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.诸如化学毒物在内的环境暴露可通过表观遗传过程改变基因表达与疾病易感性。表观遗传改变可通过生殖细胞介导的疾病易感性升高的表观遗传跨代遗传，传递给后代个体。本研究采用全表观基因组关联研究（epigenome-wide association study, EWAS），旨在探究：在妊娠期间暴露于农业杀虫剂甲氧氯的F0代大鼠的F3代曾孙辈中，是否存在与特定疾病状态相关的差异DNA甲基化区域（differential DNA methylation regions, DMRs）特异性跨代表观遗传特征。研究将仅患单一疾病的F3代甲氧氯暴露谱系大鼠的精子表观遗传谱，与未罹患任何疾病的同谱系大鼠进行对比。结果鉴定出了此类跨代大鼠的疾病特异性DMR模式，该模式可作为前列腺疾病、肾脏疾病、肥胖症及多重疾病患病风险的表观遗传生物标志物。本研究还对DMRs的染色体位置、基因组特征及基因关联进行了系统表征。疾病特异性DMR集合所包含的关联基因，此前已被证实与对应特定疾病存在相关性。未来可针对人类开发并验证此类表观遗传生物标志物，将其作为疾病易感性诊断工具，以助力预防医学发展与疾病管理。