Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease

摘要

Prostate diseases include prostate cancer, which is the second most common male neoplasia, and benign prostatic hyperplasia (BPH), which affects approximately 50% of men. The incidence of prostate disease is increasing, and some of this increase may be attributable to ancestral exposure to environmental toxicants and epigenetic transgenerational inheritance mechanisms. The goal of the current study was to determine the effects that exposure of gestating female rats to vinclozolin has on the epigenetic transgenerational inheritance of prostate disease, and to characterize by what molecular epigenetic mechanisms this has occurred. Gestating female rats (F0 generation) were exposed to vinclozolin during E8-E14 of gestation. F1 generation offspring were bred to produce the F2 generation, which were bred to produce the transgenerational F3 generation. The transgenerational F3 generation vinclozolin lineage males at 12 months of age had an increased incidence of prostate histopathology and abnormalities compared to the control lineage. Ventral prostate epithelial and stromal cells were isolated from F3 generation 20-day old rats, prior to the onset of pathology, and used to obtain DNA and RNA for analysis. Results indicate that there were transgenerational changes in gene expression, noncoding RNA expression, and DNA methylation in both cell types. Our results suggest that ancestral exposure to vinclozolin at a critical period of gestation induces the epigenetic transgenerational inheritance of prostate stromal and epithelial cell changes in both the epigenome and transcriptome that ultimately lead to prostate disease susceptibility and may serve as a source of the increased incidence of prostate pathology observed in recent years.