Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm.
Endocrine-disrupting chemicals (EDCs), among which is the antiandrogen vinclozolin (VCZ), have been reported to affect the male reproductive system. In this study, VCZ was administered to pregnant mice at the time of embryo sex determination, and its possible effects on the differentially methylated domains (DMDs) of two paternally (H19 and Gtl2) and three maternally (Peg1, Snrpn, and Peg3) imprinted genes were tested in the male offspring. The CpGs methylation status within the five gene DMDs was analyzed in the sperm, tail, liver, and skeletal muscle DNAs by pyrosequencing. In the sperm of controls, the percentages of methylated CpGs were close to the theoretical values of 100 and 0% in paternally or maternally imprinted genes respectively. VCZ decreased the percentages of methylated CpGs of H19 and Gtl2 (respective values 83.1 and 91.5%) and increased those of Peg1, Snrpn, and Peg3 (respective values 11.3, 18.3, and 11.2%). The effects of VCZ were transgenerational, but they disappeared gradually from F1 to F3. The mean sperm concentration of the VCZ-administered female offspring was only 56% of that of the controls in the F1 offspring, and it was back to normal values in the F2 and F3 offspring. In the somatic cells of controls, the percentages of methylated CpGs were close to the theoretical value of 50% and, surprisingly, VCZ altered the methylation of Peg3. We propose that the deleterious effects of VCZ on the male reproductive system are mediated by imprinting defects in the sperm. The reported effects of EDCs on human male spermatogenesis might be mediated by analogous imprinting alterations.
Stouder
Christelle
C
Department of Genetic Medicine and Development Swiss Center for Applied Human Toxicology, University of Geneva Medical School, CMU, 1 Michel-Servet, 1211 Geneva 4, Switzerland.
Paoloni-Giacobino
Ariane
A
D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D018392:Genomic Imprinting / Q000187:drug effects*; D005838:Genotype; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D010080:Oxazoles / Q000633:toxicity*; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D012098:Reproduction / Q000187:drug effects / Q000235:genetics; D013076:Sperm Count; D013081:Sperm Motility; D013091:Spermatogenesis / Q000187:drug effects* / Q000235:genetics; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013623:Tail / Q000378:metabolism; D055517:snRNP Core Proteins / Q000235:genetics
D000726:Androgen Antagonists; D052244:Endocrine Disruptors; D051741:Kruppel-Like Transcription Factors; C422882:MEG3 non-coding RNA, mouse; D010080:Oxazoles; C097901:Peg3 protein, mouse; D011506:Proteins; D062085:RNA, Long Noncoding; C103637:mesoderm specific transcript protein; D055517:snRNP Core Proteins; C025643:vinclozolin