PDF(Pubmed)
Abstract：
The parenteral nutrition (PN) received by premature newborns is contaminated with peroxides that induce global DNA hypermethylation via oxidative stress. Exposure to peroxides could be an important factor in the induction of chronic diseases such as those observed in adults who were born preterm. As endogenous H2O2 is a major regulator of glucose-lipid metabolism, our hypothesis was that early exposure to PN induces permanent epigenetic changes in H2O2 metabolism. Three-day-old guinea pigs were fed orally (ON), PN or glutathione-enriched PN (PN+GSSG). GSSG promotes endogenous peroxide detoxification. After 4 days, half the animals were sacrificed, and the other half were fed ON until 16 weeks of age. The liver was harvested. DNA methylation and mRNA levels were determined for the SOD2, GPx1, GCLC, GSase, Nrf2 and Keap1 genes. PN induced GPx1 hypermethylation and decreased GPx1, GCLC and GSase mRNA. These findings were not observed in PN+GSSG. PN+GSSG induced Nrf2 hypomethylation and increased Nrf2 and SOD2 mRNA. These observations were independent of age. In conclusion, in neonatal guinea pigs, PN induces epigenetic changes, affecting the expression of H2O2 metabolism genes. These changes persist for at least 15 weeks after PN. This disruption may signify a permanent reduction in the capacity to detoxify peroxides.
摘要：
早产儿接受的肠胃外营养（PN）被过氧化物污染，这些过氧化物通过氧化应激诱导整体DNA超甲基化。暴露于过氧化物可能是诱发慢性疾病的重要因素，例如在早产的成年人中观察到的疾病。由于内源性H2O2是糖脂代谢的主要调节因子,我们的假设是，早期暴露于PN会引起H2O2代谢的永久性表观遗传变化。3日龄豚鼠口服(ON),PN或富含谷胱甘肽的PN(PN+GSSG)。GSSG促进内源性过氧化物解毒。4天后,一半的动物被处死，另一半被喂养直到16周龄。收获肝脏。确定SOD2、GPx1、GCLC的DNA甲基化和mRNA水平，GSase,Nrf2和Keap1基因。PN诱导GPx1过度甲基化并降低GPx1，GCLC和GSasemRNA。在PN+GSSG中未观察到这些发现。PN+GSSG诱导Nrf2低甲基化并增加Nrf2和SOD2mRNA。这些观察结果与年龄无关。总之,在新生豚鼠中，PN诱导表观遗传变化，影响H2O2代谢基因的表达。这些变化在PN后持续至少15周。这种破坏可能意味着过氧化物解毒能力的永久性降低。
