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Arsenic induces overexpression of growth factors in human keratinocytes.
Germolec DR; Yoshida T; Gaido K; Wilmer JL; Simeonova PP; Kayama F; Burleson F; Dong W; Lange RW; Luster MI
Toxicol Appl Pharmacol 1996 Nov; 141(1):308-318
The effect of arsenic (7440382) on the expression of growth factors in human keratinocytes was examined. Normal human epidermal keratinocytes (NHEK) were cultured with varying concentrations of sodium-arsenite (7784465). Cultures were also pretreated with granulocyte macrophage colony stimulating factor (GMCSF) and transforming growth factor alpha (TGF alpha) antibodies. RNA extraction, reverse transcriptase polymerase chain reaction (PCR), competitive PCR, a cytokine secretion enzyme linked immunosorbent assay, cell viability tests, and a nuclear runoff assay were conducted. Arsenic added to NHEK cultures increased GMCSF, tumor necrosis factor alpha (TNF alpha), and TGF alpha messenger RNA (mRNA) transcripts within 4 hours. The expression of the c-myc protooncogene was also increased following arsenic exposure, indicating that the increased growth factor secretion accompanied cell proliferation. Significant increases in cell proliferation were observed when 0.001 to 0.005 micromolar (microM) sodium-arsenite were added to NHEK cultures. Following treatment with 4microM sodium- arsenite, the GMCSF mRNA level was elevated to 3.3x10(-3) attomoles. Only sodium-arsenite concentrations above 8microM altered cell viability. Within 18 hours of treatment with noncytotoxic concentrations of sodium-arsenite, dose dependent increases in GMCSF, TNF alpha, and TGF alpha secretion were observed. GMCSF mRNA transcription was increased by threefold following sodium-arsenite treatment. TGF alpha transcription remained unchanged following treatment. Sodium-arsenite treatment resulted in decreased TGF beta2 transcription. In the presence of actinomycin-D, exposure to suggesting that arsenic affected TGF alpha mRNA stabilization. Pretreatment with antiTGF alpha antibodies inhibited the increases in GMCSF mRNA expression and GMCSF protein secretion induced by arsenic. The authors conclude that arsenic may induce carcinogenesis by stimulating growth factors derived from keratinocytes.
NIOSH-Author; Arsenic-compounds; Growth-factors; Mammalian-cells; Ribonucleic-acids; Exposure-levels; Dose-response; Cytotoxins; Antibody-response; Cell-growth; Protein-synthesis
Issue of Publication
Toxicology and Applied Pharmacology
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