Effects of acute and chronic arsenic exposure of human-derived keratinocytes in an in vitro human skin equivalent system: A novel model of human arsenicism

W. T. Klimecki, A. H. Borchers, R. E. Egbert, R. B. Nagle, D. E. Carter, G. T. Bowden

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An organotypic culture (OTC) of a human keratinocyte cell line (HaCaT) over a human fibroblast-embedded collagen gel was used to model human epidermis in arsenicism, a syndrome that currently lacks valid experimental models. Keratinocytes were exposed acutely or chronically to a mixture of arsenate (0.5 μM), monomethylarsonic acid (MMA; 0.5 μM) and dimethylarsinic acid (DMA; 1.5 μM), or to the individual components of the mixture. OTCs were assayed for microscopic morphology, the proliferating cell marker, Ki-67, labelling and cytokeratin expression. Acute exposures resulted in an epidermal phenotype that accurately modelled early human lesions, including hyperkeratosis, acanthosis and keratin 16 induction. Chronic exposures resulted in a de-differentiated epidermal phenotype with focal nests of keratinocytes growing into the collagen gel. The keratin 8/18 pair was induced by either acute or chronic arsenic exposure, as was the proliferating cell marker, Ki-67. Exposure of keratinocytes to individual arsenic compounds demonstrated that all arsenic mixture-induced changes could be duplicated by exposure to arsenate alone. In contrast, MMA and DMA were inactive. This study establishes OTC as a useful model of arsenicism, and implicates inorganic arsenic as the ultimate carcinogen.

Original languageEnglish (US)
Pages (from-to)89-98
Number of pages10
JournalToxicology in Vitro
Issue number1-2
StatePublished - Feb 1 1997


ASJC Scopus subject areas

  • Toxicology

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