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Arch Toxicol ; 94(2): 541-552, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894355


Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a phosphorus-based flame retardant common in consumer goods and baby products. Concerns have been raised about TDCPP exposure and neurodevelopmental toxicity. However, the mechanism and early response for TDCPP-induced neurotoxicity are poorly understood. This study investigates the role of microglia-mediated neuroinflammation in TDCPP-induced neurotoxicity in mice and primary cells. TDCPP was administered to C57BL/6 pups (0, 5, or 50 mg/kg/day) via an oral gavage from postnatal days 10-38 (28 days). The results showed that TDCPP exposure for 28 days altered the gene expression of neuronal markers Tubb3, Nefh, and Nes, and led to apoptosis in the hippocampus. The mRNA levels of pro-inflammatory factors Il-1ß, Tnfα and Ccl2 dose dependently increased in the hippocampus at both 24 h and 28 days following exposure, accompanied by microglia activation characterized by an amoeboid-like phenotype. In in vitro studies using the primary microglia isolated from neonatal mice, exposure to TDCPP (0-100 µM) for 24 h resulted in cellular activation. It also increased the expression of genes responsible for inflammatory responses including surface markers and pro-inflammatory cytokines. These changes occurred in a dose-dependent fashion. Neurite outgrowth of primary mouse hippocampal neurons was inhibited by treatment with the conditioned medium harvested from microglia exposed to TDCPP. These results reveal that neonatal exposure to TDCPP induces neuronal damage through microglia-mediated inflammation. This provides insight into the mechanism of TDCPP's neurodevelopmental toxicity, and suggests that microglial cell is a sensitive responder for OPFRs exposure.

Aquat Toxicol ; 214: 105224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255847


Polybrominated diphenyl ethers (PBDEs) are distributed throughout the environment. Despite a moratorium on their use, concentrations of PBDEs in the atmosphere and in residential environments remain high due to their persistence. The environmental health risks remain concerning and one of the major adverse effects is neurodevelopmental toxicity. However, the early response and effects of PBDEs exposure on the developing brain remain unknown. In the present study, we investigated the impacts of 2,2',4,4',5-pentabrominated diphenyl ether (BDE-99) on vascular growth and vascular barrier function with an emphasis on cerebral blood vessels, in the early life stages, using a zebrafish model. No general toxicity was observed in exposing zebrafish larvae to 0-0.5 µM BDE-99 at 72 hpf. BDE-99 exposure resulted in neither general toxicity nor pronounced developmental impairment in somatic blood vessels, including intersegmental vessels (ISV) and common cardinal veins (CCV). Meanwhile, both 0.05 µM and 0.5 µM of BDE-99 reduced cerebrovascular density as well as down-regulation of VEGFA and VEGFR2 in the head. In addition, BDE-99 exposure increased vascular leakage, both in cerebral and truncal vasculature at 72 hpf. The accentuated vascular permeability was observed in the head. The mRNA levels of genes encoding tight junction molecules decreased in the BDE-99-exposed larvae, and more robust reductions in Cldn5, Zo1 and Jam were detected in the head than in the trunk. Moreover, proinflammatory factors including TNF-α, IL-1ß and ICAM-1 were induced, and the expression of neurodevelopment-related genes was suppressed in the head following BDE-99 exposure. Taken together, these results reveal that developmental exposure to BDE-99 impedes cerebrovascular growth and disturbs vascular barrier formation. The cerebral vasculature in developing zebrafish, a more sensitive target for BDE-99, may be a promising tool for the assessment of the early neurodevelopmental effects due to PBDEs exposure.

Vasos Sanguíneos/efeitos dos fármacos , Exposição Ambiental , Éteres Difenil Halogenados/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Encéfalo/irrigação sanguínea , Encéfalo/crescimento & desenvolvimento , Permeabilidade Capilar/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inflamação/genética , Inflamação/patologia , Larva/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética
Environ Pollut ; 247: 293-301, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30685670


The growing production and extensive use of organophosphate flame retardants (OPFRs) have led to an increase in their environmental distribution and human exposure. Developmental toxicity is a major concern of OPFRs' adverse health effects. However, the impact of OPFRs exposure on vascular development and the toxicity pathway for developmental defects are poorly understood. In this study, we investigated the effects of exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a frequently detected OPFR, on early vascular development, and the possible role of nuclear factor erythroid 2-related factor (Nrf2)-dependent angiogenic pathway in TDCPP's vascular toxicity. TDCPP exposure at 300 and 500 µg/L impeded the growth of intersegmental vessels (ISV), a type of microvessels, as early as 30 hpf. Consistently, a similar pattern of decreased extension and remodeling of common cardinal vein (CCV), a typical macrovessel, was observed in zebrafish at 48 hpf and 72 hpf. Developing vasculature in zebrafish was more sensitive than general developmental parameters to TDCPP exposure. The expression of genes related to VEGF signaling pathway dose-dependently decreased in TDCPP-treated larvae. In in vitro experiments using human umbilical vein endothelial cells (HUVECs), the increased cell proliferation induced by VEGF was suppressed by TDCPP exposure in a dose-dependent fashion. In addition, we found a repression of Nrf2 expression and activity in TDCPP-treated larvae and HUVECs. Strikingly, the application of CDDO-Im, a potent Nrf2 activator, enhanced VEGF and protected against defective vascular development in zebrafish. Our results reveal that vascular impairment is a sensitive index for early exposure to TDCPP, which could be considered in the environmental risk assessment of OPFRs. The identification of Nrf2-mediating VEGF pathway provides new insight into the adverse outcome pathway (AOP) of OPFRs.

Retardadores de Chama/toxicidade , Compostos Organofosforados/toxicidade , Fator A de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/fisiologia , Animais , Retardadores de Chama/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Larva/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Organofosfatos/metabolismo , Fosfatos/metabolismo , Peixe-Zebra/metabolismo
Aquat Toxicol ; 203: 19-27, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30071320


Polybrominated diphenyl ethers (PBDEs) are persistent flame retardants ubiquitously existing in various environment matrices. In spite of a recent reduction in use according to the phase-out policy, high levels of PBDEs are still found in both environmental and biological samples due to their persistent property and large-scale production over a long history. Developmental toxicity is a major health concern of PBDEs. However, the impact of PBDE exposure on vascular development remains poorly understood. In this study, we investigated the effect of low concentrations of 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47), a predominant PBDE congener, in environmental matrices and biota, on early vascular development using zebrafish. Zebrafish embryos were continuously exposed to waterborne BDE-47 at 0.06, 0.2, 0.6 µM starting from 2 h post-fertilization (hpf). Fluorescent images of vasculatures in Tg(kdrl:eGFP) zebrafish were acquired using a confocal microscope. The results indicated that BDE-47 exposure had no effect on hatching rate, survival, body weight, body length or heart rate in the early stage within 72 hpf, whereas zebrafish exposed to BDE-47 exhibited impairments in the growth of multiple types of blood vessels. The percentage of completed intersegmental vessels (ISV) at 30 hpf decreased in embryos treated with BDE-47 in a dose-dependent fashion. BDE-47 exposure led to a slight decrease in the growth of common cardinal vein (CCV), while dramatically hindered CCV remodeling process reflected by the larger CCV area and wider ventral diameter. BDE-47 exposure significantly reduced sub-intestinal vessels (SIV) area as well as the vascularized yolk area in zebrafish larvae at 72 hpf. In addition, the expression of genes related to vascular growth and remodeling was markedly suppressed in BDE-47-exposed zebrafish. These findings demonstrate the adverse effects of BDE-47 on early vascular development, and confirm the vascular toxicity of PBDEs in vivo. The results indicate that developing vasculature in zebrafish is sensitive to BDE-47 exposure, and may serve as a powerful tool for the assessment of early exposure to PBDEs.

Vasos Sanguíneos/crescimento & desenvolvimento , Exposição Ambiental/análise , Éteres Difenil Halogenados/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Animais , Animais Geneticamente Modificados , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/embriologia , Peso Corporal/efeitos dos fármacos , Retardadores de Chama/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Larva/efeitos dos fármacos , Testes de Toxicidade , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genética , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/genética