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

ABSTRACT: Exposure 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.Here, 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.Our 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.

SUBMITTER: Iqbal K

PROVIDER: S-EPMC4376074 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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

Iqbal Khursheed K Tran Diana A DA Li Arthur X AX Warden Charles C Bai Angela Y AY Singh Purnima P Wu Xiwei X Pfeifer Gerd P GP Szabó Piroska E PE

Genome biology 20150327

<h4>Background</h4>Exposure 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.<h4>Results</h4>Here, we treat gestating female mice w ...[more]

PMID: 25853433

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Project description:BackgroundWhen a biologic mechanism of interest is anticipated to operate differentially according to sex, as is often the case in endocrine disruptors research, investigators routinely estimate sex-specific associations. Less attention has been given to potential sexual heterogeneity of confounder associations with outcomes. When relationships of covariates with outcomes differ according to sex, commonly applied statistical approaches for estimating sex-specific endocrine disruptor effects may produce divergent estimates.ObjectivesWe discuss underlying assumptions and evaluate the performance of two traditional approaches for estimating sex-specific effects, stratification and product terms, and introduce a simple modeling alternative: an augmented product term approach.MethodsWe describe the impact of assumptions regarding sexual heterogeneity of confounder relationships on estimates of sex-specific effects of the exposure of interest for three approaches: stratification, traditional product terms, and augmented product terms. Using simulated and applied examples, we demonstrate properties of each approach under a range of scenarios.ResultsIn simulations, sex-specific exposure effects estimated using the traditional product term approach were biased when confounders had sex-dependent associations with the outcome. Sex-specific estimates from stratification and the augmented product term approach were unbiased but less precise. In the applied example, the three approaches yielded similar estimates, but resulted in some meaningful differences in conclusions based on statistical significance.ConclusionsInvestigators should consider sexual heterogeneity of confounder associations when choosing an analytic approach to estimate sex-specific effects of endocrine disruptors on health. In the presence of sex-dependent confounding, our augmented product term approach may be advantageous over stratification when there is prior knowledge available to fit reduced models or when investigators seek an automated test for effect measure modification. https://doi.org/10.1289/EHP334.

Dataset Information

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

Publications

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

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