Abstract

Niacin deficiency in rats decreases bone marrow NAD+, impairing PARP function. Using the micronucleus (MN) assay, this study examined altered dietary niacin status on genomic stability in rats. Weanling male Long-Evans rats were fed niacin deficient (ND), or pair-fed niacin replete (PF) diet for 3 weeks. Bone marrow MN frequency in polychromatic erythrocytes (MN-PCEs) was increased significantly (4.4-fold) by deficiency alone. As the decrease in marrow NAD+ levels was dramatic (80%), the model was extended to include adolescent rats, using 2 diets which cause moderate and mild deficiencies. ND rats with a moderate decrease in marrow NAD+ (55%), showed a significant increase in MN-PCE (1.9-fold). However, ND rats with a mild decrease in NAD+ (25%) did not have a significantly enhanced MN-PCE frequency (1.2-fold). These experiments have identified the range of marrow NAD+ levels that lead to this type of genomic instability. To further characterize the interaction between niacin status and MN formation, ethylnitrosourea (ENU) treatment (30 mg/kg) was used to induce DNA damage. ND, in the weanling model, caused a dramatic increase (3.6-fold) in ENU-induced MN-PCEs (likely clastogenic in nature). This study emphasizes the importance of niacin in the maintenance of genomic stability in rats. We are working on identification of aneugenic versus clastogenic MN to help define the mechanisms by which ND increases genomic instability. Other data from our laboratory using comet analysis suggests that clastogenicity will not account for the large increase in genomic instability due to ND alone.

Keywords: niacin deficiency, NAD+, ethylnitrosourea (ENU), micronuclei (MN)