Excess Iron Enhances Purine Catabolism Through Activation of Xanthine Oxidase and Impairs Myelination in the Hippocampus of Nursing Piglets

Abstract

Few studies have addressed the risk of nutritional iron overexposure in infancy. We previously found that excess dietary iron in nursing piglets resulted in iron overload in the liver and hippocampus and diminished socialization with novel conspecifics in a test for social novelty preference. This experiment aimed to identify metabolites and metabolic pathways affected by iron overload in the liver and hippocampus of nursing piglets. Liver and hippocampal tissues collected from 22-d-old piglets (Hampshire×Yorkshire crossbreed; 5.28±0.53 kg body weight; 50% male) that received orally 0 (NI group) or 50 mg iron/(d · kg body weight) (HI group) from postnatal day (PD) 2 to PD21 were analyzed for mRNA and protein expression and enzyme activity of xanthine oxidase (XO). Untargeted metabolomics was performed using GC-MS. Expression of myelin basic protein (MBP) in the hippocampus was determined using western blot. There were 108 and 126 metabolites identified in the hippocampus and liver, respectively. Compared with NI, HI altered 15 metabolites (P<0.05, q<0.2) in the hippocampus, including a reduction in myo-inositol (0.86-fold) and N-acetylaspartic acid (0.84-fold), 2 metabolites important for neuronal function and myelination. Seven metabolites involved in purine and pyrimidine metabolism (e.g., hypoxanthine, xanthine, and β-alanine) were coordinately changed in the hippocampus (P<0.05, q<0.2), suggesting that iron excess enhanced purine catabolism. The mRNA expression (2.3-fold) (P<0.05) and activity of XO, a rate-limiting enzyme in purine degradation, was increased. Excess iron increased hippocampal lipid peroxidation by 74% (P<0.05) and decreased MBP by 44% (P=0.053). The hepatic metabolome was unaffected. In nursing piglets, excess iron enhances hippocampal purine degradation through activation of XO, which may induce oxidative stress and alter energy metabolism in the developing brain.