Manikkam Mohan, Haque M Muksitul, Guerrero-Bosagna Carlos, Nilsson Eric E, Skinner Michael K
Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America.
PLoS One. 2014 Jul 24;9(7):e102091. doi: 10.1371/journal.pone.0102091. eCollection 2014.
Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.
包括杀菌剂、塑料、杀虫剂、二噁英和碳氢化合物在内的环境化合物，在胎儿性腺性别决定的关键时期，若其祖先接触过这些物质，那么它们可促进成年期疾病在后代子孙中的表观遗传跨代遗传。本研究检测了杀虫剂甲氧滴滴涕促进成年期疾病的表观遗传跨代遗传以及精子中相关差异DNA甲基化区域（即表观突变）的作用。在胎儿性腺发育期间（妊娠第8至14天），对妊娠的F0代雌性大鼠短暂暴露于甲氧滴滴涕，然后在成年F1和F3（曾孙后代）代后代中评估成年期疾病，以对照（暴露于赋形剂）和甲氧滴滴涕谱系后代作为研究对象。甲氧滴滴涕谱系动物中肾病、卵巢疾病和肥胖症的发病率有所增加。在雌性和雄性中，F1和F3代的疾病发病率均有所上升，且F3代中多种疾病的发病率增加。F4代回交（雌性）后代的疾病发病率增加，表明疾病传播主要通过雌性生殖系进行。在全基因组基因启动子分析中，对甲氧滴滴涕谱系雄性的F3代精子表观基因组进行分析，确定了差异DNA甲基化区域（DMR），称为表观突变。与其他暴露特异性精子表观突变特征相比，发现这些表观突变具有甲氧滴滴涕暴露特异性。观察结果表明，杀虫剂甲氧滴滴涕有可能促进疾病的表观遗传跨代遗传，并且精子表观突变似乎为跨代疾病和祖先环境暴露提供了暴露特异性表观遗传生物标志物。
