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Arsenic-induced gene expression in urinary bladder epithelium.
Simeonova PP; Wang S; Hulderman T; Luster MI
Toxicologist 2001 Mar; 60(1):204
Occupational and environmental exposure to arsenic has been related by epidemiological studies to development of skin and urinary bladder cancer. Although the mechanisms of arsenic carcinogenesis have not been defined, increasing evidence indicates the role of epigenetic mechanisms, including modulation of signaling pathways of cell growth. We demonstrated that arsenic exposure is associated with tissue accumulation of inorganic, and to lesser extent dimethylarsenicacid, as well as a persistent increase in DNA binding of the activating protein (AP)-1 transcription factor. The arsenic accumulation in urinary bladder tissue and AP-1 activation demonstrated dose-dependence and strong correlation. That was supported also by recovery studies. Arsenic levels as well as AP-1 binding started to decrease significantly after 8 weeks of recovery period. Consistent with the in vivo data, arsenic induced sustained MAP kinase and AP-1 activation in uroepithelial cell line. Arsenic-triggered epidermal growth factor receptor phosphorylation was involved but it was not initiation event of MAP kinase cascade. Gene expression studies using cDNA microarays, RNase protection assay, and reverse transcription - PCR indicated that arsenic alters the expression of a number of genes associated with cell growth, such as c-fos, c-jun, and EGR-l, as well as cell arrest, such as GADD153 and GADD45. Arsenic - induced gene expression might contribute to carcinogenesis in urinary bladder by dysregulation of the cell cycle events.
Occupational-exposure; Environmental-exposure; Genes; Arsenic-compounds; Cancer; Carcinogenesis; Bladder-disorders; Epidemiology; Bladder-cancer; Skin-cancer; Cell-growth; In-vivo-studies
Issue of Publication
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California
Page last reviewed: September 2, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division