Title: Differential susceptibility of PC12 and BRL cells and the regulatory role of HIF-1α signaling pathway in response to acute methylmercury exposure under normoxia.
Authors: Liu, Tingting; Gao, Qianqian; Yang, Bobo; Yin, Changsheng; Chang, Jie; Qian, Hai; Xing, Guangwei; Wang, Suhua; Li, Fang; Zhang, Yubin; Chen, Da; Cai, Jiyang; Shi, Haifeng; Aschner, Michael; Appiah-Kubi, Kwaku; He, Dawei; Lu, Rongzhu
Published In Toxicol Lett, (2020 Oct 01)
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.
PubMed ID: 32461003
MeSH Terms: Animals; Cell Culture Techniques; Cell Hypoxia/drug effects*; Cell Line; Cell Survival/drug effects; Dose-Response Relationship, Drug; Gene Expression Regulation/drug effects*; Hepatocytes/drug effects*; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*; Methylmercury Compounds/toxicity*; Neurons/drug effects*; PC12 Cells; RNA, Messenger/metabolism; Rats; Signal Transduction; Up-Regulation