Glyphosate Induced Transgenerational DNA Methylation and Histone Retention Sperm Epigenetic Biomarkers for Disease

The herbicide glyphosate has been shown to promote the epigenetic transgenerational inheritance of pathology and disease in subsequent great-grand offspring (F3 generation). This generational toxicology suggests the impacts of environmental exposures need to assess subsequent generations. The current study was designed to identify epigenetic biomarkers for glyphosate induced transgenerational disease. Following a transient glyphosate exposure of a gestating female rat (F0 generation), the subsequent transgenerational F3 generation, with no direct exposure, were aged to 1 year and animals with specific pathologies identified. The pathologies investigated included prostate disease, kidney disease, obesity, and presence of multiple disease. The sperm were collected from the males and used to identify specific differential DNA methylation regions (DMRs) associated with the pathologies. In addition, the differential histone retention sites (DHRs) were examined for the various pathologies as well. Unique signatures of DMRs and DHRs for each pathology were identified for the specific diseases. Interestingly, at a lower statistical threshold overlapping sets of DMRs and DHRs were identified that were common for all the pathologies. The DMR and DHR gene associations were identified and correlated with known pathology associated genes. While the disease biomarker DMR and DHR did not meet typical statistical significance levels, these results may help design future studies with reduced variability. Observations indicate transgenerational epigenetic biomarkers of disease pathology can potentially be identified in the sperm that can assess disease susceptibility. These biomarkers may also suggest epigenetic diagnostics could be used to facilitate preventative medicine.已有研究表明，除草剂草甘膦（glyphosate）可促使病理与疾病在后续曾孙代（F3代）中发生表观遗传跨代遗传（epigenetic transgenerational inheritance）。该代际毒理学现象提示，环境暴露的健康影响需纳入对后续子代的评估范畴。本研究旨在识别草甘膦诱导的跨代疾病表观遗传生物标志物。研究人员对妊娠雌鼠（F0代）实施短暂草甘膦暴露后，将未直接接触该物质的后续跨代F3大鼠饲养至1年龄，筛选出出现特定病理症状的个体。本次调研关注的病理类型包括前列腺疾病、肾脏疾病、肥胖症及多病症共存状态。研究人员从雄性个体体内采集精子，以鉴定与上述病理相关的特异性差异DNA甲基化区域（differential DNA methylation regions, DMRs）；此外，还针对各类病理情况分析了差异组蛋白保留位点（differential histone retention sites, DHRs）。研究人员为各病理类型鉴定出了独特的DMR与DHR特征谱。值得关注的是，在较低统计阈值下，可识别出所有病理类型共有的重叠DMR与DHR集合。研究还对DMR及DHR的关联基因进行了定位，并与已知的病理相关基因开展了关联分析。尽管与疾病生物标志物相关的DMR与DHR未达到常规统计显著性水平，但本研究结果可为后续降低实验变异性的研究设计提供参考。观测结果显示，可在精子中识别出与疾病病理相关的跨代表观遗传生物标志物，进而评估个体的疾病易感性。此类生物标志物或可推动表观遗传诊断技术应用于预防医学领域。