Abstract
Environmental factors can affect epigenetic events during germline reprogramming and impose distinctive transgenerational consequences onto the offspring. In this study, we examined the transgenerational effects of chlordecone (CD), an organochlorine insecticide with well-known estrogenic properties. We exposed pregnant mice to CD from embryonic day 6.5 to 15.5 and observed a reduction in spermatogonia (SG) numbers in F3, meiotic defects in spermatocytes and decrease in spermatozoa number in the first and third generation of male progeny. The RNA qRT-PCR expression analysis in F1 and transcriptomics analysis in F3 males using the whole testes revealed changes in the expression of genes associated with chromosome segregation, cell division and DNA repair. The expression of the master regulator of pluripotency, Pou5f1, decreased in foetal and increased in adult F1, but not in F3 adult testes. Analysis of histone H3K4me3 distribution revealed widespread changes in its occupancy in the genome of F1 and F3 generations. We established that 7.1% of altered epigenetic marks were conserved between F1 and F3 generations. The overlapping changes common to F1 and F3 include genes implicated in cell adhesion and transcription factor activities functions. Differential peaks observed in F1 males are significantly enriched in predicted ESR1 binding sites, some of which we confirmed to be functional. Our data demonstrate that CD-mediated impairment of reproductive functions could be transmitted to subsequent generations.
Highlights
During development, germ cells undergo comprehensive global somatic-to-germline reprogramming
We showed that embryonic exposure to the herbicide atrazine (ATZ) causes global changes in gene expression in several tissues in the third (F3) generation, with the testis harbouring the largest number of differentially expressed transcripts[14]
Where F0 mice are CD-exposed pregnant dams, F1 population males is directly exposed progeny from F0, F2 males are derived from the gametes of CD-exposed germ cells of F1, and the F3 generation is the first not directly exposed males (Supplementary Fig. 1)
Summary
Germ cells undergo comprehensive global somatic-to-germline reprogramming. It was postulated that these paternal H3K4me[3] histones existed during a poised state and that the genes corresponding to these marks were waiting to be activated[10] In line with this prediction, during the early embryonic stage, bivalently marked histones are absent at the regulatory regions governing developmental genes and subsequently become re-established in post-implantation embryos[9]. Differential epigenetic marks were found at the Pou5f1, Phf[2], Ezh[2] and Zhx[2] genes, which are essential for establishing the pluripotent state of germ cells[14] These data suggest a possible role for epigenetic modifications in the transmission of ATZ effects to subsequent generations. Epidemiological studies have suggested that continuous exposure to CD at environmental levels in adults could increase the risk of prostate cancer[26]
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