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Toxicological Sciences 65, 211-219 (2002)
Copyright © 2002 by the Society of Toxicology

MOLECULAR AND GENETIC TOXICOLOGY

Sodium Arsenite Inhibits and Reverses Expression of Adipogenic and Fat Cell-Specific Genes during in Vitro Adipogenesis

Eric M. Wauson, Amy S. Langan and Roseann L. Vorce,1

Center for Environmental Toxicology and Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6260

Arsenic causes cancer in humans, but its mechanism of action is unique among known carcinogenic agents. As a naturally occurring component of sediments and ground water, human exposure to arsenic is inevitable, necessitating the establishment of exposure limits. Because cancer is characterized as an imbalance between cell growth and differentiation, it has been hypothesized that arsenic exerts its carcinogenic effect, in part, by perturbing the balance between these antagonistic processes. Previous work in this laboratory has demonstrated that sodium arsenite prevents adipocytic differentiation of C3H 10T1/2 cells, leading to the hypothesis that the underlying mechanism involves downregulation of genes associated with adipogenesis. In support of this hypothesis, it was found that mRNA levels of peroxisome proliferative-activated receptor {gamma} (PPAR{gamma}), CCAAT-enhancer binding protein {alpha} (C/EBP{alpha}), and adipocyte-selective, fatty acid-binding protein (aP2) are decreased in arsenic-treated cells; arsenic-induced phenotypic reversion of differentiated adipocytes correlates with reduced aP2 expression. Arsenic also blocks upregulation of p21Cip1/Waf1, a factor whose expression is tightly regulated during adipogenesis. The differentiating effect of pioglitazone, which induces adipogenesis by activating PPAR{gamma}, is inhibited by arsenic, suggesting that arsenic interferes with adipogenic signaling at or below the level of PPAR{gamma}. Because C/EBP{alpha} is important in the expression of certain keratinocyte-specific genes, the negative effect of arsenic on C/EBP{alpha} might also contribute to the development of skin cancer. PPAR{gamma}, C/EBP{alpha}, and p21Cip1/Waf1 are important in numerous normal and pathological processes, including carcinogenesis, leading us to postulate that perturbation of these factors by arsenic might contribute to the carcinogenic effect of this metalloid.

Key Words: arsenic; differentiation; proliferation; cancer; adipocytes; adipogenesis; aP-2; PPAR{gamma}, C/EBP{alpha}, p21Cip1/Waf1.


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