Weaver Ian C G
Developmental Biology Program, Hospital for Sick Children, Toronto Medical Discovery East Tower, Medical & Related Sciences (MaRS) Centre, Toronto, Ontario, M5G 1X8, Canada.
Semin Fetal Neonatal Med. 2009 Jun;14(3):143-50. doi: 10.1016/j.siny.2008.12.002. Epub 2009 Feb 13.
The early nurturing environment has persistent influences on developmental programming of inter-individual differences in metabolic and endocrine function that contribute to emotional and cognitive performance through life. These effects are mediated, in part, through neonatal programming of hypothalamic-pituitary-adrenal (HPA) axis function. Animal models support this hypothesis. For example, in the rat natural variations in maternal care influence HPA axis stress reactivity in the offspring via long-term changes in tissue-specific gene expression. Studies in vivo and in vitro show that maternal licking and grooming increases glucocorticoid receptor expression in the offspring via increased hippocampal serotonergic tone accompanied by increased histone acetylase transferase activity, histone acetylation and DNA demethylation mediated by the transcription factor nerve growth factor-inducible protein-A. These effects are reversed by early postnatal cross-fostering and by pharmacological manipulations, including trichostatin A (TSA) and l-methionine administration in adulthood. These studies demonstrate that an epigenetic state of a gene can be established through early in life experience, and is potentially reversible in adult life. Accordingly, epigenetic modifications in target gene promoters in response to environmental demand may ensure stable yet dynamic regulation that mediates persistent changes in biological and behavioral phenotype over the lifespan.
早期养育环境对个体间代谢和内分泌功能差异的发育编程具有持久影响，这些差异会影响一生的情绪和认知表现。这些影响部分是通过下丘脑 - 垂体 - 肾上腺（HPA）轴功能的新生儿编程介导的。动物模型支持这一假设。例如，在大鼠中，母性照料的自然差异通过组织特异性基因表达的长期变化影响后代的HPA轴应激反应性。体内和体外研究表明，母鼠的舔舐和梳理通过增加海马5-羟色胺能张力，伴随着由转录因子神经生长因子诱导蛋白-A介导的组蛋白乙酰转移酶活性增加、组蛋白乙酰化和DNA去甲基化，增加后代糖皮质激素受体的表达。这些影响可通过出生后早期交叉寄养以及成年期的药物处理（包括曲古抑菌素A（TSA）和L-甲硫氨酸给药）逆转。这些研究表明，基因的表观遗传状态可以通过生命早期的经历建立，并且在成年期可能是可逆的。因此，响应环境需求，靶基因启动子中的表观遗传修饰可能确保稳定而动态的调节，介导整个生命周期中生物学和行为表型的持续变化。
