GSE158086
Epigenome-Wide Association Study (EWAS) Identifies Transgenerational Disease Biomarkers in Sperm Following Ancestral Exposure to the Pesticide Methoxychlor
Environmental exposures such as chemical toxicants can alter gene expression and disease susceptibility through epigenetic processes. Epigenetic changes can be passed to future generations through germ cells through epigenetic transgenerational inheritance of increased disease susceptibility. The current study used an epigenome-wide association study (EWAS) to investigate whether specific transgenerational epigenetic signatures of differential DNA methylation regions (DMRs) exist that are associated with particular disease states in the F3 generation great-grand offspring of F0 generation rats exposed during gestation to the agricultural pesticide methoxychlor. The transgenerational epigenetic profile of sperm from F3 generation methoxychlor lineage rats that have only one disease state was compared to those that have no disease. Observations identify disease specific patterns of DMRs for these transgenerational rats that can potentially serve as epigenetic biomarkers for prostate disease, kidney disease, obesity, and the presence of multiple diseases. The chromosomal locations, genomic features, and gene associations of the DMRs are characterized. Disease specific DMR sets contained DMR associated genes that have previously been shown to be associated with that specific disease. Future epigenetic biomarkers could potentially be developed and validated for humans as a disease susceptibility diagnostic tool to facilitate preventative medicine and management of disease. Overall design: Analysis of the transgenerational actions of methoxychlor used outbred Sprague Dawley female rats (F0 generation) transiently exposed (200mg/kg body weight) methoxychlor during days 8 to 14 of gestation. The F1 generation animals (direct fetal exposure) were bred to generate the F2 generation (direct germline exposure), which were bred to generate the F3 generation (transgenerational so no direct exposure).  The methoxychlor lineage animals were aged to 1 year and euthanized for pathology and sperm epigenetic analysis. No sibling or cousin breedings (crosses) were used to avoid any inbreeding artifacts. Generally 6–8 founder gestating females from different litters were bred and 25–50 individuals of each sex obtained for each generation. --------------------------- Authors state"Samples MX12, MX13, MX22, and MX24 were not included in any analysis and thus have no processed data files", "MX12 and MX13 were removed due to low sequence quality", and "MX22 and MX24 did not have any relevant disease association".