title: Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Brieño-Enríquez
authors.affiliation: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-López
authors.affiliation: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors.forename: David B
authors.initials: DB
authors.lastname: Cárdenas
authors.affiliation: Biotechnology and Cell Signaling, CNRS UMR7242, University of Strasbourg, Strasbourg, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Guibert
authors.affiliation: Biotechnology and Cell Signaling, CNRS UMR7242, University of Strasbourg, Strasbourg, France.
authors.forename: Elouan
authors.initials: E
authors.lastname: Cleroux
authors.affiliation: Institute of Biotechnology AS CR, v. v. i., Prague, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Děd
authors.affiliation: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors.forename: Juan de Dios
authors.initials: Jde D
authors.lastname: Hourcade
authors.affiliation: Institute of Biotechnology AS CR, v. v. i., Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Pěknicová
authors.affiliation: Biotechnology and Cell Signaling, CNRS UMR7242, University of Strasbourg, Strasbourg, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Del Mazo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019175:DNA Methylation; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D005854:Germ Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010080:Oxazoles / Q000633:toxicity*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D035683:MicroRNAs; D010080:Oxazoles; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; C025643:vinclozolin