Developmental Changes in Rat Brain 5′-Deiodinase and Thyroid Hormones during the Fetal Period: The Effects of Fetal Hypothyroidism and Maternal Thyroid Hormones

Abstract

ABSTRACT. We have studied the ontogenesis of 5'-deiodinase (5'D) activity in rat brain during fetal life, its capacity to respond to maternal or fetal hypothyroidism, and its regulation by maternal thyroid hormones. Type I1 5'D (5' D-11) activity increases 4-fold during the period studied (17 to 22 days of gestation), mainly between days 19 and 21. Fetal brain T4 concentrations increase in parallel with fetal plasma T4, whereas fetal brain T3 concentrations increase 18 times (days 17-21), six times more than would have been expected from the small increase in fetal plasma T3 levels. Maternal thyroidectomy did not affect 5'D-I1 activity or thyroid hormone concentrations in fetal brain (except brain T4 at 18 days of gestation). Fetal hypothyroidism, induced by giving a goitrogen (methimazole) to the mothers, depleted all fetal tissues studied, including the fetal thyroid, from thyroid hormones. By 19 days of gestation, the fetal brain was able to respond to hypothyroidism with a 3-to 5-fold increase in 5'D-I1 activity. Earlier onset of treatment with methimazole led to 2-to 3-fold increases in 5'D already at 17 and 18 days of gestation, showing that when fetal thyroid secretion starts the fetal brain 5'D-I1 is able to respond to hypothyroidism. Replacement of methimazole-treated mothers with physiological doses of T4, given by constant infusion, increased T4 and T3 concentrations in fetal brain, and inhibited fetal, as well as maternal, brain 5'D-I1 activity. But treatment of the mothers with T3 did not change T3 concentrations in the fetal brain, despite the increase in fetal plasma T3, and actually increased 5'D-I1 in fetal brain. Maternal cerebral 5'D-I1 was not inhibited by T3 treatment. Inverse relationships were found between the 5'D-I1 and thyroid hormone concentrations in the fetal brain. These correlations were not identical for fetuses from thyroidectomized and control mothers. In fetuses from thyroidectomized dams, brain 5'D-I1 is more sensitive to a decrease in brain T4 than in the progeny of control

Maternal transfer of methimazole and effects on thyroid hormone availability in embryonic tissues

“…This response was, however, not present in all brain regions, and it was less pronounced than the strong response in the brain of adult hens. Together with the fact that there was no compensatory increase in D2 activity in the brain at E6, this confirms earlier observations that the typical compensatory response of deiodinases to altered TH availability is not yet mature in young embryos/foetuses (Ruiz de Ona et al 1988, Gereben et al 2008, Sharlin et al 2010. The single changes found in D2 and MCT8 mRNA in different brain regions of E14 embryos are also not in line with a compensatory response at the level of gene expression and rather point to a delay in the normal ontogenetic expression pattern of these genes in hypothyroid MMI embryos .…”

“…Maternally derived MMI can block the developing thyroid gland as shown repeatedly in rats (Comer & Norton 1985, Ruiz de Ona et al 1988, Calvo et al 1990). However, the early vertebrate brain is highly dependent on adequate 3,5,3 0 -triiodothyronine (T 3 ) availability, and it may not yet be able to compensate for a reduced TH supply by an increase in type 2 iodothyronine deiodinase (D2) activity as observed in the adult brain (Ruiz de Ona et al 1988. Apart from inhibiting TH production, it has been found more recently that MMI may also have local anti-thyroid effects in tissues by directly suppressing transcriptional activities mediated by T 3 and its receptors (Moriyama et al 2007).…”

Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny

“…In this respect, it is interesting that the progeny from LID dams show increased audiogenic seizure susceptibility (37,48). The observed reduction in the thickness of the stratum radiatum in LID-1 and LID-2 pups suggests a reduction in the length of apical dendrites of pyramidal neurons, such as has been reported in granule and pyramidal cells of the hippocampus of goitrogen-treated hypothyroid rat pups (49).…”

“…observed in the maternal plasma (31,37,38). Thus, the thyroidectomized dams have very low circulating levels of T4 and T3 up to E21, as do all samples obtained from the conceptus between E9 and E18 -namely, E9-E12 embryotrophoblasts, E9-E12 placentas, and E13-E17 whole embryos.…”

Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism.

“…Their fetuses are also unable to synthesize enough T4 because of the lack of iodine. Thus, throughout pregnancy, the fetal brain does not receive enough T4, which is the only source of cerebral T3 during fetal development (23). This would explain the greater severity of the CNS damage caused by iodine deficiency.…”