Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring
Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring
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DOI：
10.1093/jn/135.6.1382
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发表时间：
2005-06-01
影响因子：
4.2
通讯作者：
Burdge, GC
中科院分区：
文献类型：
--
作者：
Lillycrop, KA;Phillips, ES;Burdge, GC
生命早期的环境限制会导致表型变化，而这些变化可能与以后生活中疾病风险的增加有关。这表明基因转录的持续改变。 DNA甲基化主要在子宫内形成，它提供了一种因果机制，通过这种机制，产前营养不平衡会导致基因表达的改变。我们研究了母体营养不平衡对断奶后大鼠后代糖皮质激素受体（GR）和过氧化物酶体增殖物激活受体（PPAR）基因甲基化状态和表达的影响。母鼠在整个怀孕期间饲喂对照蛋白（C；180 g/kg 蛋白加 1 mg/kg 叶酸）、限制蛋白（R；90 g/kg 酪蛋白加 1 mg/kg 叶酸）或限制蛋白加 5 mg/kg 叶酸 (RF) 饮食。断奶后 6 天处死幼仔（每组 n = 10）。通过甲基化敏感PCR测定基因甲基化，通过半定量RT-PCR测定mRNA表达。与 C 幼崽相比，R 幼崽的 PPARa 基因甲基化低 20.6%（P < 0.001），表达量高 10.5 倍。 R 幼崽中 GR 基因甲基化比 C 幼崽低 22.8% (P < 0.05)，表达量高 200% (P < 0.01)。 RF饮食阻止了这些变化。 PPARg 甲基化状态和表达在各组之间没有差异。酰基辅酶A氧化酶的表达遵循PPARa的表达。这些结果表明，不平衡的产前营养会引起持续的、基因特异性的表观遗传变化，从而改变 mRNA 表达。基因转录的表观遗传调控为胎儿编程提供了强有力的候选机制。
Environmental constraints during early life result in phenotypic changes that can be associated with increased disease risk in later life. This suggests persistent alteration of gene transcription. DNA methylation, which is largely established in utero, provides a causal mechanism by which unbalanced prenatal nutrition results in such altered gene expression. We investigated the effect of unbalanced maternal nutrition on the methylation status and expression of the glucocorticoid receptor (GR) and peroxisomal proliferator-activated receptor (PPAR) genes in rat offspring after weaning. Dams were fed a control protein (C; 180 g/kg protein plus 1 mg/kg folic acid), restricted protein (R; 90 g/kg casein plus 1 mg/kg folic acid), or restricted protein plus 5 mg/kg folic acid (RF) diet throughout pregnancy. Pups were killed 6 d after weaning (n = 10 per group). Gene methylation was determined by methylation-sensitive PCR and mRNA expression by semiquantitative RT-PCR. PPARa gene methylation was 20.6% lower (P < 0.001) and expression 10.5-fold higher in R compared with C pups. GR gene methylation was 22.8% lower (P < 0.05) and expression 200% higher (P < 0.01) in R pups than in C pups. The RF diet prevented these changes. PPARg methylation status and expression did not differ among the groups. Acyl-CoA oxidase expression followed that of PPARa. These results show that unbalanced prenatal nutrition induces persistent, gene-specific epigenetic changes that alter mRNA expression. Epigenetic regulation of gene transcription provides a strong candidate mechanism for fetal programming.