8-hydroxy-2--deoxyguanosine and Folic-Acid-Deficiency

Exposure to hexavalent chromium [Cr (VI)] can cause DNA damage, genetic instability and increase the risk of cancer development. Folate deficiency affects DNA methylation and reduces the stability of the genetic material. However, the correlation between folate deficiency and DNA damage has never been clearly elucidated in chromate workers. In this study, we recruited one hundred and fifteen workers from chromate producing facilities as testing subjects and sixty local residents without chromium exposure history served as controls. The results showed an evident accumulation of Cr in peripheral red blood cells accompanied by a significantly decreased serum folate in chromate exposed workers. The decreased serum folate was associated with an increased urinary 8-hydroxy-2'-deoxyguanosine, DNA strand breaks and global DNA hypomethylation. These findings suggest that chronic occupational chromate exposure could induce folate depletion, which may further promote DNA damages and global DNA hypomethylation. Adequate folate supplement may provide benefit to chromate sufferers in stabilization of genetic material and reduce the risk of cancer development.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Air Pollutants, Occupational; Air Pollution, Indoor; China; Chromates; Comet Assay; Deoxyguanosine; DNA Breaks; DNA Damage; DNA Methylation; Erythrocytes; Female; Folic Acid; Folic Acid Deficiency; Glutathione Peroxidase; Homocysteine; Humans; Indicators and Reagents; Male; Malondialdehyde; Occupational Exposure; Oxidation-Reduction; Superoxide Dismutase

Folate deficiency has been shown to influence carcinogenesis by creating an imbalance in the base excision repair (BER) pathway, affecting BER homeostasis. The inability to mount a BER response to oxidative stress in a folate-deficient environment results in the accumulation of DNA repair intermediates, i.e., DNA strand breaks. Our data indicate that upregulation of β-pol expression in response to oxidative stress is inhibited by folate deficiency at the level of gene expression. Alteration in the expression of β-pol in a folate-deficient environment is not due to epigenetic changes in the core promoter of the β-pol gene, i.e., the CpG islands within the β-pol promoter remain unmethylated in the presence or absence of folate. However, the promoter analysis studies show a differential binding of regulatory factors to the -36 to -7 region (the folic acid-response region, FARR) within the core promoter of β-pol. Moreover, we observe a tight correlation between the level of binding of regulatory factors with the FARR and inhibition of β-pol expression. Based on these findings, we propose that folate deficiency results in an upregulation/stability of negative regulatory factors interacting with FARR, repressing the upregulation of the β-pol gene in response to oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Base Sequence; Carcinoma, Hepatocellular; Cell Nucleus; Cells, Cultured; CpG Islands; Deoxyguanosine; DNA Damage; DNA Footprinting; DNA Methylation; DNA Polymerase beta; DNA Repair; Electrophoretic Mobility Shift Assay; Epigenomics; Folic Acid; Folic Acid Deficiency; Gene Expression Regulation; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Oxidative Stress; Promoter Regions, Genetic

Folic acid deficiency increases stroke risk. In the present study, we examined whether folic acid deficiency enhances neuronal damage and gliosis via oxidative stress in the gerbil hippocampus after transient forebrain ischemia. Animals were exposed to a folic acid-deficient diet (FAD) for 3 months and then subjected to occlusion of both common carotid arteries for 5 min. Exposure to an FAD increased plasma homocysteine levels by five- to eightfold compared with those of animals fed with a control diet (CD). In CD-treated animals, most neurons were dead in the hippocampal CA1 region 4 days after ischemia/reperfusion, whereas, in FAD-treated animals, this occurred 3 days after ischemia/reperfusion. Immunostaining for 8-hydroxy-2'-deoxyguanosine (8-OHdG) was performed to examine DNA damage in CA1 neurons in both groups after ischemia, and it was found that 8-OHdG immunoreactivity in both FAD and CD groups peaked at 12 hr after reperfusion, although the immunoreactivity in the FAD group was much greater than that in the CD group. Platelet endothelial cell adhesion molecule-1 (PECAM-1; a final mediator of neutrophil transendothelial migration) immunoreactivity in both groups increased with time after ischemia/reperfusion: Its immunoreactivity in the FAD group was much higher than that in the CD group 3 days after ischemia/reperfusion. In addition, reactive gliosis in the ischemic CA1 region increased with time after ischemia in both groups, but astrocytosis and microgliosis in the FAD group were more severe than in the CD group at all times after ischemia. Our results suggest that folic acid deficiency enhances neuronal damage induced by ischemia.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cell Death; Coronary Artery Disease; Deoxyguanosine; Disease Models, Animal; DNA Damage; Folic Acid Deficiency; Gerbillinae; Immunohistochemistry; In Situ Nick-End Labeling; Ischemic Attack, Transient; Male; Neurons; Platelet Endothelial Cell Adhesion Molecule-1; Prosencephalon