Transgenerational Epigenetic Programming of the Thyroid Axis

下丘脑-垂体-甲状腺(HPT)轴固有的是动态平衡和反馈机制， 严格控制循环和组织中的甲状腺激素(T4)和3，3，5-三碘甲状腺原氨酸(T3)的水平。这些 荷尔蒙水平反过来影响一系列对健康和适应能力至关重要的生理过程 有机体。3型脱碘酶(D3)，其功能是灭活组织中的T4和T3，是一个关键的 甲状腺激素(TH)作用的决定因素。D3是由在小鼠身上印记的基因(Dio3)编码的 人类(Dio3)。在这两个物种中，D3在母胎单位和新生儿中都高度表达， 在确保TH的浓度对发展和对 HPT轴的编程。因此，D3缺乏的小鼠改变了血清TH水平，明显的功能障碍 下丘脑、脑垂体腺和甲状腺发育受损等表型异常。我们的 来自小鼠模型的初步数据强烈表明，TH状态的改变可以通过 表观遗传机制，诱导D3在下丘脑和 后代后代的其他组织。 因此，这一建议试图调查这样的假设，即跨代表观遗传在 Dio3基因座影响HPT轴的编程和TH代谢和作用的调节 在一生中。此外，我们推测TH本身，因此动物的甲状腺状况，起着关键作用。 在设置表观遗传标记中的作用，这些标记部分地决定了D3在后续世代中的表达模式。 具体地说，我们在此建议进行以下实验： (1)确定dio3的跨代遗传模式的表型后果 在HPT轴改变的动物的后代中观察到； (2)确定引起dio3跨代模式变化的表观遗传学变化。 继承。 (3)确定TH在诱导改变的跨代表观遗传中的作用。 Dio3基因座在发育过程中和成年动物中。 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，它提供了 HPT轴具有额外的可塑性，以适应动态平衡的挑战。此外，鉴于 D3在调节细胞内TH水平方面的重要性，特别是在发育中的大脑和成人大脑中， 这一新的范式暗示了一个额外的、可遗传的成分，这可能会影响心理 健康或可想象的易患代谢或生殖功能障碍。

Intrinsic to the hypothalamic-pituitary-thyroid (HPT) axis are homeostatic and feedback mechanisms that maintain circulating and tissue levels of thyroxine (T4) and 3,3¿,5-triiodothyronine (T3) within strict limits. These hormone levels in turn influence a host of physiological processes critical to the health and adaptability of the organism. The type 3 deiodinase (D3), which functions to inactivate T4 and T3 in tissues, is a critical determinant of thyroid hormone (TH) action. The D3 is coded by a gene that is imprinted in mice (Dio3) and humans (DIO3). In both species, the D3 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 programming of the HPT axis. Thus, mice deficient in D3 have altered serum TH levels, marked dysfunction of the hypothalamus, pituitary and thyroid glands, impaired growth and other phenotypic abnormalities. Our preliminary data derived from mouse models strongly suggest that alterations in TH status, can, through epigenetic mechanisms, induce marked changes in the expression patterns of the D3 in the hypothalamus and other tissues in subsequent generations of offspring. Thus, this proposal seeks to investigate the hypothesis that transgenerational epigenetic inheritance at the Dio3 locus influences the programming of the HPT axis and the regulation of TH metabolism and action throughout life. Furthermore, we speculate that TH itself, and thus the thyroid status of the animal, plays a key role in setting the epigenetic marks that determine, in part, D3 expression patterns in subsequent generations. Specifically, we propose herein experiments to: (1) Define the phenotypic consequences of the transgenerational inheritance patterns of the Dio3 observed in the descendants of an animal with an altered HPT axis; (2) Identify the epigenetic changes responsible for the varied patterns of Dio3 transgenerational inheritance. (3) Determine the role of TH in the induction of altered transgenerational epigenetic inheritance at the Dio3 locus during development and in adult animals. Notably, this heritable process may represent a novel transgenerational mechanism that provides the HPT axis with an additional degree of plasticity to adapt to homeostatic challenges. In addition, given the importance of the D3 in modulating the intracellular levels of TH, particularly in the developing and adult brain, this new paradigm implies an additional, heritable component to the action of TH that may impact mental health or conceivably predispose to metabolic or reproductive dysfunction.