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

Iqbal K, Tran DA, Li AX, Warden C, Bai AY, Singh P, Wu X, Pfeifer GP, Szabó PE - Genome Biol. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

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Selected top hits of transgenerationally inherited DNA methylation aberrations. Prospermatogonia of G1 fetuses were treated with ED or oil control in utero as depicted in Additional file 4. Next, DNA methylation was mapped using MIRA-chip and custom Nimblegen arrays in purified G1R and G2R prospermatogonia at 17.5 dpc in triplicate and in adult spermatozoa in duplicate. Immediate and persistent changes are tabulated in Table 3 and Additional file 8. (A) Selected top persistent hits are shown from the analysis in duplicates labeled at the top according to the comparisons in Table 3 and marked with arrowheads (up for increase and down for decrease) (B) A selected IAP-flank region where common changes were detected in MGC samples between G1R and G2R at and between G2R MGC and G2R sperm. (C) The H19-Igf2 imprinted DMR is shown as a positive control for the DNA methylation signal (black rectangle). DNA methylation signals of MIRA versus input DNA are plotted as -log10 P values ranging from 0 to 8.3 for experimental and control replicate samples. Note that these top changes are minor and not highly significant.
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Fig8: Selected top hits of transgenerationally inherited DNA methylation aberrations. Prospermatogonia of G1 fetuses were treated with ED or oil control in utero as depicted in Additional file 4. Next, DNA methylation was mapped using MIRA-chip and custom Nimblegen arrays in purified G1R and G2R prospermatogonia at 17.5 dpc in triplicate and in adult spermatozoa in duplicate. Immediate and persistent changes are tabulated in Table 3 and Additional file 8. (A) Selected top persistent hits are shown from the analysis in duplicates labeled at the top according to the comparisons in Table 3 and marked with arrowheads (up for increase and down for decrease) (B) A selected IAP-flank region where common changes were detected in MGC samples between G1R and G2R at and between G2R MGC and G2R sperm. (C) The H19-Igf2 imprinted DMR is shown as a positive control for the DNA methylation signal (black rectangle). DNA methylation signals of MIRA versus input DNA are plotted as -log10 P values ranging from 0 to 8.3 for experimental and control replicate samples. Note that these top changes are minor and not highly significant.

Mentions: We found very few hits at levels 2 to 3 and no hits at level 4, despite the low cutoff values (Table 3 and Additional file 8). Some examples of the best hits of the level 2 and 3 analyses are shown in Figure 8A; these hits are unimpressive and exist at regions with generally low DNA methylation.Figure 8


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

Iqbal K, Tran DA, Li AX, Warden C, Bai AY, Singh P, Wu X, Pfeifer GP, Szabó PE - Genome Biol. (2015)

Selected top hits of transgenerationally inherited DNA methylation aberrations. Prospermatogonia of G1 fetuses were treated with ED or oil control in utero as depicted in Additional file 4. Next, DNA methylation was mapped using MIRA-chip and custom Nimblegen arrays in purified G1R and G2R prospermatogonia at 17.5 dpc in triplicate and in adult spermatozoa in duplicate. Immediate and persistent changes are tabulated in Table 3 and Additional file 8. (A) Selected top persistent hits are shown from the analysis in duplicates labeled at the top according to the comparisons in Table 3 and marked with arrowheads (up for increase and down for decrease) (B) A selected IAP-flank region where common changes were detected in MGC samples between G1R and G2R at and between G2R MGC and G2R sperm. (C) The H19-Igf2 imprinted DMR is shown as a positive control for the DNA methylation signal (black rectangle). DNA methylation signals of MIRA versus input DNA are plotted as -log10 P values ranging from 0 to 8.3 for experimental and control replicate samples. Note that these top changes are minor and not highly significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig8: Selected top hits of transgenerationally inherited DNA methylation aberrations. Prospermatogonia of G1 fetuses were treated with ED or oil control in utero as depicted in Additional file 4. Next, DNA methylation was mapped using MIRA-chip and custom Nimblegen arrays in purified G1R and G2R prospermatogonia at 17.5 dpc in triplicate and in adult spermatozoa in duplicate. Immediate and persistent changes are tabulated in Table 3 and Additional file 8. (A) Selected top persistent hits are shown from the analysis in duplicates labeled at the top according to the comparisons in Table 3 and marked with arrowheads (up for increase and down for decrease) (B) A selected IAP-flank region where common changes were detected in MGC samples between G1R and G2R at and between G2R MGC and G2R sperm. (C) The H19-Igf2 imprinted DMR is shown as a positive control for the DNA methylation signal (black rectangle). DNA methylation signals of MIRA versus input DNA are plotted as -log10 P values ranging from 0 to 8.3 for experimental and control replicate samples. Note that these top changes are minor and not highly significant.
Mentions: We found very few hits at levels 2 to 3 and no hits at level 4, despite the low cutoff values (Table 3 and Additional file 8). Some examples of the best hits of the level 2 and 3 analyses are shown in Figure 8A; these hits are unimpressive and exist at regions with generally low DNA methylation.Figure 8

Bottom Line: 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.

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus