Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Ovarian Pathology and Granulosa Cell Epigenome and Transcriptome Alterations: Ancestral Origins of PCO and POI

Two of the most prevalent ovarian diseases affecting women's fertility and health are Primary Ovarian Insufficiency (POI) and Polycystic Ovarian Syndrome (PCOS). Previous studies have shown that exposure to a number of environmental toxicants can promote the epigenetic transgenerational inheritance of ovarian disease, including decreases in the primordial follicle pool of oocytes that are similar to what is seen in POI, and increases in ovarian cysts that are similar to what is seen in PCOS. In the current study, transgenerational changes to the transcriptome and epigenome of ovarian granulosa cells are characterized in F3 generation rats after ancestral vinclozolin or DDT exposures compared to controls. There was an increase in ovarian disease in transgenerational F3 generation vinclozolin and DDT lineage rats at one year of age compared to F3 generation controls. In purified granulosa cells from 20 day old F3 generation females 164 differentially methylated regions (DMRs) (p<1e-06) were found in the F3 generation vinclozolin lineage, and 293 DMRs (p<1e-06) in the DDT lineage, compared to controls. The long non-coding RNAs (lncRNAs) and small non-coding RNAs (sncRNAs) were found to be differentially expressed in both the vinclozolin and DDT lineages with the sncRNAs having 492 sncRNAs (p<1 x 10-4) in the vinclozolin lineage and 1,085 sncRNAs (p<1 x 10-4) in the DDT lineage. The lncRNAs were differentially expressed with 123 and 51 in the vinclozolin and DDT lineages, respectively (p<1 x 10-4). Differentially expressed mRNAs were found in the vinclozolin lineage at 174 mRNAs (p<1 x 10-4) and the DDT lineage at 212 mRNAs (p<1 x 10-4). These transgenerational epigenetic changes contribute to the dysregulation of the ovary and disease susceptibility that can occur in later life. This suggests that ancestral exposure to toxicants is potentially a major risk factor that must be considered in the molecular etiology of ovarian disease.

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