The etiology of many neurodevelopmental disorders remains largely unknown. Although environmental factors may influence their onset, familial studies have shown that schizophrenia, autism, depression, bipolar disorder, and others, all have a variable but strong genetic component. However, candidate genes for these conditions, as identified by genetic linkage analysis and transgenic animal models, can only explain a low percentage of clinical cases. This suggests that important determinants of disease lie elsewhere. Here we propose that epigenetic alterations in the type 3 deiodinase gene (Dio3), either caused by current environmental factors or inherited from previous generations, can lead to brain phenotypes of relevance to neurological disorders. As Dio3 tightly controls thyroid hormone availability across the developing and adult brain, its level of expression is critical to ensure distinct, appropriate levels of thyroid hormone action and normal patterns of gene expression. Dio3 is highly expressed in the central nervous system, and its role in this tissue is likely overlooked in the clinical setting. Clinical diagnosis of thyroid hormone abnormalities is based on serum parameters. However, alterations in Dio3 expression can markedly modify thyroid hormone action in the brain without noticeable changes in the circulating levels of the hormone. In this project, we propose to use several mouse models created or identified in our laboratory that carry genetic and epigenetic alterations affecting the dosage and expression of Dio3 and, thus, the degree of thyroid hormone action in the brain. In these models we will determine several parameters of importance to neurological conditions in humans, such as neonatal and adult patterns of brain gene expression, adult brain morphology and social behavior. In addition, we propose to define the epigenetic footprint of thyroid hormone by analyzing in certain tissues the epigenetic marks that result from developmental overexposure to thyroid hormone. We anticipate demonstrating that Dio3 has an important role for brain development and function and that epigenetic factors affecting Dio3 dosage, de novo or inherited from previous generations, can produce significant neurological phenotypes in genetically intact individuals. This work could have a major impact in our understanding of how susceptibility to neurological conditions can be inherited, highlighting the role of epigenetic information in directly causing disease or triggering it in genetically predisposed individuals. Ultimately, this research may lead to novel epigenetic-based clinical tools for risk assessment, prevention and response to treatment of certain neurological conditions.

Public Health Relevance

We propose to test the hypothesis that alterations in thyroid hormone action in the brain may occur as a result of epigenetic modifications in a gene that tightly controls thyroid hormone availability in this tissue, and that these modifications can be induced by the environment and inherited by subsequent generations, with ultimate consequences from brain development and function. This hypothesis aims at filling the existent gap of knowledge about the etiology of many neurological disorders that exhibit a high degree of heritability and yet very few clinical cases can be completely attributed to purely genetic factors This concept may prove a major novel insight into the origins of these conditions and ultimately lead to new diagnostic tools and clinical interventions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Desmond, Nancy L
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Maine Medical Center
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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
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

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