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https://hdl.handle.net/2440/14350
Type: | Journal article |
Title: | The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro |
Author: | Crott, J. Mashiyama, S. Ames, B. Fenech, M. |
Citation: | Cancer Epidemiology, Biomarkers and Prevention, 2001; 10(10):1089-1096 |
Publisher: | Amer Assoc Cancer Research |
Issue Date: | 2001 |
ISSN: | 1055-9965 1538-7755 |
Statement of Responsibility: | Jimmy W. Crott, Susan T. Mashiyama, Bruce N. Ames, and Michael Fenech |
Abstract: | We performed a comprehensive study on the genotoxic and cytotoxic effects of in vitro folic acid deficiency on primary human lymphocytes. Lymphocytes were cultured in medium containing 12-120 nM folic acid for 9 days in a novel cytokinesis-block micronucleus (CBMN) assay system (n = 20). Besides identifying optimal folic acid concentrations for in vitro genomic stability, we tested the hypothesis that lymphocytes from individuals homozygous for the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism (TTs, n = 10) are protected against chromosome damage relative to controls (CCs, n = 10) under conditions of folic acid deficiency. This hypothesis is based on the assumption that reduced MTHFR activity in TT lymphocytes causes a diversion of 5,10-methylene tetrahydrofolate toward thymidine synthesis, which minimizes uracil-induced double-stranded DNA breakage. Cells were scored for micronuclei, apoptosis, necrosis, nucleoplasmic bridges, and nuclear budding. The latter two endpoints are indicative of chromosome rearrangements and gene amplification, respectively, and to the best of our knowledge, this is the first report of their association with folic acid concentration. Folic acid concentration correlated significantly (P < 0.0001) and negatively (r, -0.63 to -0.74) with all markers of chromosome damage, which were minimized at 60-120 nM folic acid, much greater than concentrations assumed "normal," but not necessarily optimal in plasma. Two-way ANOVA revealed no effect of the MTHFR genotype on any of the endpoints. Results show that the C677T polymorphism does not affect the ability of a cell to resist chromosome damage induced by folic acid deficiency in this in vitro system. |
Keywords: | Lymphocytes Cells, Cultured Humans Folic Acid Deficiency Chromosome Aberrations Methylenetetrahydrofolate Dehydrogenase (NADP) Analysis of Variance Probability Sensitivity and Specificity Polymorphism, Genetic Reference Values Female Male |
Rights: | Copyright © 2013 American Association for Cancer Research |
Appears in Collections: | Aurora harvest 2 Pharmacology publications |
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