Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.
Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.
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DOI：
10.1371/journal.pone.0102091
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Skinner MK
中科院分区：
文献类型：
--
作者：
Manikkam M;Haque MM;Guerrero-Bosagna C;Nilsson EE;Skinner MK
环境化合物，包括杀菌剂，塑料，农药，二恶英和碳氢化合物可以促进表观遗传的跨代遗传的成人发病的疾病在后代后代祖先暴露在胎儿性腺性别决定的关键时期。本研究检查了农药甲氧滴滴涕促进成人发病疾病的表观遗传跨代遗传和精子中相关的差异DNA甲基化区域（即表位突变）的作用。妊娠F0代雌性大鼠在胎儿性腺发育期间（妊娠第8至14天）短暂暴露于甲氧滴滴涕，然后在成年F1和F3（曾孙后代）代后代中评估成年发病疾病，以作为对照（暴露于溶剂）和甲氧滴滴涕谱系后代。甲氧滴滴涕谱系动物中肾脏疾病、卵巢疾病和肥胖症的发病率增加。在雌性和雄性中，F1和F3代的发病率均增加，F3代的多种疾病发病率增加。F4代反向异交（雌性）后代的发病率增加，表明疾病传播主要通过雌性生殖系传播。甲氧滴滴涕谱系雄性的F3代精子表观基因组的分析在全基因组基因启动子分析中鉴定了称为表突变的差异DNA甲基化区域（DMR）。与其他暴露特异性精子表位突变特征相比，发现这些表位突变是甲氧滴滴涕暴露特异性的。观察表明，农药甲氧滴滴涕有可能促进疾病的表观遗传跨代遗传，精子表观突变似乎提供了跨代疾病和祖先环境暴露的暴露特异性表观遗传生物标志物。
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.
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