Impact of oxidative DNA damage on germ cell differentiation ; Impact des dommages oxydatifs de l'ADN sur la différenciation des cellules germinales

Only germ cells (GCs) can undergo meiosis, an essential mechanism for the formation of the haploid gametes needed for sexual reproduction. Meiosis is a complex, finely regulated process whose proper functioning depends in mammals on events occurring before the onset of meiotic during fetal and neonatal life. Many environmental pollutants (EPs), such as bisphenol A (BPA), can disrupt germline differentiation and/or meiosis, resulting in fertility defects. A first part of my thesis examined the effects of fetal exposure to two structural analogues of BPA, bisphenol A Diglycidyl Ether (BADGE) and bisphenol AF (BPAF), on ovogenesis in mice. We observed a defect in germline differentiation (maintenance of pluripotency and delay in meiotic initiation), an increase in the number of MLH1 foci, a meiotic recombinase, and an increase in aneuploid oocytes. Using a xenograft model, we also studied the impact of chronic exposure to a mixture of plasticizers, BPA and Diethylhexyl Phthalate (DEHP), on human male fetal differentiation. As observed in the murine ovary, the human fetal testis displayed a delay in CG differentiation following exposure to this mixture of pollutants. Furthermore, exposed CG show an increased capacity to form seminoma (testicular cancer) when transplanted into an adult mouse testis. The maintenance of GC pluripotency following fetal exposure to various PEs, regardless of gonadal somatic context (ovary and testis) and species (human and mouse), suggests a common, yet unknown, mechanism of action. Among possible molecular mechanisms, most PEs have a pro-oxidant effect. The most commonly observed lesion after oxidation in the nucleus is 8-oxo-7,8-dihydroguanine (8-OdG), resulting from the oxidation of a guanine. In addition to its mutagenic effect, this oxidative damage can have direct epigenetic repercussions by recruiting the transcriptional machinery, or indirect epigenetic repercussions by affecting the chromatin environment or interfering with proteins involved in DNA methylation/demethylation. ...