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.
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Authors | 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 |
Journal | Toxicology letters
(Toxicol Lett)
Vol. 331
Pg. 82-91
(Oct 01 2020)
ISSN: 1879-3169 [Electronic] Netherlands |
PMID | 32461003
(Publication Type: Journal Article)
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Copyright | Copyright © 2020 Elsevier B.V. All rights reserved. |
Chemical References |
- Hif1a protein, rat
- Hypoxia-Inducible Factor 1, alpha Subunit
- Methylmercury Compounds
- RNA, Messenger
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Topics |
- 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, metabolism)
- Methylmercury Compounds
(toxicity)
- Neurons
(drug effects)
- PC12 Cells
- RNA, Messenger
(metabolism)
- Rats
- Signal Transduction
- Up-Regulation
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