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Exposure to Endocrine Disruptor Induces Transgenerational Epigenetic Deregulation of MicroRNAs in Primordial Germ Cells

机译：内分泌干​​扰物的暴露诱导原始生殖细胞中microRNA的跨代表观遗传去调控。

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In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs) during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation.
机译：在哺乳动物中，在胎儿发育过程中，生殖细胞分化在原始生殖细胞（PGC）中启动。产前暴露于环境毒物（例如内分泌干扰物）可能会改变PGC的分化，雄性种系的发育并诱发跨代表观遗传疾病。抗雄激素化合物Vinclozolin代表分子对生殖细胞产生转世效应的范例。我们在小鼠中进行了长春新碱的产前暴露，并连续三个世代分析了表型和分子变化。在F1至F3代中，观察到成年男性的胚胎PGC数量减少，凋亡细胞率增加以及生育率降低。 Blimp1是PGC分化的关键调节剂。我们显示产前暴露于vinclozolin会解除PGC中特定的microRNA的表达，例如miR-23b和miR-21，在连续三代男性中诱导Lin28 / let-7 / Blimp1途径的不平衡。根据胞嘧啶甲基化的全球图谱确定，我们没有发现证据表明PGC或成熟精子中DNA甲基化的显着变化。我们的数据表明，胚胎暴露于环境内分泌干扰物会诱导影响生殖细胞分化关键调控途径的microRNA表达的跨代表观遗传失调。

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