Folic acid deficiency increases sensitivity to DNA damage by glucose and methylglyoxal.
Leigh DonnellanBradley S SimpsonVarinderpal S DhillonMaurizio CostabileMichael FenechPermal DeoPublished in: Mutagenesis (2022)
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.
Keyphrases
- dna damage
- induced apoptosis
- high glucose
- oxidative stress
- type diabetes
- cell cycle arrest
- endothelial cells
- blood glucose
- dna repair
- endoplasmic reticulum stress
- dengue virus
- cardiovascular disease
- metabolic syndrome
- gene expression
- adipose tissue
- cell proliferation
- wild type
- hydrogen peroxide
- insulin resistance
- risk assessment
- zika virus
- glycemic control
- replacement therapy
- genome wide
- stress induced