Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells.
Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells.
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DOI：
10.1371/journal.pone.0124296
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Del Mazo J
中科院分区：
文献类型：
--
作者：
Brieño-Enríquez MA;García-López J;Cárdenas DB;Guibert S;Cleroux E;Děd L;Hourcade Jde D;Pěknicová J;Weber M;Del Mazo J
在哺乳动物中，在胎儿发育过程中，在原始生殖细胞（PGC）中启动生殖细胞分化。产前暴露于环境毒物（例如内分泌干扰物）可能会改变PGC分化，男性种系的发展并诱导转世表观遗传疾病。抗雄激素化合物Vinclozolin代表了分子的范式示例，从而导致对生殖细胞的转世作用。我们在小鼠中进行了产前暴露于vinclozolin，并分析了三代后代的表型和分子变化。在F1到F3世代中，观察到胚胎PGC的数量减少以及凋亡细胞率的增加以及成年男性的生育率降低。 Blimp1是PGC分化的关键调节剂。我们表明，产前暴露于vinclozolin会在PGC中取消特定的microRNA，例如miR-23b和miR-21，在三个世代相传的男性中诱导Lin28/let-7/Blimp1途径的不平衡。根据胞嘧啶甲基化的全球图确定，我们没有发现PGC或成熟精子中DNA甲基化显着变化的证据。我们的数据表明，胚胎暴露于环境内分泌干扰物上会诱导跨代表观遗传学的消失，影响了影响生殖细胞分化的关键调节途径的microRNA的表达。
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.
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