Exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) induces vascular toxicity through Nrf2-VEGF pathway in zebrafish and human umbilical vein endothelial cells.
Exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) induces vascular toxicity through Nrf2-VEGF pathway in zebrafish and human umbilical vein endothelial cells.
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DOI：
10.1016/j.envpol.2018.12.066
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发表时间：
2019-04
影响因子：
8.9
通讯作者：
X. Zhong;Jiahuang Qiu;Jianmeng Kang;X. Xing;Xiongjie Shi;Yanhong Wei
中科院分区：
文献类型：
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作者：
X. Zhong;Jiahuang Qiu;Jianmeng Kang;X. Xing;Xiongjie Shi;Yanhong Wei
有机磷酸酯阻燃剂（OPFR）的生产和广泛使用导致其环境分布和人类暴露增加。发育毒性是OPFR对健康的不良影响的主要问题。然而，OPFRs暴露对血管发育的影响和发育缺陷的毒性途径知之甚少。在这项研究中，我们研究了暴露于三（1，3-二氯-2-丙基）磷酸盐（TDCPP），一种经常检测到的OPFR，对早期血管发育的影响，以及核因子红细胞2相关因子（Nrf 2）依赖性血管生成途径在TDCPP的血管毒性中的可能作用。300和500 μg/L的TDCPP暴露早在30 hpf就阻碍了节间血管（ISV）的生长，这是一种微血管。在48 hpf和72 hpf时，斑马鱼的主静脉（CCV）也出现了类似的扩张和重塑减少的现象。发育中的斑马鱼血管比一般发育参数更敏感TDCPP曝光。TDCPP处理的幼虫中VEGF信号通路相关基因的表达呈剂量依赖性降低。在体外实验中，使用人脐静脉内皮细胞（HUVECs），由VEGF诱导的细胞增殖的增加被TDCPP以剂量依赖的方式抑制。此外，我们发现了抑制Nrf 2的表达和活性在TDCPP处理的幼虫和HUVECs。引人注目的是，应用CDDO-Im，一种有效的Nrf 2激活剂，增强了VEGF并保护斑马鱼免受血管发育缺陷的影响。结果表明，血管损伤是TDCPP早期暴露的敏感指标，可作为OPFR环境风险评价的参考指标。Nrf 2介导的VEGF通路的鉴定为OPFR的不良结局通路（AOP）提供了新的见解。
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. Inin vitroexperiments 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.