Sodium arsenite inhibits terminal differentiation of murine C3H 10T1/2 preadipocytes

Cancer represents an imbalance between cell proliferation and differentiation, two processes that are coordinately and antagonistically regulated. Aberrant cell proliferation is considered to be an important etiological factor in the development of arsenic-induced cancer, suggesting that arsenic also dysregulates differentiation. Based on evidence that arsenic modulates mitogenic events that antagonize the process of differentiation, this study addresses the hypothesis that sodium arsenite inhibits insulin/dexamethasone-induced differentiation of C3H 10T1/2 preadipocytes; it was further postulated that arsenic-treated cells retain mitogenic responsiveness under differentiating conditions. To test this hypothesis, the differentiation capacity of C3H 10T1/2 preadipocytes was examined in control cells and cells treated with sodium arsenite. Differentiation was assessed morphologically and quantified by Oil Red-O staining of accumulated lipids. The effect of long-term arsenic exposure on mitogenic competence was quantified by flow cytometry, [(3)H]thymidine incorporation, and cell counting under conditions favorable for adipocyte differentiation. Results indicate that arsenic inhibits morphological differentiation of wild-type C3H 10T1/2 preadipocytes. Short-term arsenic exposure inhibits differentiation in a dose-dependent manner, with arsenic concentrations > or = 3 microM producing a significant inhibition of dexamethasone/insulin-induced lipid accumulation. Furthermore, arsenic-treated cells exhibit an accentuated response to mitogenic stimulation under differentiating conditions. These data suggest that arsenic exposure results in the inhibition of cellular programming required for terminal differentiation of C3H 10T1/2 preadipocytes and that cells acquire mitogenic hyperresponsiveness. The ability of arsenic to dysregulate the balance between proliferation and differentiation is proposed to be one mechanism by which this metalloid causes cancer in humans.