Effect of hepatic methyl donor status on urinary excretion and DNA damage in B6C3F1 mice treated with sodium arsenite.
This study evaluated the effect of hepatic methyl donor status on the ability of sodium arsenite (2.5, 5.0 and 10.0 mg/kg) administered by gavage once or on four consecutive days to induce DNA damage in male B6C3F1 mice. Maintenance on a choline-deficient (CD) diet prior to treatment resulted in mice with hepatic methyl donor deficiency (HMDD) and altered arsenical metabolism, as demonstrated by a decreased total urinary excretion of inorganic and organic arsenicals. The alkaline (pH > 13) Single Cell Gel (SCG) assay was used to evaluate for the induction of DNA damage (single strand breaks, alkali labile sites, DNA crosslinking) in blood leukocytes, liver parenchymal cells, and cells sampled from bladder, lung, and skin, while the bone marrow erythrocyte micronucleus (MN) assay was used to assess for the induction of chromosomal damage in bone marrow cells. Treatment with sodium arsenite once or four times induced a significant decrease in DNA migration (indicative of DNA crosslinking) in bladder and liver parenchymal cells of hepatic methyl donor sufficient (HMDS) mice, but in skin cells of HMDD mice. Both HMDD and HMDS mice exhibited a significant increase in the frequency of micronucleated polychromatic erythrocytes (MN-PCE) in bone marrow following four, but not following one, treatments. However, the positive response occurred at a lower dose for HMDS mice and, in these mice, bone marrow toxicity, as demonstrated by a significant reduction in the percentage of PCE, was present also. These results indicate that hepatic methyl donors deficiency significantly decreases the total urinary excretion of orally administered sodium arsenite and markedly modulates target organ arsenic-induced DNA damage, with an apparent shift from liver and bladder to skin.
Tice
R R
RR
Integrated Laboratory Systems, Research Triangle Park, NC 27709, USA.
Yager
J W
JW
Andrews
P
P
Crecelius
E
E
D000284:Administration, Oral; D000818:Animals; D018053:Arsenites / Q000008:administration & dosage / Q000633:toxicity*; D002796:Choline Deficiency / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D019175:DNA Methylation; D004032:Diet; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D017670:Sodium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D014554:Urination / Q000187:drug effects*
D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite