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FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED GENOTOXICITY IN MICE
Citation:
McDorman, E., B Collins, S. F. Thai, J A. Barnes, J C. Fuscoe, AND J W. Allen. FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED GENOTOXICITY IN MICE. Presented at GEMS fall meeting, RTP, NC, 11/6/2001.
Description:
Folate deficiency increases background levels of DNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary folate deficiency on arsenic induction of micronuclei (MN) in peripheral blood cells. Male C57Bl/6J mice were fed folate-deficient (FD) or folate-sufficient (FS) diets for 7
weeks. During week 7, mice on each diet were given 4 consecutive daily doses of sodium arsenite (0,2.5,5, or 10 mg/kg) or acrylarnide (positive control; 50 mg/kg) via oral gavage. Red blood cell folate levels were reduced by 50% in mice fed the FD diet. Increases in micronucleated polychromatic erythrocyte levels observed were approximately twice as high in FD mice as compared to FS mice at 10 mg/kg. The effect of arsenic in combination with folate deficiency was greater than the sum of the effects of arsenic and folate deficiency alone. No interaction between arsenic exposure and folate deficiency was observed in micronucleated
normochromatic erythrocytes. Very few MN from either control or treated animals revealed kinetochore immunostaining, indicating that MN were derived from chromosome breakage rather than from whole chromosome loss. These MN results indicate that folate deficiency enhances arsenic-induced clastogenesis at high doses. Because arsenic and folate
deficiency both interfere with DNA repair, alterations in repair processes may contribute to the high MN levels observed. Experiments currently underway in this laboratory are investigating the role of imbalanced DNA base excision repair in the increased arsenic-induced clastogenesis observed in FD mice. Levels of apurinic/apyrimidinic sites and DNA
single strand breaks are being measured by probe-slot-blot assays, while changes in the expression of relevant genes are being evaluated by microarray analysis and real-time PCR. (This abstract does not represent EPA policy.)