Liu Chunsheng, Su Guanyong, Giesy John P, Letcher Robert J, Li Guangyu, Agrawal Ira, Li Jing, Yu Liqin, Wang Jianghua, Gong Zhiyuan
College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
Collaborative Innovation Center for Efficient and Health Production of Fisheries in Hunan Province.
Sci Rep. 2016 Jan 8;6:19045. doi: 10.1038/srep19045.
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish.
磷酸三（1,3 - 二氯 - 2 - 丙基）酯（TDCIPP）在环境介质中频繁被检测到，并且对野生动物和人类具有不良健康影响。它被认为具有肝毒性，但其分子机制仍不清楚。在本研究中，成年雄性斑马鱼暴露于TDCIPP，并通过RNA测序（RNA-Seq）和逆转录定量聚合酶链反应（RT-qPCR）检测肝脏整体基因表达，以了解TDCIPP诱导肝毒性的分子机制。我们的结果表明，暴露于TDCIPP显著上调了参与内质网应激和Toll样受体（TLR）途径的基因表达，这意味着存在炎症反应，炎症相关生物标志物基因的上调支持了这一点。通过组织学观察浸润中性粒细胞的增加以及直接观察暴露于TDCIPP后的Tg(lysC:DsRed)斑马鱼肝脏中Ds-Red荧光蛋白标记的中性粒细胞募集，进一步证实了肝脏炎症。为了进一步表征TDCIPP的肝毒性，检测了肝毒性生物标志物基因的表达、肝脏组织病理学和形态学。暴露于TDCIPP显著上调了几种肝毒性生物标志物基因（gck、gsr和nqo1）的表达，并导致肝脏空泡化、细胞凋亡以及肝脏大小增加。总体而言，我们的结果表明，暴露于TDCIPP会诱导斑马鱼肝脏炎症并导致肝毒性。
