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影响子代表型。为验证该假说，研究人员将携带内皮型一氧化氮合酶（eNOS）基因敲除杂合子的雌性小鼠与野生型（wild type）小鼠，分别与雄性野生型小鼠进行交配繁育。随后研究人员评估了母体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，eNOS基因敲除杂合雌性母鼠产下的雄性野生型子代的出生体重更低。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。伴随该变化的是，不同基因的表达与DNA甲基化水平存在性别特异性差异。雌雄子代的肝脏全局DNA甲基化水平均显著升高。同时，雌雄子代的肝脏碳水化合物代谢相关参数均出现下降。此外，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功能。该效应呈现性别特异性，且对雌性子代的不利影响更为显著。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。值得注意的是，这些后天获得的表观遗传表型改变可持续至成年阶段。