We performed a cross-sectional study (n = 49 males, 57 females) and a randomized double-blind placebo-controlled dietary intervention study (n = 31/32 per group) to determine the effect of folate and vitamin B12 (B12) on DNA damage (micronucleus formation and DNA methylation) and plasma homocysteine (HC) in young Australian adults aged 18-32 years. None of the volunteers were folate deficient (i.e. red blood cell folate <136 nmol/l) and only 4.4% (all females) were vitamin B12 deficient (i.e. serum vitamin B12 <150 pmol/l). The cross-sectional study showed that (i) the frequency of micronucleated cells (MNCs) was positively correlated with plasma HC in males (R = 0.293, P < 0.05) and (ii) in females MNC frequency was negatively correlated with serum vitamin B12 (R = -0.359, P < 0.01) but (iii) there was no significant correlation between micronucleus index and folate status. The results also showed that the level of unmethylated CpG (DNA) was not significantly related to vitamin B12 or folate status. The dietary intervention involved supplementation with 3.5x the recommended dietary intake (RDI) of folate and vitamin B12 in wheat bran cereal for three months followed by ten times the RDI of these vitamins via tablets for a further three months. In the supplemented group, MNC frequency was significantly reduced during the intervention by 25.4% in those subjects with initial MNC frequency in the high 50th percentile but there was no change in those subjects in the low 50th percentile for initial MNC frequency. The reduction in MNC frequency was significantly correlated with serum vitamin B12 (R = -0.49, P < 0.0005) and plasma HC (R = 0.39, P < 0.006), but was not significantly related to red blood cell folate. DNA methylation status was not altered in the supplemented group. The greatest decrease in plasma HC (by 37%) during the intervention was observed in those subjects in the supplemented group with initial plasma HC in the high 50th percentile, and correlated significantly with increases in red blood cell folate (R = -0.64, P < 0.0001) but not with serum vitamin B12. The results from this study suggest that (i) MNC frequency is minimized when plasma HC is below 7.5 micromol/l and serum vitamin B12 is above 300 pmol/l and (ii) dietary supplement intake of 700 microg folic acid and 7 microg vitamin B12 is sufficient to minimize MNC frequency and plasma HC. Thus, it appears that elevated plasma HC, a risk factor for cardiovascular disease, may also be a risk factor for chromosome damage.
We performed a biochemical and cytogenetic epidemiological study to establish if there are significant differences between vegetarians (V) and non-vegetarians (NV) in their peripheral blood lymphocyte micronucleus (MN) index, which is a measure of chromosome damage rate. The levels of plasma vitamin C (VIT-C), vitamin E (VIT-E), vitamin B12 (B12) and folic acid were also analysed to assess if differences in chromosome damage rates were associated with these potentially antimutagenic micronutrients. Volunteers were classified as either 'vegetarian' if they had abstained from eating any flesh foods for at least 3 years prior to the study or 'non-vegetarian' if they consumed meat or meat products at least 5 days/week for at least 3 years before participation in the study. The volunteers in the study consisted of 47 male and 79 female V and 66 male and 72 female NV, all of whom were non-smokers for at least 3 years prior to the study. The age of the volunteers varied between 20 and 89 years. There was no significant difference in the slope of the age-related increase in MN index of V and NV of either sex. However, the MN index was significantly lower in NV males in the age group 20-40 years and significantly lower for V males in the 41-60 years age group. No difference between the MN index of older males was detectable and there also was no difference in the MN index of V and NV females across all age groups. V were generally found to have significantly higher plasma levels of VIT-C and folic acid, significantly lower levels of B12, and similar levels of VIT-E when compared with NV. VIT-C correlated positively with MN index in young males, but the reverse was true for B12. In young females folate and B12 appeared to correlate negatively with MN index. VIT-E had no apparent impact on MN index. These data suggest that the level of folate and B12 may be more important than VIT-C or VIT-E in minimizing chromosome damage rates in human lymphocytes. Overall, the data from this study do not support the hypothesis that V have a lower genetic damage rate than NV.
Using human lymphocytes and the cytokinesis-block micronucleus (CBMN) assay we have recently shown that excision-repairable DNA lesions induced by methylnitrosourea (MNU) and ultraviolet (UV) light (254 nm) can be converted to micronuclei (MNi) within one cell cycle if cytosine arabinoside (ARA-C) is added during the G1 phase of the cell cycle after mitogen stimulation. We have proposed that this conversion resulted from the inhibition by ARA-C of the gap-filling step during excision repair which results in the formation of single-stranded breaks at repair sites; these breaks are then converted to chromatid or chromosome breaks and subsequently to MNi on completion of nuclear division. To confirm this hypothesis we have examined the origin of MNi induced by ARA-C by using anti-kinetochore antibodies and found that between 77 and 86% of these MNi are kinetochore-negative which supports the idea that they originate mainly from acentric chromosome fragments. We have also demonstrated that combining ARA-C treatment with hydroxyurea (HU) during G1 provides a synergistic improvement in the conversion of spontaneous (4-fold increment) or MNU-induced (2-fold increment) excision-repairable DNA lesions to MNi when compared to the effects with ARA-C alone. HU treatment on its own did not influence micronucleus expression in untreated cells and cells treated with MNU.
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