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.

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 actions of thyroid hormones in subsequent generations by altering the ability of offspring to metabolize these regulatory compounds. We propose that this novel process not only influences the function of the thyroid axis itself, but also has important consequences with regards to human development and subsequent neurologic, metabolic and reproductive function and disease in later life.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Malozowski, Saul N
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Maine Medical Center
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Stohn, J P; Martinez, M E; Zafer, M et al. (2017) Increased aggression and lack of maternal behavior in Dio3-deficient mice are associated with abnormalities in oxytocin and vasopressin systems. Genes Brain Behav :
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
Stohn, J Patrizia; Martinez, M Elena; Matoin, Kassey et al. (2016) MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated With the Absence of a Functional Type 3 Deiodinase. Endocrinology 157:3266-77
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
Martinez, Maria Elena; Cox, David F; Youth, Brian P et al. (2016) Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14. Eur J Hum Genet 24:1617-1621
Hernandez, Arturo (2015) 3,5-diiodo-L-thyronine (t2) in dietary supplements: what are the physiological effects? Endocrinology 156:5-7
Martinez, M Elena; Charalambous, Marika; Saferali, Aabida et al. (2014) Genomic imprinting variations in the mouse type 3 deiodinase gene between tissues and brain regions. Mol Endocrinol 28:1875-86
Charalambous, M; da Rocha, S T; Hernandez, A et al. (2014) Perturbations to the IGF1 growth pathway and adult energy homeostasis following disruption of mouse chromosome 12 imprinting. Acta Physiol (Oxf) 210:174-87
Galton, Valerie Anne; Hernandez, Arturo; St Germain, Donald L (2014) The 5'-deiodinases are not essential for the fasting-induced decrease in circulating thyroid hormone levels in male mice: possible roles for the type 3 deiodinase and tissue sequestration of hormone. Endocrinology 155:3172-81

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