Transgenerational epigenetic programming of the thyroid axis

Mainehealth, Portland ME

Investigators

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Abstract

Endocrine diseases such as obesity, type 2 diabetes and thyroid conditions exhibit relatively high heritability according to epidemiological and familial studies, but genetic mutations identified to date can only explain a very small proportion of clinical cases. This gap raises the possibility that abnormal epigenetic information, elicited by environmental circumstances and transmitted between generations, significantly contribute to the missing heritability of these conditions. In this regard, thyroid abnormalities are very prevalent in humans, but studies defining the consequences for endocrine pathophysiology in the children and descendants of affected individuals are sorely lacking. Based on preliminary observations on a mouse model of developmental thyrotoxicosis due to functional loss of the type 3 deiodinase (DIO3) and subsequent impairment in thyroid hormone clearance, we hypothesize that developmental paternal thyrotoxicosis causes in the offspring a broad and complex syndrome affecting the regulation of energy balance and multiple endocrine systems of relevance to obesity and type 2 diabetes, including including the thyroid axis, the leptin-melanocortin system and insulin-glucose homeostasis. Preliminary data indicate that this syndrome, which we termed "SOFT" for "Syndrome Of Father's Thyrotoxicosis", exhibits sexually dimorphic severity, and features obesity, aberrant insulin-glucose homeostasis, altered physiological responses to fasting a a high fat diet, and abnormalities in molecular markers of the thyroid axis, and leptin-melanocortin and ghrelin systems.  The aims of the project will further characterize SOFT, establish its molecular and physiological basis, and define how it is paternally trasnmitted and generated in the offspring. Aim 1 will determine the role of neonatal leptin in the generation of SOFT. We will test whether the blunted peak of neonatal leptin exihibited by the offspring of thyrotoxic fathers is responsible for the abnormal endocrine programming characteristic of adult mice with SOFT. Aim 2 will determine the role of paternal Thra in the generation of SOFT. We will test whether the establishment of an altered germ line epigenome in thyrotoxic fathers and the developmental abnormalities and generation of SOFT in their offspring requires the mediation of the alpah sioform of the thyroid hormone receptor. We anticipate our work will generate a novel paradigm for the non-genetic but heritable etiology and susceptibility to endocrine conditions, including obesity, type 2 diabetes and thyroid disease. This heritability would be dependent on a paternal history of abnormal thyroid hormone status, a highly pevalent occurrence in humans not only in adult life, but also during fetal development due to maternal thyroid disease. Our research will uncover new mechanisms underlying the heritability of these endocrine conditions. Our results will support comparable translational studies in humans that will ultimately provide novel epigenetic tools and markers for the close monitoring, effective prevention and advisable treatment of endocrine pathologies.