C. K. TEDAM UNIVERSITY OF TECHNOLOGY AND APPLIED SCIENCES

Differential susceptibility of PC12 and BRL cells and the regulatory role of HIF-1α signaling pathway in response to acute methylmercury exposure under normoxia.

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.