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EFFECT OF DIETARY FOLATE DEFICIENCY ON ARSENIC GENOTOXICITY IN MICE
McDorman, E., B W. Collins, AND J W. Allen. EFFECT OF DIETARY FOLATE DEFICIENCY ON ARSENIC GENOTOXICITY IN MICE. Presented at Society of Toxicology Annual Meeting, Philadelphia, PA, March 19-23, 2000.
Arsenic, a human carcinogen found in drinking water supplies throughout the world, is clastogenic in human and rodent cells. An estimated ten percent of Americans are deficient in folate, a methyl donor necessary for normal nucleotide metabolism, DNA synthesis, and DNA methylation. Folate deficiency has been shown to enhance the activity of several mutagens, and may also increase arsenic genotoxicity. We are evaluating induction of micronuclei (MN) in peripheral blood erythrocytes of male C57Bl/6J mice fed folate-deficient (FD; 0 mg/kg diet) or folate-replete (FR; 5 mg/kg) diets for 7 weeks. During week 7, mice on each diet (n = 4 per group) were given 4 consecutive daily doses of sodium arsenite (0, 2.5, 5, or 10 mg/kg in water) or acrylamide (positive control; 50 mg/kg in water) via oral gavage. Kinetochore immunostaining was employed to help distinguish between MN resulting from chromosome breakage and MN resulting from chromosome loss. Statistically significant increases in MN were observed in both FD and FR mice at 5 and 10 mg/kg arsenite in polychromatic erythrocytes (PCEs), but not normochromatic erythrocytes (NCEs). At 10 mg/kg, MN-PCE levels were 4-fold higher than controls (16.1 ? 3.9/1000 vs. 4.1 ? 0.8/1000), while increases in FR mice were less dramatic (5.6 ? 1.3/1000 vs. 3.4 ? 0.7/1000). For all dose groups, MN-NCEs were higher in FD mice than in FR mice. The observed MN were of the negative kinetochore staining type, suggesting that they derived from chromosome breakage rather than whole chromosome loss. Our results indicate that dietary folate deficiency increases arsenic-induced clastogenesis at high doses. Since both arsenic and folate deficiency interfere with DNA repair, dysregulation of this process may contribute to the high MN levels observed.