Transgenerational glucose intolerance with Igf2/H19 epigenetic alterations in mouse islet induced by intrauterine hyperglycemia.
Transgenerational glucose intolerance with Igf2/H19 epigenetic alterations in mouse islet induced by intrauterine hyperglycemia.
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作者：
Ding GL;Wang FF;Shu J;Tian S;Jiang Y;Zhang D;Wang N;Luo Q;Zhang Y;Jin F;Leung PC;Sheng JZ;Huang HF
妊娠糖尿病（GDM）已被证明与后代患糖尿病的高风险有关。但是，所涉及的机制和跨代传播的可能性仍不清楚。我们将雄性和雌性成年对照和GDM小鼠的第一代后代（F1-GDM）杂交，以获得四组的第二代（F2）后代：C β-C β，C β-GDM β，GDM β-C β和GDM β-GDM β。我们发现，出生体重显着增加F2后代通过父系糖耐量受损（IGT）。无论F1-GDM伴或不伴IGT，IGT的高风险在F2后代中早在3周就出现，并通过双亲谱系，特别是父系进行。雄性后代IGT较雌性明显，具有亲代特征和性别特异性传递。在GDM的F1和F2代中，印记基因Igf 2和H19在胰岛中的表达均下调，这可能是由于差异甲基化区域的异常甲基化状态所致，这可能是GDM导致胰岛超微结构和功能受损的机制之一。此外，在成年F1-GDM的精子中发现了改变的Igf 2和H19基因表达，无论是否存在IGT，表明生殖细胞中的表观遗传学变化有助于跨代传递。
Gestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved and the possibilities of transgenerational transmission are still unclear. We intercrossed male and female adult control and first-generation offspring of GDM (F1-GDM) mice to obtain the second-generation (F2) offspring in four groups: C♂-C♀, C♂-GDM♀, GDM♂-C♀, and GDM♂-GDM♀. We found that birth weight significantly increased in F2 offspring through the paternal line with impaired glucose tolerance (IGT). Regardless of birth from F1-GDM with or without IGT, high risk of IGT appeared as early as 3 weeks in F2 offspring and progressed through both parental lineages, especial the paternal line. IGT in male offspring was more obvious than that in females, with parental characteristics and sex-specific transmission. In both F1 and F2 offspring of GDM, the expression of imprinted genes Igf2 and H19 was downregulated in pancreatic islets, caused by abnormal methylation status of the differentially methylated region, which may be one of the mechanisms for impaired islet ultrastructure and function. Furthermore, altered Igf2 and H19 gene expression was found in sperm of adult F1-GDM, regardless of the presence of IGT, indicating that changes of epigenetics in germ cells contributed to transgenerational transmission.
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