Center for Reproductive Biology School of Biological Sciences, Washington State University, Pullman, WA, USA.
Epigenetics. 2021 Oct;16(10):1150-1167. doi: 10.1080/15592294.2020.1853319. Epub 2020 Dec 9.
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 diseases using an epigenome-wide association study (EWAS). Following transient glyphosate exposure of gestating female rats (F0 generation), during the developmental period of gonadal sex determination, 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 glyphosate lineage males with only an individual disease and used to identify specific differential DNA methylation regions (DMRs) and the differential histone retention sites (DHRs) associated with that pathology. 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. This is one of the first observations that sperm histone retention can potentially act as a biomarker for specific diseases. The DMR and DHR associated genes were identified and correlated with known pathology specific-associated genes. Observations indicate transgenerational epigenetic biomarkers of disease pathology can be identified in the sperm that appear to assess disease susceptibility. These biomarkers suggest epigenetic diagnostics could potentially be used to facilitate preventative medicine.
除草剂草甘膦已被证明可促进随后的曾孙代（F3 代）病理和疾病的表观遗传跨代遗传。这种代际毒理学表明，需要评估环境暴露对后代的影响。本研究旨在使用全基因组关联研究（EWAS）鉴定草甘膦诱导的跨代疾病的表观遗传生物标志物。在妊娠雌性大鼠（F0 代）短暂暴露草甘膦后，在生殖性别决定的发育期间，随后的跨代 F3 代没有直接暴露，其年龄达到 1 岁，并确定了具有特定病理的动物。研究的病理包括前列腺疾病、肾脏疾病、肥胖症和多种疾病的存在。从具有单一疾病的草甘膦系雄性中收集精子，并用于鉴定与该病理相关的特定差异 DNA 甲基化区域（DMR）和差异组蛋白保留位点（DHR）。为每种特定疾病确定了 DMR 和 DHR 的独特特征。有趣的是，在较低的统计阈值下，确定了与所有病理相关的重叠 DMR 和 DHR 集。这是首次观察到精子组蛋白保留可能作为特定疾病的生物标志物。鉴定了与 DMR 和 DHR 相关的基因，并与已知的特定病理相关基因进行了相关性分析。观察结果表明，可以在精子中识别出疾病病理的跨代表观遗传生物标志物，这些标志物似乎可以评估疾病易感性。这些生物标志物表明，表观遗传诊断可能可用于促进预防医学。
