Transgenerational epigenetic programming of the thyroid axis

下丘脑-垂体-甲状腺轴(HPTA)和瘦素-黑素皮质素系统(LMS)的内在动态平衡和反馈机制将循环和组织中的甲状腺素(T4)、3，3‘，5-三碘甲腺原氨酸(T3)和瘦素(LEP)水平维持在严格的限度内。这些内分泌系统反过来影响对机体的新陈代谢、健康和适应性至关重要的一系列生理过程。3型脱碘酶(Dio3)的功能是使组织中的T4和T3失活，它是由老鼠和人类身上印记的基因编码的。Dio3在母胎单位和新生儿中高度表达，在确保TH浓度对于发育和HPTA和LMS的规划是最佳的方面发挥关键作用。因此，缺乏dio3的小鼠血清TH水平发生改变，下丘脑、垂体、甲状腺和脂肪组织明显功能障碍。我们的初步数据表明，发育过剩的T3改变了胚系的表观遗传信息，包括dio3基因和其他发育基因的信息。这会导致随后几代人HPTA和LMS的个体发育和设定点发生变化，从而导致代谢性疾病的易感性。因此，这一建议试图调查一种假设，即发育过度暴露于T3会引起dio3基因和其他相关基因座跨代表观遗传的变化，并影响后代HPTA和LMS的编程以及整个生命过程中TH活动和能量平衡的调节。具体地说，基于我们关于T_3过度发育引起胚系表观遗传信息改变的数据，我们在这里建议实验：(1)确定由祖先发育过度暴露于T_3所引起的在dio3基因座和其他与HPTA和LMS发育相关的基因座位上发生改变的表观遗传标记的遗传模式；(2)描述这种改变的表观遗传对HPTA和LMS的个体发育、功能和生理适应性的表型后果。值得注意的是，这种可遗传的过程可能代表了一种新的跨代机制，它影响HPTA和LMS适应动态平衡挑战的可塑性程度，从而减少或加剧肥胖的倾向。此外，鉴于Dio3在调节TH的细胞内水平和由T3过量引起的表观遗传学改变的广度方面的重要性，这个新的范例暗示了一个额外的、可遗传的成分，这可能对其他影响心理健康或生殖功能的疾病状态具有重要意义。

Intrinsic to the hypothalamic-pituitary-thyroid axis (HPTA) and the leptin-melanocortin system (LMS) are homeostatic and feedback mechanisms that maintain circulating and tissue levels of thyroxine (T4), 3,3',5- triiodothyronine (T3) and Leptin (LEP) within strict limits. These endocrine systems in turn influence a host of physiological processes critical to the metabolic health and adaptability of the organism. The type 3 deiodinase (DIO3) functions to inactivate T4 and T3 in tissues and is coded by a gene that is imprinted in mice and humans. DIO3 is highly expressed in the maternal-fetal unit and in the neonate, where it plays a critical role in ensuring that concentrations of TH are optimal for development and for the programming of the HPTA and the LMS. Thus, mice deficient in DIO3 have altered serum TH levels, marked dysfunction of the hypothalamus, pituitary and thyroid glands and adipose tissue. Our preliminary data suggest that a developmental excess of T3 modifies the epigenetic information of the germ line, including the Dio3 locus and that of other developmental genes. This leads in subsequent generations to alterations in the ontogeny and set points of the HPTA and the LMS, with consequences for the susceptibility to metabolic disease. Thus, this proposal seeks to investigate the hypothesis that developmental overexposure to T3 elicits changes in the transgenerational epigenetic inheritance at the Dio3 locus and at other relevant loci and influences in descendants the programming of the HPTA and LMS and the regulation of TH action and energy balance throughout life. Specifically, and based on our data concerning the alterations in the epigenetic information of germ line caused by a developmental excess of T3, we propose herein experiments to: (1) Define the patterns of inheritance of altered epigenetic marks at the Dio3 locus and at other gene loci of relevance to the development of the HPTA and the LMS that are caused by an ancestral developmental overexposure to T3; (2) Delineate the phenotypic consequences of such altered epigenetic inheritance for the ontogeny, function and physiological adaptability of the HPTA and the LMS. Notably, this heritable process may represent a novel transgenerational mechanism that impacts the degree of plasticity by which the HPTA and the LMS adapt to homeostatic challenges, reducing or exacerbating the propensity to develop obesity. In addition, given the importance of the DIO3 in modulating the intracellular levels of TH and the breadth of epigenetic alterations caused by an excess of T3, this new paradigm implies an additional, heritable component that may be of significance to other disease states affecting mental health or reproductive function.