Abstract
Hypoxia-inducible factor 1 (HIF-1) is a critical nuclear transcription factor for adaptation to hypoxia; its regulatable subunit, HIF-1α, is a cytoprotective regulatory factor. We examined the effects of methylmercury (MeHg) in rat adrenal pheochromocytoma (PC12) cells and the rat hepatocyte cell line BRL. MeHg treatment led to time- and concentration-dependent toxicity in both lines with statistically significant cytotoxic effects at 5 μM and 10 μM in PC12 and BRL, respectively, at 0.5 h. HIF-1α protein levels were significantly decreased at 2.5 (PC12) and 5 (BRL) μM MeHg. Furthermore, MeHg reduced the protein levels of HIF-1α and its target genes (glucose transporter-1, vascular endothelial growth factor-A and erythropoietin). Overexpression of HIF-1α significantly attenuated MeHg-induced toxicity in both cell types. Notably, cobalt chloride, a pharmacological inducer of HIF-1α, significantly attenuated MeHg-induced toxicity in BRL but not PC12. In both cell lines, an inhibitor of prolyl hydroxylase, 3, 4-dihydroxybenzoic acid, and the proteasome inhibitor carbobenzoxy-L-leucyl-L-leucyl-L-leucinal(MG132), antagonized MeHg toxicity, while 2-methoxyestradiol, a HIF-1α inhibitor, significantly increased it. These data establish that: (a) neuron-like PC12 cells are more sensitive to MeHg than non-neuronal BRL cells; (b) HIF-1α plays a similar role in MeHg-induced toxicity in both cell lines; and (c) upregulation of HIF-1α offers general cytoprotection against MeHg toxicity in PC12 and BRL cell lines.
Keywords
Methylmercury; HIF-1αPC12BRL; Cytoprotection; Cellular susceptibility
Authors
Tingting Liu
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Qianqian Gao
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Bobo Yang
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Changsheng Yin
Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Jie Chang
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Hai Qian
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Guangwei Xing
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Suhua Wang Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Fang Li
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Yubin Zhang
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Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Shanghai 200032, China
Da Chen
School of Environment, Jinan University, Guangzhou, Guangdong 510632, China
Jiyang Cai
Department of Physiology, College of Medicine, University of Oklahoma Health Science Center, Lindsay, Oklahoma City, OK 73104, USA
Haifeng Shi
Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Michael Aschner
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Kwaku Appiah-Kubi
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Department of Applied Biology, C. K. Tedam University of Technology and Applied Sciences, Navrongo, UK-0215-5321, Ghana
Dawei He
Center for Experimental Research, Kunshan Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215130, China
Rongzhu Lu
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
Center for Experimental Research, Kunshan Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215130, China
Corresponding author at: Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.