Folic acid deficiency increases sensitivity to DNA damage by glucose and methylglyoxal

• Published in: Mutagenesis Vol. 37; no. 1; pp. 24 - 33
• Main Authors: Donnellan, Leigh, Simpson, Bradley S, Dhillon, Varinderpal S, Costabile, Maurizio, Fenech, Michael, Deo, Permal
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 02.04.2022
• Subjects: Diabetes Mellitus, Type 2; DNA Damage; Editor's Choice; Folic Acid - pharmacology; Folic Acid Deficiency; Glucose - pharmacology; Humans; Original Manuscripts; Pyruvaldehyde - toxicity; nutrient interactions; glucose; micronuclei; folic acid; oxidative stress; dicarbonyl stress
• ISSN: 0267-8357; 1464-3804; 1464-3804
• DOI: 10.1093/mutage/geac003

Abstract Type 2 diabetes (T2D) is associated with elevated frequencies of micronuclei (MNi) and other DNA damage biomarkers. Interestingly, individuals with T2D are more likely to be deficient in micronutrients (folic acid, pyridoxal-phosphate, cobalamin) that play key roles in one-carbon metabolism and maintaining genomic integrity. Furthermore, it has recently been shown that deficiencies in these nutrients, in particular folic acid leaves cells susceptible to glucose-induced DNA damage. Therefore, we sought to investigate if the B lymphoblastoid WIL2-NS cell line cultured under folic acid-deficient conditions was more sensitive to DNA damage induced by glucose, or the reactive glycolytic byproduct methylglyoxal (MGO) and subsequent advanced glycation endproduct formation. Here, we show that only WIL2-NS cultured under folic acid-deficient conditions (23 nmol/l) experience an increase in MNi frequency when exposed to high concentrations of glucose (45 mmol/l) or MGO (100 µmol/l). Furthermore, we showed aminoguanidine, a well-validated MGO and free radical scavenger was able to prevent further MNi formation in folic acid-deficient cells exposed to high glucose, which may be due to a reduction in MGO-induced oxidative stress. Interestingly, we also observed an increase in MGO and other dicarbonyl stress biomarkers in folic acid-deficient cells, irrespective of glucose concentrations. Overall, our evidence shows that folic acid-deficient WIL2-NS cells are more susceptible to glucose and/or MGO-induced MNi formation. These results suggest that individuals with T2D experiencing hyperglycemia and folic acid deficiency may be at higher risk of chromosomal instability.