Niacin deficiency delays DNA excision repair and increases spontaneous and nitrosourea-induced chromosomal instability in rat bone marrow.
We have shown that niacin deficiency impairs poly(ADP-ribose) formation and enhances sister chromatid exchanges and micronuclei formation in rat bone marrow. We designed the current study to investigate the effects of niacin deficiency on the kinetics of DNA repair following ethylation, and the accumulation of double strand breaks, micronuclei (MN) and chromosomal aberrations (CA). Weanling male Long-Evans rats were fed niacin deficient (ND), or pair fed (PF) control diets for 3 weeks. We examined repair kinetics by comet assay in the 36h following a single dose of ethylnitrosourea (ENU) (30mg/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 8h after ENU. Repair kinetics between 12 and 30h were significantly delayed by ND, with a doubling of area under the MTM curve during this period. O(6)-ethylation of guanine peaked by 1.5h, was largely repaired by 15h, and was also delayed in bone marrow cells from ND rats. ND significantly enhanced double strand break accumulation at 24h after ENU. ND alone increased chromosome and chromatid breaks (four- and two-fold). ND alone caused a large increase in MN, and this was amplified by ENU treatment. 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 O(6)-ethylation, MN and CA, in the absence of altered comet results, suggests additional mechanisms are also leading to chromosomal instability. These data support the idea that the bone marrow cells 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.
Kostecki
Lisa M
LM
Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
Thomas
Megan
M
Linford
Geordie
G
Lizotte
Matthew
M
Toxopeus
Lori
L
Bartleman
Anne-Pascale
AP
Kirkland
James B
JB
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D043171:Chromosomal Instability / Q000187:drug effects / Q000502:physiology*; D002869:Chromosome Aberrations; D020552:Comet Assay; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D005038:Ethylnitrosourea / Q000633:toxicity; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D015162:Micronucleus Tests; D009525:Niacin / Q000172:deficiency*; D051381:Rats; D020318:Rats, Long-Evans
D018736:DNA Adducts; D009525:Niacin; C007673:6-ethylguanine; D006147:Guanine; D005038:Ethylnitrosourea