Parental Iron Deficiency Programs Oxidative Stress and Epigenetic Demethylase Dysregulation (TET and KDM2) in...

Iron deficiency (ID) is the most widespread micronutrient deficiency globally and has been increasingly linked to disturbances in cellular redox balance and metabolic regulation. Emerging evidence indicates that parental nutritional status can influence offspring physiology through intergenerational programming mechanisms. However, the molecular pathways through which parental ID affects oxidative stress and epigenetic regulation in subsequent generations remain poorly understood. The present study investigated whether oxidative stress and altered expression of iron-dependent epigenetic regulators contribute to these effects. ID was induced in parental (F0) flies by feeding a diet containing 200 µmol bathophenanthroline disulphonate for two weeks prior to mating. F1 and F2 offspring were maintained on either a normal diet (ND) or a high-fat diet (HFD). Antioxidant enzyme activities (SOD and Gtpx), were measured enzymatically, while the expression of oxidative stress markers (Sod1, Gtpx) and epigenetic demethylases (Tet and Kdm2) was quantified using RT-qPCR. Parental ID induced a sustained oxidative stress phenotype across generations. SOD activity and mRNA expression were significantly elevated in both paternal and maternal lineages, particularly under HFD conditions. In contrast, Gtpx activity declined in F1 and F2 offspring exposed to HFD but increased in those maintained on ND. Expression of the iron-dependent demethylases Tet and Kdm2 exhibited dynamic generational patterns, with reduced expression in later generations following parental ID. Collectively, these findings indicate that parental ID induces persistent oxidative stress and alters the expression of key epigenetic regulatory enzymes across generations. This suggests a potential mechanistic pathway linking micronutrient deficiency to inherited metabolic susceptibility.