Abstract

PARP function has been implicated in excision repair and resistance to recombination events. To probe the effect of dietary niacin status on these processes, male Long-Evans rats were fed niacin deficient (ND), or pair fed control (PF) diets for 3 weeks. Bone marrow cells were collected for further analysis at various times after ENU treatment (0–36 hours for comet assay, 0 or 6 hours for chromosomal aberrations (CA)). We have examined repair kinetics by comet assay in the 36 hours following a single dose of ENU (100 mg/kg bw). There was no effect of ND on mean tail moment (MTM) before ENU treatment, or on the development of strand breaks between 0 and 8 hours after ENU. Repair kinetics between 8 and 36 hours were significantly delayed by ND, with a doubling of area under the MTM curve during this period. We also found that ND alone increased CA levels in nucleated bone marrow cells (4-fold), and caused a similar increase in ENU-induced chromatid aberrations. While repair kinetics suggest that ND may be acting by creating catalytically-inactive PARP molecules with a dominant-negative effect on repair processes, the effect of ND alone on CA frequency suggests additional mechanisms are leading to genomic instability. These data support the idea that the bone marrow of niacin deficient cancer patients may be more sensitive to the side effects of genotoxic chemotherapy, resulting in acute bone marrow suppression and chronic development of secondary leukemias.

Keywords: Ethylnitrosourea, chromosomal aberrations, comet, excision repair, recombination