Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogramming

Abstract

BackgroundExposure to environmental endocrine-disrupting chemicals during pregnancy reportedly causes transgenerationally inherited reproductive defects. We hypothesized that to affect the grandchild, endocrine-disrupting chemicals must alter the epigenome of the germ cells of the in utero-exposed G1 male fetus. Additionally, to affect the great-grandchild, the aberration must persist in the germ cells of the unexposed G2 grandchild.ResultsHere, we treat gestating female mice with vinclozolin, bisphenol A, or di-(2-ethylhexyl)phthalate during the time when global de novo DNA methylation and imprint establishment occurs in the germ cells of the G1 male fetus. We map genome-wide features in purified G1 and G2 prospermatogonia, in order to detect immediate and persistent epigenetic aberrations, respectively. We detect changes in transcription and methylation in the G1 germline immediately after endocrine-disrupting chemicals exposure, but changes do not persist into the G2 germline. Additional analysis of genomic imprints shows no persistent aberrations in DNA methylation at the differentially methylated regions of imprinted genes between the G1 and G2 prospermatogonia, or in the allele-specific transcription of imprinted genes between the G2 and G3 soma.ConclusionsOur results suggest that endocrine-disrupting chemicals exert direct epigenetic effects in exposed fetal germ cells, which are corrected by reprogramming events in the next generation. Avoiding transgenerational inheritance of environmentally-caused epigenetic aberrations may have played an evolutionary role in the development of dual waves of global epigenome reprogramming in mammals.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0619-z) contains supplementary material, which is available to authorized users.

Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells

“…A small fraction of genomic elements such as mouse intracisternal A particles (IAP) was reported to escape this global gDNA demethylation, and their possible roles in the transgenerational epigenetic inheritance have been proposed (2,9,15). On the other hand, a recent study detected aberrant 5meC distributions in the spermatogonial gDNA of mice prenatally exposed to endocrine disruptors, but these epimutations were not persistent in the subsequent generation beyond the germline epigenetic reprogramming (6). The fate of epimutations introduced in the reprogramming-resistant genomic elements still remains to be documented.…”

“…Multigenerational transmission of a nongenetic phenotype is considered transgenerational when it is persistent beyond the epigenetic reprogramming in primordial germ cells (PGCs) (1,2), potentially conveying illness including metabolic diseases, malignancies, reproductive defects, or behavioral alterations (2,4,5). However, this is still a controversial subject due partly to the lack of direct experimental demonstration of transgenerational epigenetic alterations escaping the epigenetic erasure in mammalian PGCs (2,6,7).…”

Undercover: gene control by metabolites and metabolic enzymes

“…A recent study tested the effects of in utero exposure to endocrine-disrupting chemicals on gene transcription and DNA methylation in mice and found that these are not inherited across generations (Iqbal et al 2015). Likewise, the offspring of human parents affected by thalidomide-induced embryopathy did not display an increased occurrence of related defects (Smithells 1998;Strömland et al 2002).…”

On the origin of sperm epigenetic heterogeneity

“…In addition to the aforementioned factors (Donkin et al 2015, Pacchierotti & Spanò 2015, other environmental influences such as endocrine disruptors (e.g. vincozolin and bisphenol A) have been described as having an impact specifically on the epigenetic programming of the male germ line and causing epimutations in sperm (Manikkam et al 2013, Iqbal et al 2015. Finally, ageing is able to change the SSC composition of testis and might also alter the proportion of aberrantly methylated sperm found in an ejaculate (Paul & Robaire 2013;Fig.…”