Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish.

Chunsheng Liu,Jianghua Wang,Robert J Letcher,Guanyong Su,Liqin Yu,Ira Agrawal,Jing Li,John P Giesy,Guangyu Li,Zhiyuan Gong

doi:10.1038/srep19045

Abstract

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.

Highlights

Like PBDEs, TDCIPP is not chemically bonded to the related products and it is released to the environment [2]
Injection of TDCIPP to chicken eggs has resulted in a significant accumulation of TDCIPP in the liver and changes of expression of hepatic genes related to xenobiotic metabolism, thyroid hormone pathway and immune responses[22,23]
To analyse transcriptomic responses in the liver following acute TDCIPP exposure, four RNA libraries were constructed for RNA-Seq: two replicates from the TDCIPP treatment group (1 mg/L, 4 days) and two replicates from the 0.01% dimethyl sulfoxide (DMSO) vehicle treatment group

Summary

Introduction

Like PBDEs, TDCIPP is not chemically bonded to the related products and it is released to the environment [2]. Exposure to TDCIPP in primary cultured avian hepatocytes causes cytotoxicity with deregulation of genes involved in phase I and II metabolism, thyroid hormone pathway, lipid regulation and growth[21]. Injection of TDCIPP to chicken eggs has resulted in a significant accumulation of TDCIPP in the liver and changes of expression of hepatic genes related to xenobiotic metabolism, thyroid hormone pathway and immune responses[22,23]. These studies suggest that liver is a target for TDCIPP exposure, to support reliable risk assessment, underlying molecular mechanisms for hepatotoxicity need to be further explored. The hepatotoxicity of TDCIPP was further characterized by measuring the expression of biomarker genes for hepatotoxicity and the change of liver histology and morphology

Methods

Results

Conclusion