Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner

Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous <i>eNOS</i> knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the <i>eNOS</i> gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.

母体环境因素可通过诱导表观遗传适应机制，对子代表型产生影响。进阶版胎儿编程假说提出，即便不存在原发性遗传缺陷，母体遗传变异仍可通过表观遗传修饰，间接对子代表型产生影响。为验证该假说，本研究将杂合子雌性内皮型一氧化氮合酶（eNOS）敲除小鼠与野生型小鼠，分别与雄性野生型小鼠进行交配。随后本研究评估了母体eNOS缺乏对野生型子代肝脏表型的影响。相较于野生型母鼠所产子代，杂合子雌性eNOS敲除母鼠所产的雄性野生型子代，其出生体重显著降低。此外，子代出现了性别特异性的肝脏表型：因肝脂肪变性导致肝脏重量增加。伴随这一现象的，是不同基因的表达与DNA甲基化水平存在性别特异性差异。雄性与雌性子代的肝脏整体DNA甲基化水平均显著升高。此外，雄性与雌性子代的肝脏糖代谢相关指标均出现下降。除此之外，雄性子代的肝脏内多种氨基酸水平均有所降低。母体遗传改变（如eNOS基因的部分缺失）可在不传递内在遗传缺陷的前提下，影响野生型子代的肝脏代谢。该效应呈现性别特异性，且对雌性子代的负面影响更为显著。该研究结果表明，母体遗传缺陷可在缺陷本身不发生遗传的情况下，通过表观遗传机制改变子代表型。尤为重要的是，这些获得性表观遗传表型改变可持续至成年阶段。