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
(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.