Transgenerational Disease Specific Epigenetic Sperm Biomarkers after Ancestral Exposure to Dioxin

Dioxin is one of the most common historic industrial contaminants with several major industry and government accidents having exposed large numbers of the worldwide population over the past century. Previous rat studies have demonstrated the ability of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) exposure to promote the epigenetic transgenerational inheritance of disease susceptibility in subsequent generations. The types of disease observed include testis, ovary, kidney, prostate and obesity pathologies. The current study was designed to use an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation biomarkers for specific transgenerational diseases. The transgenerational F3 generation dioxin lineage male rats with and without a specific disease were compared to identify differential DNA methylation regions (DMRs). The genomic features of the DMRs are characterized. Observations demonstrate that disease specific epimutation DMRs exist for the transgenerational dioxin lineage rats that can potentially be used as epigenetic biomarkers for testis, ovary, kidney, prostate and obesity diseases. These disease specific DMRs were associated with genes that have previously been shown to be linked with these diseases. This EWAS for transgenerational disease identified epigenetic biomarkers and provides the proof of concept of the potential to develop similar biomarkers for humans to diagnose disease susceptibilities and facilitate preventative medicine.二噁英（Dioxin）是历史上最为常见的工业污染物之一，在过去一个世纪间，多起重大工业事故及政府相关事故曾导致全球大量人群暴露于该污染物环境中。既往大鼠研究已证实，二噁英（2,3,7,8-四氯二苯并对二噁英，TCDD）暴露可诱导疾病易感性在子代中发生表观遗传跨代遗传。本次研究观测到的病变类型涵盖睾丸病变、卵巢病变、肾脏病变、前列腺病变以及肥胖症。本研究采用表观基因组全关联研究（epigenome-wide association study, EWAS）方法，旨在筛选针对特定跨代疾病的潜在精子DNA甲基化生物标志物。研究对携带与不携带特定疾病的跨代F3代二噁英谱系雄性大鼠开展比对分析，以识别差异DNA甲基化区域（differential DNA methylation regions, DMRs），并对该类DMRs的基因组特征进行表征。研究结果表明，二噁英谱系跨代大鼠存在疾病特异性表观突变DMRs，可作为睾丸、卵巢、肾脏、前列腺疾病及肥胖症的表观遗传生物标志物。此类疾病特异性DMRs与既往已被证实与上述疾病存在关联的基因密切相关。本项跨代疾病表观基因组全关联研究成功筛选出表观遗传生物标志物，验证了开发同类人类生物标志物以诊断疾病易感性、助力预防医学发展的可行性。