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Integration of metabolomics and transcriptomics reveals short-chain chlorinated paraffin-induced hepatotoxicity in male Sprague-Dawley rat

文献类型： 外文期刊

作者： Geng, Ningbo 1 ; Ren, Xiaoqian 1 ; Gong, Yufeng 1 ; Zhang, Haijun 1 ; Wang, Feidi 3 ; Xing, Liguo 4 ; Cao, Rong 1 ; Xu, J 1 ;

作者机构： 1.Chinese Acad Sci, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, Dalian 116023, Liaoning, Peoples R China

2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China

3.Zhejiang Acad Agr Sci, Inst Qual & Stand Agroprod, Hangzhou 310021, Zhejiang, Peoples R China

4.Shenyang Res Inst Chem Ind Ltd, Safety Evaluat Ctr, Shenyang 110021, Liaoning, Peoples R China

5.Univ Saskatchewan, Toxicol Program, Saskatoon, SK, Canada

6.Univ Saskatchewan, Dept Vet Biomed Sci, Saskatoon, SK, Canada

关键词： SCCPs; Transcriptomic; Metabolomic; PPAR alpha; Energy metabolism

期刊名称：ENVIRONMENT INTERNATIONAL （ 影响因子：9.621； 五年影响因子：10.72 ）

ISSN： 0160-4120

年卷期： 2019 年 133 卷

页码：

收录情况： SCI

摘要： Background: Short-chain chlorinated paraffins (SCCPs) used in various industrial applications have been listed as new POPs. Previous studies based on high-dose exposures indicate their hepatotoxicity. However, their mechanisms of toxicity or adverse outcome pathways and health risks remain largely unknown. Objectives: This study aimed to evaluate metabolic consequences of chronic dietary exposure to SCCPs at low doses and reveal the molecular mechanisms underlying hepatotoxicity of SCCPs. Methods: A combination of transcriptomics and metabolomics, together with general pathophysiological tests were performed to assess the hepatic response of male rats exposed to SCCPs. Results: Our results highlight two major modes of action: Inhibition of energy metabolism and activation of the peroxisome proliferator-activated receptor alpha (PPAR alpha). Exposure to SCCPs suppressed oxidative phosphorylation, glycolysis, gluconeogenesis and turnover of ATP-ADP-AMP and thus results in deficiencies of amino acids and nucleotides in liver of the rat. Exposure to SCCPs affected expression levels of 13 genes downstream of PPAR alpha that encode proteins associated with metabolism of fatty acids. As a result, peroxisomal and mitochondrial fatty acid beta-oxidation, microsomal fatty acid omega-oxidation, and lipogenesis were accelerated. Conclusions: Results of this work strongly support the conclusion that low-dose exposure to SCCPs can result in adverse outcomes in the rat model. Significant SCCP-induced inhibition of energy metabolism occurs at environmentally relevant dosages, which suggests that SCCPs exhibit metabolic toxicity. Interactions of SCCPs with PPAR alpha signaling pathway can explain the disruption of lipids and amino acids metabolism.

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