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

Tingting Liu, Qianqian Gao, Bobo Yang, Changsheng Yin, Jie Chang, Hai Qian, Guangwei Xing, Suhua Wang, Fang Li, Yubin Zhang, Da Chen, Jiyang Cai, Haifeng Shi, Michael Aschner, Kwaku Appiah-Kubi, Dawei He, Rongzhu Lu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)82-91
Number of pages10
JournalToxicology Letters
Volume331
DOIs
StatePublished - Oct 1 2020

Keywords

  • BRL
  • Cellular susceptibility
  • Cytoprotection
  • HIF-1α
  • Methylmercury
  • PC12

ASJC Scopus subject areas

  • Toxicology

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