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Gene expression of normal human epidermal keratinocytes modulated by trivalent arsenicals
Author(s) -
Bailey Kathryn A.,
Hester Susan D.,
Knapp Geremy W.,
Owen Russell D.,
Thai SheauFung
Publication year - 2010
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20677
Subject(s) - carcinogen , biology , carcinogenesis , gene expression , gene , keratinocyte , toxicity , proinflammatory cytokine , human skin , arsenic , microbiology and biotechnology , cancer research , biochemistry , genetics , cell culture , chemistry , immunology , medicine , inflammation , organic chemistry
Chronic exposure to inorganic arsenic (iAs) is associated with the development of benign and malignant human skin lesions including nonmelanoma skin cancers. The precise arsenical form(s) responsible for this carcinogenic effect are unknown, although trivalent inorganic arsenic (iAs III ) and two of its toxic metabolites, monomethylarsonous acid (MMA III ) and methylarsinous acid (DMA III ), are attractive candidates. In an effort to better understand and compare their toxic effects in the skin, we compared the global gene expression profiles of normal human epidermal keratinocytes (NHEKs) exposed to varying noncytotoxic/slightly cytotoxic concentrations of iAs III , MMA III , and DMA III for 24 h. Exposure to each arsenical treatment group exhibited a dose effect in the number of altered genes and the magnitude of expression change in NHEKs. The most significant gene expression changes associated with iAs III and MMA III exposure were consistent with several key events believed to be important to As‐driven skin carcinogenesis, namely induction of oxidative stress, increased transcript levels of keratinocyte growth factors, and modulation of MAPK and NF‐κB pathways. At both comparable arsenical concentrations and comparable NHEK toxicity, greater potential carcinogenic effects were observed in MMA III ‐exposed NHEKs than those exposed to iAs III , including involvement of more proinflammatory signals and increased transcript levels of more growth factor genes. In contrast, none of these above‐mentioned transcriptional trends were among the most significantly altered functions in the DMA III treatment group. This study suggests the relative capacity of each of the tested arsenicals to drive suspected key events in As‐mediated skin carcinogenesis is MMA III > iAs III with little contribution from DMA III . © 2010 Wiley‐Liss, Inc.