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.

Public Health Relevance

In this proposal we will determine the role of a unique inherited epigenetic mechanism whereby the thyroid status of an ancestor influences the programming of hormonal and neuroendocrine systems that are critical for the regulation of energy balance. We aim to identify the patterns of inheritance of the subjacent altered epigenetic marks and how they associate with the functional parameters of the thyroid axis and leptin-melanocortin system in normal and challenging physiological situations. We propose that this novel process of epigenetic inheritance is highly relevant to the unique manner in which an individual regulates food intake and metabolic rate and to his inherited but non-genetic susceptibility to metabolic disease and obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1)
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Burch, Henry B
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Martinez, M Elena; Duarte, Christine W; Stohn, J Patrizia et al. (2018) Thyroid hormone influences brain gene expression programs and behaviors in later generations by altering germ line epigenetic information. Mol Psychiatry :
Hernandez, Arturo; Stohn, J Patrizia (2018) The Type 3 Deiodinase: Epigenetic Control of Brain Thyroid Hormone Action and Neurological Function. Int J Mol Sci 19:
van der Spek, Anne H; Surovtseva, Olga V; Jim, Kin Ki et al. (2018) Regulation of Intracellular Triiodothyronine Is Essential for Optimal Macrophage Function. Endocrinology 159:2241-2252
Hernandez, Arturo (2018) Thyroid Hormone Deiodination and Action in the Gonads. Curr Opin Endocr Metab Res 2:18-23
Hernandez, Arturo (2018) Thyroid Hormone Role and Economy in the Developing Testis. Vitam Horm 106:473-500
Stohn, J P; Martinez, M E; Zafer, M et al. (2018) Increased aggression and lack of maternal behavior in Dio3-deficient mice are associated with abnormalities in oxytocin and vasopressin systems. Genes Brain Behav 17:23-35
van der Spek, Anne H; Jim, Kin Ki; Karaczyn, Aldona et al. (2018) The Thyroid Hormone Inactivating Type 3 Deiodinase Is Essential for Optimal Neutrophil Function: Observations From Three Species. Endocrinology 159:826-835
Ng, Lily; Liu, Hong; St Germain, Donald L et al. (2017) Deletion of the Thyroid Hormone-Activating Type 2 Deiodinase Rescues Cone Photoreceptor Degeneration but Not Deafness in Mice Lacking Type 3 Deiodinase. Endocrinology 158:1999-2010
Wu, Zhaofei; Martinez, M Elena; St Germain, Donald L et al. (2017) Type 3 Deiodinase Role on Central Thyroid Hormone Action Affects the Leptin-Melanocortin System and Circadian Activity. Endocrinology 158:419-430
Martinez, M Elena; Karaczyn, Aldona; Stohn, J Patrizia et al. (2016) The Type 3 Deiodinase Is a Critical Determinant of Appropriate Thyroid Hormone Action in the Developing Testis. Endocrinology 157:1276-88

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