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  2. Waterborne copper exposure up-regulated lipid deposition through the methylation of GRP78 and PGC1α of grass carp Ctenopharyngodon idella

Waterborne copper exposure up-regulated lipid deposition through the methylation of GRP78 and PGC1α of grass carp Ctenopharyngodon idella

  • Ecotoxicol Environ Saf. 2020 Dec 1;205:111089. doi: 10.1016/j.ecoenv.2020.111089.
Yi-Huan Xu 1 Yi-Chuang Xu 1 Christer Hogstrand 2 Tao Zhao 1 Li-Xiang Wu 1 Mei-Qin Zhuo 1 Zhi Luo 3
Affiliations

Affiliations

  • 1 Laboratory of Molecular Nutrition and Environmental Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China.
  • 2 Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
  • 3 Laboratory of Molecular Nutrition and Environmental Toxicology for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: [email protected].
Abstract

Early molecular events after the exposure of heavy metals, such as aberrant DNA methylation, suggest that DNA methylation was important in regulating physiological processes for Animals and accordingly could be used as environmental biomarkers. In the present study, we found that copper (Cu) exposure increased lipid content and induced the DNA hypermethylation at the whole genome level. Especially, Cu induced hypermethylation of glucose-regulated protein 78 (grp78) and Peroxisome Proliferator-activated Receptor gamma coactivator-1α (pgc1α). CCAAT/enhancer binding protein α (C/EBPα) could bind to the methylated sequence of grp78, whereas C/EBPβ could not bind to the methylated sequence of grp78. These synergistically influenced grp78 expression and increased lipogenesis. In contrast, DNA methylation of PGC1α blocked the specific protein 1 (SP1) binding and interfered mitochondrial function. Moreover, Cu increased Reactive Oxygen Species (ROS) production, activated endoplasmic reticulum (ER) stress and damaged mitochondrial function, and accordingly increased lipid deposition. Notably, we found a new toxicological mechanism for Cu-induced lipid deposition at DNA methylation level. The measurement of DNA methylation facilitated the use of these epigenetic biomarkers for the evaluation of environmental risk.

Keywords

Copper; DNA methylation; ER stress; Lipid metabolism; Mitochondrial dysfunction.

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