Brieño-Enríquez Miguel A, García-López Jesús, Cárdenas David B, Guibert Sylvain, Cleroux Elouan, Děd Lukas, Hourcade Juan de Dios, Pěknicová Jana, Weber Michael, Del Mazo Jesús
Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
Biotechnology and Cell Signaling, CNRS UMR7242, University of Strasbourg, Strasbourg, France.
PLoS One. 2015 Apr 21;10(4):e0124296. doi: 10.1371/journal.pone.0124296. eCollection 2015.
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.
在哺乳动物中，生殖细胞分化在胎儿发育期间的原始生殖细胞（PGC）中启动。产前暴露于环境毒物，如内分泌干扰物，可能会改变PGC分化、雄性生殖系发育，并诱导跨代表观遗传紊乱。抗雄激素化合物乙烯菌核利是一种对生殖细胞产生跨代效应的典型分子实例。我们在小鼠中进行了产前乙烯菌核利暴露，并分析了连续三代的表型和分子变化。在F1至F3代中观察到胚胎PGC数量减少、凋亡细胞率增加以及成年雄性生育率下降。Blimp1是PGC分化的关键调节因子。我们发现，产前乙烯菌核利暴露会使PGC中的特定微小RNA（如miR-23b和miR-21）失调，在连续三代雄性中诱导Lin28/let-7/Blimp1通路失衡。通过胞嘧啶甲基化全局图谱确定，我们没有发现PGC或成熟精子中DNA甲基化有显著变化的证据。我们的数据表明，胚胎暴露于环境内分泌干扰物会诱导跨代表观遗传失调，影响生殖细胞分化关键调节通路的微小RNA表达。
