Examination of Generational Impacts of Adolescent Chemotherapy: Ifosfamide and Potential for Epigenetic Transgenerational Inheritance

The current study was designed to use a rodent model to determine if exposure to the chemotherapy drug ifosfamide during puberty can induce altered phenotypes and disease in the grand-offspring of exposed individuals through epigenetic transgenerational inheritance. Numerous toxicant exposures during critical developmental windows can have generational impacts through this non-genetic inheritance mechanism. Pathologies such as delayed pubertal onset, kidney disease and multiple pathologies were observed to be significantly more frequent in the F1 generation offspring of ifosfamide lineage females. The F2 generation grand-offspring ifosfamide lineage males had transgenerational pathology phenotypes of early pubertal onset and reduced testis pathology. Reduced levels of anxiety were observed in both males and females from the exposure lineage in the transgenerational F2 generation grand-offspring. Differential DNA methylated regions (DMRs) were also identified in chemotherapy and control lineages sperm in the F1 and F2 generations. The transgenerational alterations in sperm epigenetics provides a molecular mechanism for the ancestral impacts of chemotherapy. Therefore, chemotherapy exposure can impact pathology and disease susceptibility in subsequent generations. Overall design: The transgenerational actions of control vehicle phosphate buffered saline (PBS) and ifosfamide (8.5mg/kg of body weight) treatments administered to pubertal male rats (F0 generation) once every three days for three treatments, starting at 26 days of age were investigated. Therefore, the F0 generation pubertal male was exposed to chemotherapy and as an adult bred to generate the F1 generation and F1 generation adult bred to generate the F2 generation for a transgenerational assessment. Analysis of sperm differential DNA methylation regions (DMRs) between F1 and F2 generation ifosfamide and control lineage animals was assessed with methylated DNA immunoprecipitation (MeDIP) followed by next generation sequencing (MeDIP-Seq). Several samples do not have an associated processed data file