ToxSci Advance Access originally published online on March 10, 2008
Toxicological Sciences 2008 103(2):325-334; doi:10.1093/toxsci/kfn048
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Heme-oxygenase 1 Gene Expression is a Marker for Hexavalent Chromium-Induced Stress and Toxicity in Human Dermal Fibroblasts
Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health (NIOSH), Morgantown, West Virginia
1 To whom correspondence should be addressed at MS 3014, Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505. Fax: (304) 285-5708. E-mail: pjoseph1{at}cdc.gov.
Received November 19, 2007; accepted February 27, 2008
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Abstract |
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Several adverse health effects, including irritant and allergic contact dermatitis, have been reported among workers who are occupationally exposed to chromium-containing compounds. Human dermal fibroblasts were used as an in vitro experimental model to study the potential mechanisms underlying hexavalent chromium [Cr(VI)]–induced dermal toxicity. Exposure of the fibroblasts to 5µM Cr(VI) (LC50 for a 24-h exposure period) followed by microarray analysis of the gene expression profile revealed overexpression of several genes including those involved in cell stress response. The cellular level of glutathione, the major antioxidant molecule present in the cells, was significantly lower in the Cr(VI)-treated cells compared to the corresponding control cells. The Cr(VI)-induced overexpression of heme-oxygenase 1 messenger RNA (HO-1) in the fibroblasts was significantly blocked by actinomycin D and by inhibitors of MAP kinase pathways. The Cr(VI)-induced cytotoxicity and the overexpression of the HO-1 gene were dependent on the glutathione level of the fibroblasts. Buthionine sulfoximine-mediated GSH depletion resulted in enhanced Cr(VI) cytotoxicity and further overexpression of the HO-1 gene. On the other hand, elevated cellular levels of glutathione resulting from pretreating the cells with GSH significantly protected the cells against the Cr(VI)-induced cytotoxicity and blocked the HO-1 gene's overexpression. Pretreating the fibroblasts with N-acetyl cysteine also significantly reduced the Cr(VI)-induced cytotoxicity and overexpression of the HO-1 gene. In conclusion, depletion of GSH leading to cellular stress is a major mechanism responsible for Cr(VI)-induced cytotoxicity. Furthermore, the expression level of HO-1 gene is a marker for Cr(VI)-induced cell stress leading to cytotoxicity.
Key Words: hexavalent chromium; cell stress; glutathione; cytotoxicity; heme-oxygenase 1 gene.
2 Present address: CyDex, Inc., 10513 W. 84th Terrace, Lenexa, KS 66214.
Disclaimer: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the National Institute for Occupational Safety and Health.