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.本研究旨在利用啮齿动物模型（rodent model），探究青春期暴露于化疗药物异环磷酰胺（ifosfamide）是否可通过表观遗传跨代遗传（epigenetic transgenerational inheritance），使暴露个体的孙辈出现表型改变与疾病。诸多在关键发育窗口期暴露的有毒物质，均可通过这一非遗传遗传机制对多代个体产生跨代影响。研究观察到，异环磷酰胺谱系雌性的子一代（F1）个体中，青春期启动延迟、肾脏疾病及多种病理特征的发生率显著升高。异环磷酰胺谱系雄性的孙一代（F2）个体，则表现出两类跨代病理表型：青春期启动提前与睾丸病理异常风险降低。在跨代的孙一代（F2）暴露谱系中，雌雄个体均呈现出焦虑水平降低的表型。子一代与孙一代的化疗暴露组与对照组精子样本中，均鉴定出差异DNA甲基化区域（differential DNA methylated regions, DMRs）。精子表观遗传组的跨代改变，为化疗暴露的祖先效应提供了分子机制。综上，化疗药物暴露可影响后续世代的病理发生与疾病易感性。