Perinatal programming of adult rat germ cell death after exposure to xenoestrogens: role of microRNA miR-29 family in the down-regulation of DNA methyltransferases and Mcl-1.

Different studies have pointed out that developmental exposure to environmental endocrine disruptors can induce long-term testicular germ cell death probably through epigenetic mechanisms. By using a model of early neonatal post-natal day (PND) 1 to 5 exposure of male rats to a xenoestrogen, estradiol benzoate (EB), we investigated the role of microRNA and DNA methyltransferases (DNMT) on the developmental effects of EB on the adult germ cell death process. Neonatal exposure to EB induced adult germ cell apoptosis together with a dose-dependent increase in miR-29a, miR-29b, and miR-29c expression. Increased miR-29 expression resulted in a decrease in DNMT1, DNMT3a, and DNMT3b and antiapoptotic myeloid cell leukemia sequence 1 (Mcl-1) protein levels as shown in 1) germ cells of adult rats exposed neonatally to EB and 2) in spermatogonial GC-1 transfected with miR-29. The DNMT decrease was associated with a concomitant increase in transcript levels of DNA methylation target genes, such as L1td1–1 ORF1 and O...