Physiologic Significance of Epigenetic Regulation of Thyroid Hormone Target Gene Expression

Abstract

Background: In previous publications, we have reported our findings demonstrating that exposure to high maternal levels of thyroid hormones (TH) has life-long effects on the wildtype (WT, without THRB mutation) progeny of mothers with resistance to thyroid hormone beta (RTHβ). The mechanism of this epigenetic effect remains unclear. Objectives: We reviewed the mechanisms involved in the epigenetic regulation of TH target genes and understand how they may explain the reduced sensitivity to TH in the WT progeny of RTHβ mothers. Methods: The availability of a large, formerly genotyped Azorean population with many individuals harboring the THRB mutation, R243Q, provided us a model to study the influence of fetal exposure to high maternal TH levels. Results: The thyroid-stimulating hormone (TSH) response in WT adults was less suppressible following the administration of L-triiodothyronine (L-T 3 ). This finding suggests reduced sensitivity to TH that is induced by an epigenetic mechanism resulting from exposure to high maternal levels of TH during pregnancy. The persistence of this effect across 3 generations of WT subjects favors transgenerational epigenetic inheritance. Based on preliminary studies in mice, we identified the naturally imprinted gene encoding deiodinase type 3, i.e., DIO3, as a possible mediator of this epigenetic effect through increased inactivation of TH. Conclusion: Increased D3 expression and consequently increased T 3 degradation appear to be responsible for the reduced sensitivity of the anterior pituitary to administered L-T 3 . The imprinted DIO3 gene may be a candidate gene that mediates the epigenetic effect induced by exposure to high maternal levels of TH. However, we cannot exclude the role of other TH-responsive genes.

Thyroid Function at Age Fifty After Prenatal Famine Exposure in the Dutch Famine Birth Cohort

“…The reduced TSH levels at age 50 in women exposed to famine conditions in mid gestation might be the result of epigenetic alterations within the regulation of the HPT axis. It has been suggested that tissue-specific changes in the epigenetic expression of deiodinase enzymes, which activate and deactivate thyroid hormones, may be a putative mechanism by which such changes in the regulation of the HPT axis can occur (1,36,37). Research by Anselmo et al (2019) on the intergenerational effect of foetal exposure to abnormally high maternal thyroid hormone levels in an Azorean population has shown that even in the third generation, reduced sensitivity to administered thyroid hormones is found (37).…”

“…Research by Anselmo et al (2019) on the intergenerational effect of foetal exposure to abnormally high maternal thyroid hormone levels in an Azorean population has shown that even in the third generation, reduced sensitivity to administered thyroid hormones is found (37). They speculated that the pituitary expression of the deiodinase 3 enzyme, which inactivates thyroid hormones by deiodination of the inner ring of both T4 and T3, is increased after exposure to maternal hyperthyroidism during pregnancy (36). The opposite might be true in the context of maternal malnutrition during pregnancy, which has been shown to lead to decreased thyroid hormone levels, specifically T3, compared to well-nourished women (38).…”

Neuropsychological Alterations in Patients with Congenital Hypothyroidism Treated with Levothyroxine: Linked Factors and Thyroid Hormone Hyposensitivity

“…It may also lead to a deficient supply of L-T 4 and a deficit in the mechanism of action of this hormone at the brain level and, consequently, a state of mild THH in the CNS of the patient with CH. To our knowledge, this hypothesis has not been explored at a molecular level in patients or animal models; however, previous research has shown a link between neonatal thyroid status and the sensitivity to THs at the brain level [ 123 , 124 , 125 , 126 , 127 , 128 ]. Srichomkwun et al [ 125 ] demonstrated that the exposure to high concentrations of THs during intrauterine life causes brain THH in humans and mice.…”

“…This effect is persistent until adulthood in both species and is accompanied by changes in the expression of deiodinases in the hypothalamus and pituitary. Interestingly, THH derived from intrauterine hyperthyroidism is persistent throughout three generations in the male human line [ 124 ] and is linked to an epigenetic phenomenon in the genes encoding the various molecules involved in the supply or mechanism of action of THs in the CNS [ 123 ].…”

ZFP36L2 Role in Thyroid Functionality

“…The transcriptional mechanisms controlling thyroid development and function, including epigenetic aspects, have been deeply investigated [16]. Although the regulation of mRNA stability is also an important mechanism regulating differential gene expression, particularly in developmental processes [17], its role in congenital hypothyroidism has been neglected.…”