GSE163412
Ancestral Plastics Exposure Induces Transgenerational Disease Specific Sperm Epigenome-Wide Association Biomarkers Methylation Epimutation Biomarkers for Specific Transgenerational Disease
Plastic derived compounds are one of the most frequent daily world-wide exposures. Previously a mixture of plastic derived toxicants involving bisphenol A (BPA), Bis(2-ethylhexyl) phthalate (DEHP), and dibutyl phthalate (DBP) at lower dose exposures of a gestating female rat were found to promote the epigenetic transgenerational inheritance of disease to the offspring (F1 generation), grand-offspring (F2 generation) and great-grand-offspring (F3 generation). Epigenetic analysis of the male sperm was found to result in differential DNA methylation regions (DMRs) in the transgenerational F3 generation male sperm. The current study is distinct and was designed to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. Observations show disease specific DMRs called epimutations in the transgenerational F3 generation great-grand-offspring rats ancestrally exposed to plastics. The epigenetic DMR biomarkers were identified for testis disease, kidney disease, and multiple (=2) diseases. These disease sperm epimutation biomarkers were found to be predominantly disease specific. The genomic locations and features of these DMRs were identified. Interestingly, the disease specific DMR associated genes were previously shown to be linked with each of the specific diseases. Therefore, the germline has ancestrally derived epimutations that potentially transmit transgenerational disease susceptibilities. Epigenetic biomarkers for specific diseases could be used as diagnostics to facilitate clinical management of disease and preventative medicine. Overall design: Analysis of the transgenerational actions of multiple pesticide chemicals used outbred Sprague Dawley female rats (F0 generation) transiently exposed to the plastic compound mixture (BPA 25 mg/kg BW/day, DEHP 375 mg/kg BW /day, and DBP 33mg/kg BW/day)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 plastics 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. Several samples are not included in the processed data files. These samples were not included in the DMR analyses due to not having relevant diseases. However, they are part of the project and a future reanalysis may require them.