The etiology of many neurodevelopmental disorders including autism, schizophrenia and attention-deficit hyperactive disorder remains poorly understood. It is accepted that environmental factors may be involved and that the heritability of those conditions is relatively high. Numerous epidemiological and genome-wide association studies in affected populations have identified environmental factors and candidate genes increasing the susceptibility to those conditions. However, those genetic and environmental factors can only account for a small percentage of the clinical cases. This suggests that additional environmental influences remain unidentified, and that the majority of the heritable component of those conditions is of non-genetic origin. We hypothesize that brain overexposure to thyroid hormone during development is an important factor contributing to both the environmental and non-genetic heritable components in the etiology of neurodevelopmental disorders. To test this hypothesis, we will use mouse models with genetic and epigenetic deficiency in DIO3, the main brain determinant controlling thyroid hormone action.
In Specific Aim #1, we will determine what are the consequences of allele-specific inactivation of Dio3 globally or specifically in neurons for the brain programs of gene expression, adult brain structure and behavior.
In Specific Aim #2, we will profile the fetal and neonatal brain expression and the adult brain structure and behavior of genetically normal mouse descendants of ancestral mice that were exposed to an excess of thyroid hormone during development. We will compare the results of developmental gene expression in different parts of the brain with their adult behavior and with the altered epigenome of exposed ancestors to define which brain developmental programs, brain regions, brain functions, and related neurodevelopmental disorders that are affected by abnormal epigenetic inheritance originated in ancestral overexposure to thyroid hormones. Based on the abnormal regulation of circadian rhythms that is typically associated with neurodevelopmental disorders and is also observed in mice lacking the Dio3 gene, we will identify the molecular and developmental basis by which developmental exposure to thyroid hormone excess leads to the abnormal programming of the circadian clock (Specific Aim #3). We anticipate that our work will greatly advance our understanding of the etiology of complex neurodevelopmental conditions and demonstrate the breakthrough concept that a developmental excess of thyroid hormone influences the susceptibility to those conditions directly in the present generation and indirectly in descendants via epigenetic mechanisms of inheritance.

Public Health Relevance

The origins of neurodevelopmental disorders like autism, schizophrenia, attention-deficit hyperactive disorder and others are not well understood, but they include relatively high heritability and environmental influences. Using epidemiological and genetic studies of affected populations, investigators have identified environmental factors and candidate genes that influence the likelihood of disease onset, but they can only explain a very small percentage of actual clinical cases for those conditions. To fill this gap of knowledge, we propose to test the hypothesis that brain overexposure to thyroid hormone during development, which may occur as a result of maternal disease or due to undetected disregulation of the gene that controls such exposure, contributes to the susceptibility to neurodevelopmental disorders in the current individual and also in subsequent generations via mechanisms of inheritance that do not affect the genetic code.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096050-08
Application #
9595399
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Winsky, Lois M
Project Start
2012-06-26
Project End
2022-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Maine Medical Center
Department
Type
DUNS #
071732663
City
Portland
State
ME
Country
United States
Zip Code
04102
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 :
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
Medina, Mayrin C; Fonesca, Tatiana L; Molina, Judith et al. (2014) Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic ?-cells and disrupts glucose homeostasis. Endocrinology 155:3160-71

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