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

Abstract

Epidemiological studies from both iodine-sufficient and -deficient human populations strongly suggest that early maternal hypothyroxinemia (i.e., low circulating free thyroxine before onset of fetal thyroid function at midgestation) increases the risk of neurodevelopmental deficits of the fetus, whether or not the mother is clinically hypothyroid. Rat dams on a low iodine intake are hypothyroxinemic without being clinically hypothyroid because, as occurs in pregnant women, their circulating 3,5,3′-triiodothyronine level is usually normal. We studied cell migration and cytoarchitecture in the somatosensory cortex and hippocampus of the 40-day-old progeny of the iodine-deficient dams and found a significant proportion of cells at locations that were aberrant or inappropriate with respect to their birth date. Most of these cells were neurons, as assessed by single- and double-label immunostaining. The cytoarchitecture of the somatosensory cortex and hippocampus was also affected, layering was blurred, and, in the cortex, normal barrels were not formed. We believe that this is the first direct evidence of an alteration in fetal brain histogenesis and cytoarchitecture that could only be related to early maternal hypothyroxinemia. This condition may be 150–200 times more common than congenital hypothyroidism and ought to be prevented both by mass screening of free thyroxine in early pregnancy and by early iodine supplementation to avoid iodine deficiency, however mild

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.…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Severe iodine deficiency before and throughout gestation results in a rat model of neurological cretinism (330) with brain alterations similar to those described in human affected populations (342)(343)(344). Given that feeding on LID can potentially decrease fertility, particularly if the state of iodine deficiency is severe enough to reduce serum T 3 , LID alone might not act quickly enough to create a state of iodine deficiency in the fetus.…”

An ontological view of the human embryo. A paradigm

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