PDF(Pubmed)
Abstract：
Intergenerational and transgenerational epigenetic effects resulting from conditions in previous generations can contribute to environmental adaptation as well as disease susceptibility. Previous studies in rodent and human models have shown that abnormal developmental exposure to thyroid hormone affects endocrine function and thyroid hormone sensitivity in later generations. Since the imprinted type 3 deiodinase gene (Dio3) regulates sensitivity to thyroid hormones, we hypothesize its epigenetic regulation is altered in descendants of thyroid hormone overexposed individuals. Using DIO3-deficient mice as a model of developmental thyrotoxicosis, we investigated Dio3 total and allelic expression and growth and endocrine phenotypes in descendants. We observed that male and female developmental overexposure to thyroid hormone altered total and allelic Dio3 expression in genetically intact descendants in a tissue-specific manner. This was associated with abnormal growth and neonatal levels of thyroid hormone and leptin. Descendant mice also exhibited molecular abnormalities in the Dlk1-Dio3 imprinted domain, including increased methylation in Meg3 and altered foetal brain expression of other genes of the Dlk1-Dio3 imprinted domain. These molecular abnormalities were also observed in the tissues and germ line of DIO3-deficient ancestors originally overexposed to thyroid hormone in utero. Our results provide a novel paradigm of epigenetic self-memory by which Dio3 gene dosage in a given individual, and its dependent developmental exposure to thyroid hormone, influences its own expression in future generations. This mechanism of epigenetic self-correction of Dio3 expression in each generation may be instrumental in descendants for their adaptive programming of developmental growth and adult endocrine function.
摘要：
前几代条件引起的代际和跨代表观遗传效应可有助于环境适应以及疾病易感性。先前在啮齿动物和人体模型中的研究表明，甲状腺激素的异常发育暴露会影响后代的内分泌功能和甲状腺激素敏感性。由于印迹3型脱碘酶基因（Dio3）调节甲状腺激素的敏感性，我们假设其表观遗传调控在甲状腺激素过度暴露个体的后代中发生了改变.使用DIO3缺陷小鼠作为发育性甲状腺毒症模型，我们调查了Dio3在后代中的总和等位基因表达以及生长和内分泌表型。我们观察到，男性和女性发育过度暴露于甲状腺激素以组织特异性方式改变了遗传完整后代中总的和等位基因的Dio3表达。这与甲状腺激素和瘦素的异常生长和新生儿水平有关。后代小鼠在Dlk1-Dio3印迹域中也表现出分子异常，包括Meg3甲基化增加和Dlk1-Dio3印迹域其他基因的胎儿脑表达改变。在最初在子宫内过度暴露于甲状腺激素的DIO3缺陷祖先的组织和种系中也观察到了这些分子异常。我们的结果提供了一种新的表观遗传自我记忆范例，通过该范例，Dio3基因剂量在给定个体中，以及它对甲状腺激素的依赖性发育暴露，影响自己在后代中的表达。这种在每一代中Dio3表达的表观遗传自校正机制可能对后代的发育生长和成人内分泌功能的适应性编程有帮助。
