Epigenetic developmental programming and intergenerational effects of thyroid hormones

Abstract

Mounting evidence is showing that altered signaling through the nuclear hormone receptor superfamily can cause abnormal, long-term epigenetic changes which translate into pathological modifications and susceptibility to disease. These effects seem to be more prominent if the exposure occurs early in life, when transcriptomic profiles are rapidly changing. At this time, the coordination of the complex coordinated processes of cell proliferation and differentiation that characterize mammalian development. Such exposures may also alter the epigenetic information of the germ line, potentially leading to developmental changes and abnormal outcomes in subsequent generations. Thyroid hormone (TH) signaling is mediated by specific nuclear receptors, which have the ability to markedly change chromatin structure and gene transcription, and can also regulate other determinants of epigenetic marks. TH exhibits pleiotropic effects in mammals, and during development, its action is regulated in a highly dynamic manner to suit the rapidly evolving needs of multiple tissues. Their molecular mechanisms of action, timely developmental regulation and broad biological effects place THs in a central position to play a role in the developmental epigenetic programming of adult pathophysiology and, through effects on the germ line, in inter- and trans-generational epigenetic phenomena. These areas of epigenetic research are in their infancy, and studies regarding THs are limited. In the context of their characteristics as epigenetic modifiers and their finely tuned developmental action, here we review some of the observations underscoring the role that altered TH action may play in the developmental programming of adult traits and in the phenotypes of subsequent generations via germ line transmission of altered epigenetic information. Considering the relatively high prevalence of thyroid disease and the ability of some environmental chemicals to disrupt TH action, the epigenetic effects of abnormal levels of TH action may be important contributors to the non-genetic etiology of human disease.

Keywords: Behavior; Brain development; Brown adipose tissue; Dio2; Dio3; Germ cells; Hypothalamic-pituitary-thyroid axis; Liver steatosis; Thyroid hormone; Transgenerational epigenetics.

Figure 1.

Regulation of thyroid hormone action. A, Thyroid hormones T4 and T3 secreted into the circulation by the thyroid gland can enter target cells through different cell membrane transporters. Deiodinases 1 and 2 (DIO1 and DIO2) can convert T4 into the active hormone T3, which will bind nuclear receptors alpha and beta (TRα, β) and regulate gene transcription. Cellular T4 and T3 can be converted into inactive metabolites by deiodinase 3 (DIO3). B, In the absence of T3, unliganded receptors promote close chromatin by recruiting co-repressors and histone deacetylases (HDACs), as well as promoting methylation or TH response elements (TREs) in the genome. Upon T3 binding to the receptors, which may act as homodimers or heterodimers with retinoid X receptor (RXR), co-activators and histone acetylases (HTAs) are recruited and DNA de-methylation may occur, opening chromatin to transcription factors and RNA polymerase II, and promoting transcription of target genes, some of which may include epigenetic modifiers such as microRNAs and histone and DNA methyl-transferases. Close and open lollipops indicate DNA methylation or lack of it, respectively. Green circles represent histone acetylation (modified from (Anselmo & Chaves, 2020)).

Figure 2.

Ontogeny of THs and timing of deiodinase switch in tissues. Serum levels of T3 and T4 are low in rodent early development. They rise steadily after birth and reach a peak during the third week of life, settling on adult levels (dotted line) shortly thereafter. Many tissues exhibit a switch between peaks of DIO3 and DIO2 expression that is independent of serum concentrations of THs, indicating a timely, tissue-specific need for increased T3 action. The approximate timing of the deiodinase switch is indicated for the hypothalamus, BAT and cochlea (Hernandez et al., 2021).

Figure 3.

Developmental overexposure to TH and adult physiology. A, Developmental interval of TH overexposure and adult defects in HPT axis physiology for Neo-T4, Dio3KO and RTHβ rodent models. B, Adult abnormalities in mouse models of cell-specific thyrotoxicosis due to loss in of DIO3 function in brown adipocyte progenitors and POMC-expressing cells. C, Alterations in epigenetic signature, transcriptome and disease susceptibility in the adult liver of mice lacking a neonatal pulse of T3 action secondary to DIO2 activation. E13.5, embryonic day 13.5; P0, P7, postanatal day 0, 7, respectively. (Based on references cited in the main text).

Figure 4.

Inter- and trans-generational epigenetic effects in different models of developmental overexposure to TH. Phenotypes in the exposed generation (F0) and F1 and F2 generations of Neo-T4 rats (A), Dio3ko mice (B) and humans born to RTHβ mothers. (Based on references cited in the main text).