Environmentally relevant concentrations of fipronil selectively disrupt venous vessel development in zebrafish embryos/larvae.
Environmentally relevant concentrations of fipronil selectively disrupt venous vessel development in zebrafish embryos/larvae.
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DOI：
10.1016/j.chemosphere.2023.139146
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发表时间：
2023-06
期刊：
影响因子：
8.8
通讯作者：
Ya Ma;Qicheng Zhu;Shili Luo;Fenghong Zhang;Lei Liu;Zhi Mengxue;Zhuyi Zhang;Xiaolian Cao;Xuelin Qiu;Xiangyu Zeng;D. Ji;Chenxin Li;X. Zhong;Jianshe Wang;Yanhong Wei
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作者：
Ya Ma;Qicheng Zhu;Shili Luo;Fenghong Zhang;Lei Liu;Zhi Mengxue;Zhuyi Zhang;Xiaolian Cao;Xuelin Qiu;Xiangyu Zeng;D. Ji;Chenxin Li;X. Zhong;Jianshe Wang;Yanhong Wei
杀虫剂氟虫腈广泛分布在水生环境中，在一般人群中经常被检测到。尽管氟虫腈暴露对胚胎生长的不利影响已被广泛记载，但其发育毒性的早期反应在很大程度上是未知的。在本研究中，我们探索了氟虫腈的敏感靶点，重点关注斑马鱼胚胎/幼虫和培养的人内皮细胞的血管损伤。早期暴露于5 ~ 500 μg/L氟虫腈可抑制肠下静脉丛（SIVP）、尾静脉丛（CVP）和总基数静脉（CCV）的生长。氟虫腈环境相关浓度低至5 μg/L时，静脉血管发生损伤，而一般毒性指标无明显变化。相反，背主动脉（DA）或节间动脉（ISA）的血管发育不受影响。此外，血管标志物和血管类型特异性功能基因的mRNA水平在静脉基因nr2f2、ephb4a和flt4中显著降低，而在动脉基因中没有明显变化。同样，与人主动脉内皮细胞相比，人脐静脉内皮细胞在细胞死亡和细胞骨架破坏方面表现出更明显的变化。此外，分子对接支持氟虫腈及其代谢物对与静脉发育相关的蛋白（如BMPR2和SMARCA4）具有更强的亲和力。这些结果揭示了氟虫腈暴露后血管反应的异质性。对静脉的优先影响赋予了更高的敏感性，使它们成为监测氟虫腈发育毒性的适当目标。
The pesticide fipronil is widely dispersed in aquatic environments and frequently detected in the general population. Although the adverse effects on embryonic growth by fipronil exposure have been extensively documented, the early responses for its developmental toxicity are largely unknown. In the present study, we explored the sensitive targets of fipronil, focusing on vascular injury using zebrafish embryos/larvae and cultured human endothelial cells. Exposure to 5–500 μg/L fipronil at the early stage impeded the growth of sub-intestinal venous plexus (SIVP), caudal vein plexus (CVP), and common cardinal veins (CCV). The damages on venous vessels occurred at exposure to the environmentally relevant concentration as low as 5 μg/L fipronil, whereas no significant change was observed in general toxicity indexes. In contrast, vascular development of the dorsal aorta (DA) or intersegmental artery (ISA) was not affected. In addition, the mRNA levels of vascular markers and vessel type-specific function genes exhibited significant decreases in venous genes, includingnr2f2,ephb4a, andflt4, but no appreciable change in arterial genes. Likewise, the more pronounced changes in cell death and cytoskeleton disruption were shown in human umbilical vein endothelial cells as compared with human aortic endothelial cells. Furthermore, molecular docking supported a stronger affinity of fipronil and its metabolites to the proteins correlated with venous development, such as BMPR2 and SMARCA4. These results reveal the heterogeneity in developing vasculature responsive to fipronil's exposure. The preferential impacts on the veins confer higher sensitivity, allowing them to be appropriate targets for monitoring fipronil's developmental toxicity.