Hypothyroidism and brain developmental players.

R G Ahmed

doi:10.1186/s13044-015-0013-7

Abstract

Most of our knowledge on the mechanisms of thyroid hormone (TH) dependent brain development is based on clinical observations and animal studies of maternal/fetal hypothyroidism. THs play an essential role in brain development and hormone deficiency during critical phases in fetal life may lead to severe and permanent brain damage. Maternal hypothyroidism is considered the most common cause of fetal TH deficiency, but the problem may also arise in the fetus. In the case of congenital hypothyroidism due to defects in fetal thyroid gland development or hormone synthesis, clinical symptoms at birth are often mild as a result of compensatory maternal TH supply. TH transporters (THTs) and deiodinases (Ds) are important regulators of intracellular triiodothyronine (T3) availability and therefore contribute to the control of thyroid receptors (TRs)-dependent CNS development and early embryonic life. Defects in fetal THTs or Ds may have more impact on fetal brain since they can result in intracellular T3 deficiency despite sufficient maternal TH supply. One clear example is the recent discovery of mutations in the TH transporter (monocarboxylate transporter 8; MCT8) that could be linked to a syndrome of severe and non reversible psychomotor retardation. Even mild and transient changes in maternal TH levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Animal studies are needed to increase our understanding of the exact role of THTs and Ds in prenatal brain development.

Highlights

Most of our knowledge on the mechanisms of thyroid hormone (TH) dependent brain development is based on clinical observations and animal studies of maternal/fetal hypothyroidism
AThe human protein symbol is presented, if TH transport has been demonstrated in different species including humans. bIf a transporter only transports iodothyronine derivatives, specificity is high (+++)
If more than five ligands are known, the transporter is denoted as multispecific (+)

Summary

12 W 14 W 16 W 16-20 W

- Total serum T4 and T3 are low, free T4 is relatively high. - rT3 is noticed in serum relatively high. - TH synthesis begins in fetal thyroid. - Decreased mRNA expression of OATP1A2 but no change for OATP4A1 at 9–12 W compared to term. - Expressions of mRNAs encoding MCT8, MCT10, 14 GD OATP1A2 and LAT1 are significantly lower prior to 14 W compared to term. - TH synthesis begins in fetal thyroid. - D3 is observed in placenta and fetal epithelial cells. - A steady increase in serum TH levels begins and continues to term. - TRs and TH are observed in fetal brain. - TRH mRNA is detected in neurons of the fetal hypothalamus. - TRH mRNA is detected in the developing paraventricular nuclei of the hypothalamus. - TRH is produced in low levels in hypothalamus and increases approximately threefold by GDI9.5. E14 fetuses are increased dramatically because of maturation of hormone synthesis of the fetal thyroid gland. - D2 mRNA is noticed in cell clusters throughout the brain, in rhombencephalon. - Several elements of the TH action cascade are observed in the brain of embryos long before their own thyroid gland starts hormone secretion.

22-32 W 40 W

Findings

10-20 PND 14-50 PND