Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei.
Folic acid deficiency can lead to uracil incorporation into DNA, hypomethylation of DNA, inefficient DNA repair and increase chromosome malsegregation and breakage. Because ionising radiation increases demand for efficient DNA repair and also causes chromosome breaks we hypothesised that folic acid deficiency may increase sensitivity to radiation-induced chromosome breakage. We tested this hypothesis by using the cytokinesis-block micronucleus assay in 10 day WIL2-NS cell cultures at four different folic acid concentrations (0.2, 2, 20, and 200 nM) that span the "normal" physiological range in humans. The study showed a significant dose-dependent increase in frequency of binucleated cells with micronuclei and/or nucleoplasmic bridges with decreasing folic acid concentration (P<0.0001, P=0.028, respectively). These biomarkers of chromosomal instability were also increased in cells irradiated (1.5 Gy gamma-rays) on day 9 relative to un-irradiated controls (P<0.05). Folic acid deficiency and gamma-irradiation were shown to have a significant interactive effect on frequency of cells containing micronuclei (two-way ANOVA, interaction P=0.0039) such that the frequency of radiation-induced micronucleated cells (i.e. after subtracting base-line frequency of un-irradiated controls) increased with decreasing folic acid concentration (P-trend<0.0001). Aneuploidy of chromosome 21, apoptosis and necrosis were increased by folic acid deficiency but not by ionising radiation. The results of this study show that folate status has an important impact on chromosomal stability and is an important modifying factor of cellular sensitivity to radiation-induced genome damage.
Beetstra
Sasja
S
CSIRO Health Sciences and Nutrition, P.O. Box 10041, Gouger Street, Adelaide BC 5000, SA, Australia.
Thomas
Philip
P
Salisbury
Carolyn
C
Turner
Julie
J
Fenech
Michael
M
D000782:Aneuploidy; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D002891:Chromosomes, Human, Pair 21; D048749:Cytokinesis; D004305:Dose-Response Relationship, Drug; D005492:Folic Acid / Q000378:metabolism / Q000494:pharmacology; D005494:Folic Acid Deficiency / Q000378:metabolism*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D015162:Micronucleus Tests; D008954:Models, Biological; D011836:Radiation Tolerance; D011839:Radiation, Ionizing
D005492:Folic Acid