Adipocyte Epigenetic Alterations and Potential Therapeutic Targets in Transgenerationally Inherited Lean and Obese Phenotypes Following Ancestral Exposure to Environmental Toxicants

This study examines the transgenerational adipocyte (fat cell) epigenetic alterations in F3 generation obese and lean rats ancestrally exposed to DDT and atrazine. Adipocytes were isolated from the gonadal fat pad of F3 generation 1-year old rats ancestrally exposed to DDT, atrazine, or vehicle control in order to obtain adipocyte DNA for DNA methylation analysis. Observations indicate that there were differential DNA methylated regions (DMRs) in the adipocytes with the lean or obese phenotypes compared to control normal (non-obese or lean) populations. Interestingly, there were epigenetic changes that were distinct when comparing the lean and obese DMRs between the control and exposure lineage groups. DMR gene associations were identified which included common set of genes previously shown to associate with adipocyte pathology. The comparison of epigenetic alterations indicated that there were substantial overlaps between the different treatment lineage groups for both the lean and obese phenotypes. Novel correlated genes and gene pathways associated with DNA methylation were identified, and may aid in the discovery of potential therapeutic targets for metabolic diseases such as obesity.本研究针对祖先暴露于滴滴涕（DDT）与莠去津（atrazine）的F3代肥胖及瘦型大鼠的跨代脂肪细胞（adipocyte）表观遗传改变展开分析。研究人员从祖先分别暴露于DDT、莠去津或赋形剂对照的1龄F3代大鼠的性腺脂肪垫（gonadal fat pad）中分离脂肪细胞，以获取脂肪细胞DNA用于DNA甲基化分析。观测结果显示，相较于对照正常（非肥胖/瘦型）群体，具有瘦型或肥胖表型的脂肪细胞中存在差异甲基化区域（differentially methylated regions, DMRs）。有趣的是，在对照与暴露谱系组之间对比瘦型与肥胖型DMR时，可观察到截然不同的表观遗传变化。研究已鉴定出DMR相关基因，其中包含此前被证实与脂肪细胞病理相关的共有基因集。对表观遗传改变的对比分析表明，针对瘦型与肥胖表型的不同处理谱系组之间均存在大量重叠区域。本研究还鉴定出与DNA甲基化相关的新型关联基因及基因通路，或可助力发现肥胖等代谢疾病的潜在治疗靶点。