenesis. In this study, 0, 300, and 500 mg/kg/day of BDE-209 were administered to pregnant adult mice by oral gavage from gestation day 7 to postnatal day 21. SerW3 cells were treated with methylpiperidino pyrazole (MPP) for 30 min before being treated with 50 µg/mL of BDE-209. BDE-209 increases ERα in time- and dose-dependent manners and decreases formin 1 and BTB-associated protein in F1 male mice. Furthermore, BDE-209 impairs the structure and function of the BTB. Activation of ERα signaling could disrupt the BTB, leading to spermatogenesis dysfunction. The results identified the role of ERα in BTB disruption during spermatogenesis and suggested that BTB disruption occurs because of exposure to BDE-209, which could potentially affect spermatogenesis. In conclusion, Sertoli cells seem to be the primary target of BDE-209 in the perinatal period, and this period constitutes a critical window of susceptibility to BDE-209. Also, the SerW3 cell model may not be a particularly useful cell model for studying the function of the cytoskeleton.
Assuntos
Barreira Hematotesticular/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Éteres Difenil Halogenados/toxicidade , Células de Sertoli/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Animais , Barreira Hematotesticular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Proteínas Fetais/metabolismo , Forminas , Éteres Difenil Halogenados/administração & dosagem , Éteres Difenil Halogenados/farmacocinética , Masculino , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/metabolismo , Proteínas Nucleares/metabolismo , Gravidez , Transdução de Sinais/efeitos dos fármacos , Espermatogênese/fisiologia , Testículo/efeitos dos fármacosRESUMO
Decabromodiphenyl ether (BDE-209), a congener of polybrominated diphenyl ethers (PBDEs), is used as flame retardant and affects thyroid homeostasis. Thyroid hormones (THs) play crucial role in Leydig cell differentiation and steroidogenesis during early life. Present study examined the effect of maternal BDE-209 exposure during lactation on testicular steroidogenesis and spermatogenesis in relation to thyroid hormone receptor alpha 1 (THRα1) and possible mechanism(s) of its action in prepubertal Parkes mice offspring. Lactating female Parkes mice were orally gavaged with 500, and 700â¯mg/kg body weight of BDE-209 in corn oil from postnatal day (PND) 1 to PND 28. Lactating mothers and male pups were sacrificed on PND 28. Maternal BDE-209 exposure markedly affected testicular histopathology, steroidogenesis and germ cell dynamics with downregulated expressions of various steroidogenic markers in mice offspring. Serum THs levels were markedly reduced in both pups and lactating mothers compared to controls. Expression of proliferating cell nuclear antigen and THRα1 also deceased in testes of BDE-209-exposed mice offspring. In silico analysis by molecular docking was performed successfully for steroidogenic facor-1 (SF-1) and THRα1 with BDE-209 and T3. Maternal BDE-209 exposure during lactation affects testicular steroidogenesis, spermatogenesis and expression of THRα1 in prepubertal mice offspring through downregulation of SF-1.
Assuntos
Ciclo Celular/efeitos dos fármacos , Hormônios Esteroides Gonadais/biossíntese , Éteres Difenil Halogenados/toxicidade , Lactação , Exposição Materna , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Receptores alfa dos Hormônios Tireóideos/metabolismo , 17-Hidroxiesteroide Desidrogenases/metabolismo , Administração Oral , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Feminino , Éteres Difenil Halogenados/administração & dosagem , Masculino , Camundongos , Simulação de Acoplamento Molecular , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Antígeno Nuclear de Célula em Proliferação/metabolismo , Conformação Proteica , Razão de Masculinidade , Fator Esteroidogênico 1/metabolismo , Testículo/enzimologia , Testículo/metabolismo , Testículo/patologia , Receptores alfa dos Hormônios Tireóideos/químicaRESUMO
BDE-209, a congener of polybrominated diphenyl ethers (PBDEs), is mainly used as flame retardant and accounts for over 82% of total PBDE usage. PBDEs have recently been detected in human milk and cord blood. BDE-209 possesses weak estrogenic/anti-estrogenic properties and evokes hyperglycemia through impaired glucose homeostasis in rat liver. However, little is known of the effect of lactational exposure to BDE-209 on germ cell survival in relation to testicular glucose homeostasis, estradiol and oxidative status during prepubertal period. The present study, therefore, evaluated the effect of maternal exposure to BDE-209 during lactation on above-mentioned parameters with reference to Cx43 and p27Kip1 in prepubertal Parkes (P) mice offspring. Lactating female P mice were orally gavaged with 500, and 700mg/kg body weight of BDE-209 in corn oil from postnatal day (PND) 0 to PND 28; male pups were euthanized at PND 21 and 28. Maternal exposure to BDE-209 during lactation increased germ cell apoptosis with altered expressions of various cell survival and apoptotic markers along with decreased expression of Cx43 and p27Kip1 in prepubertal mice offspring. Testicular glucose and lactate concentrations were markedly reduced in these pups with down-regulation in GLUT3 and GLUT8 expressions and decreased LDH activity. Rise in oxidative stress in testes with increased estrogen level in these pups was also noted. In conclusion, our results suggest that maternal BDE-209 exposure during lactation affects germ cell survival with altered testicular glucose homeostasis and oxidative status through down-regulation of Cx43 and p27Kip1 in prepubertal mice offspring.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Éteres Difenil Halogenados/administração & dosagem , Lactação , Exposição Materna/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Conexina 43/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Relação Dose-Resposta a Droga , Feminino , Retardadores de Chama/administração & dosagem , Retardadores de Chama/toxicidade , Células Germinativas/efeitos dos fármacos , Glucose/metabolismo , Éteres Difenil Halogenados/toxicidade , Ácido Láctico/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Testículo/efeitos dos fármacosRESUMO
Polybrominated diphenyl ethers (PBDEs) are flame retardants generally employed in manufacturing household items. Surface water may remove and carry these chemicals to the drainage upon disposal of the items, and ultimately the chemicals enter our food chain. 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) is a PBDE congener commonly found in contaminated seafood. The placenta is the site of nutrient exchange and is responsible for reproductive hormone secretion during pregnancy. In the present study, pregnant ICR mice were given p.o. daily doses of BDE-47 at 0, 0.36, 3.6, 36 mg/kg for 4 days (from E13.5 to E16.5). Compared to the control group, increased rates of stillborn and low birth weight were observed in mice treated with 36 mg BDE-47/kg. Plasma testosterone and progesterone levels were reduced in mice treated with 36 mg BDE-47/kg. In addition, the group treated with 3.6 mg/kg of BDE-47 displayed decreased growth hormone (Gh) peptide expression in the placental tissue extracted at E17.5. As this peptide stimulates growth, the expression pattern might suggest compromised fetal development. Further analysis indicated that mitogen-activated protein kinases (MAPK) were activated in the placental tissue of the BDE-47-treatment groups. The activation of these signaling molecules might affect the hormonal and other physiological functions in the tissue.
Assuntos
Éteres Difenil Halogenados/farmacologia , Placenta/metabolismo , Animais , Feminino , Éteres Difenil Halogenados/administração & dosagem , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Placenta/efeitos dos fármacos , Gravidez , Complicações na Gravidez/induzido quimicamente , Alimentos Marinhos/efeitos adversos , Poluição da ÁguaRESUMO
The toxicity of decabromodiphenyl ether (BDE-209) has been reported in several studies. However, there is not much known about the toxicological biomarkers that characterize BDE-209 exposure. In this study, we subcutaneously exposed mice to 0.025 mg/kg/day BDE-209 on postnatal days 15 and sacrificed the animals at 12 weeks of age (day 84). Flow injection analysis and hydrophilic interaction chromatography-triple quadrupole mass spectrometry were used to determine the serum metabolomes of these mice in order to characterize the effects of BDE-209 exposure. Data analysis showed a good separation between control and exposed mice (R(2) = 0.953, Q(2) = 0.728, and ANOVA of the crossvalidated residuals (CVANOVA): Pvalue = 0.0317) and 54 metabolites were identified as altered in the exposed animals. These were selected using variable importance (VIP) and loadings scaled by a correlation coefficient criteria and orthogonal partial least squares discriminant analysis (OPLSDA). BDE209exposed mice showed lower levels of long-chain acylcarnitines and citrate cycle-related metabolites, and higher levels of some amino acids, long-chain phospholipids, and short-chain acylcarnitines. The disruption of fatty acid, carbohydrate, and amino acid metabolism observed in the serum metabolome might be related to the previously observed impaired spermatogenesis in mice with early postnatal exposure to a low dose of BDE-209.
Assuntos
Éteres Difenil Halogenados/toxicidade , Metabolômica , Análise de Variância , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Cromatografia de Afinidade , Análise Discriminante , Feminino , Análise de Injeção de Fluxo , Éteres Difenil Halogenados/administração & dosagem , Injeções Subcutâneas , Análise dos Mínimos Quadrados , Masculino , Metabolômica/métodos , Camundongos Endogâmicos ICR , Reprodutibilidade dos Testes , Fatores Sexuais , Espectrometria de Massas em TandemRESUMO
Objective: To study changes in expression of claudin-11 and proteins related to mitogen-activated protein kinase (MAPK) signaling pathways, as well as the ultrastructure of the blood testis barrier (BTB), in male ICR mice exposed to decabromodiphenyl ether (BDE-209). Methods: Fifty-two mice, 4 weeks of age, weighing 15-21 g, were provided with adaptive feeding for 1 week. Mice were randomly divided into 4 groups, named control, low-dose, medium-dose and high-dose groups. The treated groups received BDE-209, by intragastric gavage, at doses, respectively, of 100, 300 and 500 mg/kg. Mice were sacrificed after 6 weeks and organs harvested on ice, weighed and stored at -80 °C. The ultrastructure of testicular tissues was examined by electron microscopy. Western blotting was used to detect proteins related to the MAPK pathway, including p38 mitogen activated protein kinase (p38), phosphorylated p38 (p-p38), extracellular regulated protein kinase 1/2 (ERK1/2) , phosphorylated ERK1/2 (p-ERK1/2) , c-jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK) and the BTB tight junction protein claudin-11. Analyze the difference between each groups. Results: At sacrifice, the body weights in each treated group were compared with those in the control group weighing (41.14 ± 0.60) g. Compared with controls, body weights were significantly different (P<0.05) in the middle dose, at (39.97 ± 0.66) g and high dose, at (39.98± 0.55) g in control group. The coefficients of the testis were significantly lower (P<0.05) in each treated group than in controls, with values of (0.37±0.0)%, (0.31±0.05)% and (0.31±0.04)% for low-dose, medium-dose and high-dose groups, respectively. The epidymus coefficient values were also significantly lower than controls (P<0.05), with values of (0.16±0.06)%, (0.11±0.05)% and (0.07±0.03)%, respectively in the same three dose groups. Electron microscopy ultrastructure showed that, compared with the control group, the testes in the middle and high dose groups had closely connected fractures, cell edema and more vacuoles. Compared with in the control group, levels of p-p38 and p-JNK in testicular tissue were significantly increased (P<0.05). In the control group and in low-, medium- and high-dose groups, the p-p38/p38 ratios were 1.35±0.13, 3.46±0.10, 5.71±0.26 and 4.79±0.21, respectively. The corresponding p-JNK/JNK ratios were 2.07±0.0, 4.77±0.18, 3.63±0.06 and 4.85±0.15. Claudin-11 levels were significantly lower (P<0.05) than control values in each dosed group. The corresponding values in control, low-dose, medium-dose and high-dose groups were 8.33±0.36, 2.06±0.27, 3.37±0.27 and 1.55±0.19, respectively. Conclusion: BDE-209 increased expression of proteins in the MAPK pathway and decreased expression of the BTB tight junction protein claudin-11 in testicular tissue. It also caused ultrastructural damage to the Sertoli cell BTB tight junctions. This suggested that BDE-209 might damage Sertoli cells BTB through effects on the MAPK pathway.
Assuntos
Barreira Hematotesticular/efeitos dos fármacos , Éteres Difenil Halogenados/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Testículo/irrigação sanguínea , Testículo/efeitos dos fármacos , Animais , Éteres Difenil Halogenados/administração & dosagem , Éteres Difenil Halogenados/efeitos adversos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases , Células de Sertoli/efeitos dos fármacos , Testículo/metabolismo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Brominated flame retardants (BFRs) are a large group of different substances used in numerous products to prevent fire hazards. Some of them are persistent in the environment, accumulate in the food chain and are of toxicological concern, while for others current data are limited. Meanwhile, BFRs have been found in many environmental media, foods, and biota including humans. This review presents recent findings obtained from monitoring data in environmental media relevant for human exposure, as well as dietary exposure. In this context, concentrations in indoor and ambient air and in house dust are outlined. Furthermore, we summarize human biomonitoring data on BFR levels in blood and breast milk. Current estimates of the overall exposure of the general population using different relevant subsets are also addressed. All of these data are discussed in relation to currently available toxicological reference values used for risk assessment purposes. Obviously, the exposure of the general population varies considerably in different parts of the world and even within countries. Polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) show the highest intake during infancy. While the highest intake for BDE 47 for all groups was observed in the US, the total BDE 209 and HBCD intake was highest in the UK. For HBCD and all PBDEs except BDE 209, diet accounts for a large proportion of the total intake during infancy in all countries. With regard to toddlers and adults, the contribution of diet to total intake is high in Germany and the UK, while in the US, the high concentrations of PBDE in dust resulted in a notably smaller proportion of the intake being attributed to diet.
Assuntos
Exposição Ambiental/análise , Poluentes Ambientais/análise , Retardadores de Chama/análise , Éteres Difenil Halogenados/administração & dosagem , Hidrocarbonetos Bromados/administração & dosagem , Dieta , Poeira , Incêndios/prevenção & controle , Éteres Difenil Halogenados/sangue , Humanos , Hidrocarbonetos Bromados/sangue , Leite HumanoRESUMO
Tri-decabrominated diphenyl ethers (tri-decaBDEs), isomer-specific hexabromocyclododecanes (HBCDs) and 14 emerging brominated flame retardants (EBFRs) were determined in Swedish market basket samples, two pooled breast milk samples and house dust collected in homes of first-time mothers. Daily dietary and dust intakes were estimated for the mothers and their toddlers and compared to previously reported levels in serum of both the mothers and toddlers and in feces of the toddlers (n=20). Diet was the main contributor for intake of ΣpentaBDE and α-tetrabromoethylcyclohexane (DBE-DBCH) for both mothers and toddlers. For ΣoctaBDE, ΣHBCD and pentabromobenzene (PBBz), dietary intake was more important for mothers while house dust ingestion was more important for toddlers. House dust was the main exposure route for ΣdecaBDE, decabromodiphenyl ethane (DBDPE), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB), bis(2-ethylhexyl)tetrabromophthalate (BEH-TEBP), bis(2,4,6-tribromophenoxy) ethane (BTBPE) and pentabromotoluene (PBT) for both mothers and toddlers. Significant correlations (Spearmans, α<0.05) were found between the mothers' BDE serum concentrations and their consumption of meat and fish while no correlations were found between BFR dietary intake and serum or feces concentrations in toddlers. Octa-decaBDE congener concentrations in serum and feces of toddlers were significantly correlated to those in house dust. BDE-207 and -208 concentrations in serum of mothers were significantly correlated with the nonaBDEs in house dust. The correlations between house dust and internal concentrations and comparison of the house dust and dietary contributions to the estimated daily intakes suggest that dust exposure plays a larger role for the octa-decaBDE body burden in toddlers than in their mothers.
Assuntos
Poeira/análise , Monitoramento Ambiental/estatística & dados numéricos , Retardadores de Chama/análise , Contaminação de Alimentos/análise , Éteres Difenil Halogenados/análise , Carga Corporal (Radioterapia) , Fezes/química , Feminino , Retardadores de Chama/administração & dosagem , Éteres Difenil Halogenados/administração & dosagem , Humanos , Lactente , Mães , SuéciaRESUMO
OBJECTIVES: Octabromodiphenyl ether (OctaBDE) was used as a flame retardant applied mostly in the manufacture of plastics utilized in the electrical and electronic industries. Owing to its long half-life and being regarded as an environmental pollutant, OctaBDE, like other polybrominated diphenyl ethers, has been classified as a persistent organic pollutant (POP). This study was carried out to assess the effects of oxidative stress (redox homeostasis) induced in rats by OctaBDE. MATERIAL AND METHODS: Female Wistar rats exposed intragastrically to OctaBDE at single (25, 200 or 2000 mg/kg b.w.), or repeated (0.4, 2, 8, 40 or 200 mg/kg/day) doses during 7-28 days were used in the experiment. Selected oxidative stress parameters were determined in the liver and blood serum. RESULTS: Administration (single or repeated) of OctaBDE to rats resulted in the impaired redox homeostasis, as evidenced by the increased levels of reduced (GSH) and oxidized (GSSG) glutathione in the liver, the reduced total antioxidant status (TAS) in serum and the increased concentration of malondialdehyde (MDA) in the liver. After multiple doses of OctaBDE, elevated activity of glutathione transferase (GST) in the liver was also noted. CONCLUSIONS: After repeated administration of OctaBDE at the lowest dose (0.4 mg/kg/day), changes were observed in the parameters (MDA, TAS, GSSG) indicative of oxidative stress.
Assuntos
Biomarcadores/análise , Éteres Difenil Halogenados/toxicidade , Estresse Oxidativo , Animais , Feminino , Éteres Difenil Halogenados/administração & dosagem , Ratos , Ratos Wistar , Testes de ToxicidadeRESUMO
Exposure to low doses of neurotoxic pollutants during early brain development is a public health concern. Perinatal exposure to polybrominated diphenyl ethers (PBDEs) has been associated with neurodevelopmental effects in infants and long-term behavioral alterations in rodents. Decabromodiphenyl ether (BDE-209) is extensively used in the industry, with its potential risk to humans still under examination. In a previous study, we found that a single postnatal administration of BDE-209 impaired spatial learning in mice at 12 months of age, but a similar alteration was present in young mice carrying a specific genotype of apolipoprotein E (apoE). On the basis of our results, the main goal of the current investigation was to assess whether the same exposure to BDE-209 would affect the neurodevelopment of apoE transgenic mice. We used a functional observational battery (FOB) to evaluate the physical and neuromotor maturation of transgenic mice carrying different apoE polymorphisms (ε2, ε3, and ε4). On postnatal day 10, BDE-209 was administered orally at 0, 10 and 30 mg/kg and neurodevelopmental screening was carried out until postnatal day 36. We observed a subtle delay in eye opening in mice carrying the apoE4 genotype. Exposure to the high dose of BDE-209 retarded the eye opening of apoE2 mice, but no other developmental features were affected. The results indicate few effects of BDE-209 during development, while the vulnerability conferred by the apoE genotype may vary depending on age. Identifying relevant early gene-environment interactions is fundamental for a better understanding of adult health and disease.
Assuntos
Apolipoproteínas E/genética , Comportamento Animal/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Neurotoxinas/toxicidade , Fatores Etários , Animais , Animais Recém-Nascidos , Feminino , Retardadores de Chama/administração & dosagem , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Neurotoxinas/administração & dosagemRESUMO
Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) at doses of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine (IFN-γ, IL-2 and TNF-α) production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenes expressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.