Ningbo Geng1, Xiaoqian Ren2, Yufeng Gong1, Haijun Zhang3, Feidi Wang4, Liguo Xing5, Rong Cao1, Jiazhi Xu1, Yuan Gao1, John P Giesy6, Jiping Chen7. 1. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China. 2. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China; University of Chinese Academy of Sciences, Beijing 100049, China. 3. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China. Electronic address: hjzhang@dicp.ac.cn. 4. Institute of Quality and Standard for Agro-Products, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China. 5. Safety Evaluation Center of Shenyang Research Institute of Chemical Industry Ltd, Shenyang 110021, China. 6. Toxicology Program and Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK, Canada. 7. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China. Electronic address: chenjp@dicp.ac.cn.
Abstract
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 α (PPARα). 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 PPARα that encode proteins associated with metabolism of fatty acids. As a result, peroxisomal and mitochondrial fatty acid β-oxidation, microsomal fatty acid ω-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 PPARα signaling pathway can explain the disruption of lipids and amino acids metabolism.
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 α (PPARα). 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 PPARα that encode proteins associated with metabolism of fatty acids. As a result, peroxisomal and mitochondrial fatty acid β-oxidation, microsomal fatty acid ω-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 PPARα signaling pathway can explain the disruption of lipids and amino acids metabolism.