A Moderate and Transient Deficiency of Maternal Thyroid Function at the Beginning of Fetal Neocorticogenesis Alters Neuronal Migration

Abstract

Epidemiological studies and case reports show that even a relatively minor degree of maternal hypothyroxinemia during the first half of gestation is potentially dangerous for optimal fetal neurodevelopment. Our experimental approach was designed to result in a mild and transient period of maternal hypothyroxinemia at the beginning of corticogenesis. Normal rat dams received the goitrogen 2-mercapto-1-methyl-imidazole for only 3 d, from embryonic d 12 (E12) to E15. Maternal thyroid hormones decreased transiently to 70% of normal serum values, without clinical signs of hypothyroidism. Dams were injected daily with 5-bromo-2'-deoxyuridine (BrdU) during 3 d, from E14-E16 or E17-E19. Their pups were tested for audiogenic seizure susceptibility 39 d after birth (P39) and killed at P40. Cells that had incorporated BrdU were identified by immunocytochemistry, and quantified: numerous heterotopic cells were found, whether labeled at E14-E16 or E17-E19, that were identified as neurons. The cytoarchitecture and the radial distribution of BrdU-labeled neurons was significantly affected in the somatosensory cortex and hippocampus of 83% of the pups. The radial distribution of gamma-aminobutyric acidergic neurons was, however, normal. The infusion of dams with T4 between E13 and E15 avoided these alterations, which were not prevented when the T4 infusion was delayed to E15-E18. In total, 52% of the pups born to the goitrogen-treated dams responded to an acoustic stimulus with wild runs, followed in some by seizures. When extrapolated to man, these results stress the need for prevention of hypothyroxinemia before midpregnancy, however moderate, and whichever the underlying cause.

Behavioral deficits associated with fetal alcohol exposure are reversed by prenatal thyroid hormone treatment: a role for maternal thyroid hormone deficiency in FAE

“…26 The specific effects of mild maternal hypothyroxinemia, a subtle decrease in serum T4 levels with no increase in thyroid-stimulating hormone (TSH) concentrations, on fetal brain development have recently been ascertained. 27,28 These studies show migration defects in the fetal cortex and the CA1 and CA3 of the hippocampus that could potentially cause the behavioral deficits observed in other studies.…”

“…It is interesting though that GAP-43 and RC3/ neurogranin belong to the same calpacitin protein family 89 and RC3 is known to be regulated by thyroid hormones both developmentally 90 and in adulthood. 91 The findings that prenatal hypothyroid state can permanently alter fetal brain cytoarchitecture 27,28 suggest that thyroid hormone-regulated mediators of neuronal migration and apoptosis might be involved in this phenomenon, a hypothesis that needs further experimental explorations.…”

MECHANISMS IN ENDOCRINOLOGY: Maternal thyroid dysfunction during pregnancy and behavioural and psychiatric disorders of children: a systematic review

“…In turn, the aforementioned adverse events during pregnancy can disrupt the function of the developing nervous system resulting in poor offspring neurodevelopment (9). Both animal and human studies have established that important phases of neocortex development can be altered by early maternal thyroid dysfunction and result in persistent negative consequences in offspring (10,11,12,13). One of the mechanism by which thyroid hormones may influence brain development is via the regulation of the expression of brain-derived neurotrophic factor and Reln gen; Reln produces Reeln, essential for the proper migration and the establishment of neocortical layers (14).…”

Autoimmune Thyroid Disease in Pregnancy: A Review

“…In some studies, preterm delivery has been found to be 3-fold more common in hypothyroid pregnant women and has also been associated with an increase in spontaneous abortions, [52][53][54] although no adverse outcomes were found in a very large study of mild (subclinical) disease. 55 Another worrying danger associated with maternal hypothyroxinemia (especially when present during the first trimester) is the adverse consequences to child neuropsychointellectual development, as has been demonstrated by several studies 6,16,25,56,57 (Table 3). Whether very mild hypothyroidism has the same associations remains uncertain.…”