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）固有的稳态和反馈机制维持循环和组织水平的甲状腺素（T4）， 3,3'，5-三碘甲状腺原氨酸（T3）和瘦素（LEP）在严格的限制。这些内分泌系统反过来影响一系列对机体代谢健康和适应性至关重要的生理过程。3型脱碘酶（DIO3）的功能是使组织中的T4和T3失活，并由一种在小鼠和人类中留下印记的基因编码。DIO3在母胎单位和新生儿中高度表达，它在确保TH浓度为发育最佳以及HPTA和LMS的编程中起着关键作用。因此，缺乏DIO3的小鼠血清TH水平发生改变，下丘脑、垂体、甲状腺和脂肪组织出现明显功能障碍。我们的初步数据表明，发育过量的T3改变了种系的表观遗传信息，包括Dio3位点和其他发育基因的表观遗传信息。这导致在后代中HPTA和LMS的个体发生和设定点发生改变，从而导致对代谢性疾病的易感性。因此，本研究旨在探讨发育过度暴露于T3引发Dio3位点和其他相关位点的跨代表观遗传变化，并影响后代HPTA和LMS的编程以及TH作用和能量平衡的调节。具体而言，根据我们关于发育过量T3引起种系表观遗传信息改变的数据，我们提出了以下实验：(1)确定祖先发育过度暴露于T3导致的Dio3位点和其他与HPTA和LMS发育相关的基因位点表观遗传标记改变的遗传模式；(2)描述这种改变的表观遗传对HPTA和LMS的个体发生、功能和生理适应性的表型影响。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适应稳态挑战的可塑性程度，从而减少或加剧肥胖的倾向。此外，考虑到DIO3在调节细胞内TH水平中的重要性以及过量T3引起的表观遗传改变的广度，这一新的范式暗示了一个额外的、可遗传的成分，可能对影响心理健康或生殖功能的其他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.