Abstract
Thyroid hormone is essential for proper development of brain and modest degrees of developmental thyroid hormone insufficiency can result severe neurological deficits. We used an animal model to study the role of thyroid hormones (THs) during the gestation days and early postnatal days on developing rat brain. Dose-dependent thyroid hormone insufficiency in dams was induced by methimazole (MMI). In the first study-group thyroid hormone deficiency was induced by delivery of methimazole (MMI) to dams via drinking water at the doses of 50, 75 and 100 ppm from early gestation (GD 3) until weaning of the pups (PN20). In the second study-group hypothyroid rats were treated with 200 μg of thyroxine hormone. Pups were sacrificed on postnatal days (PN) 20. Maternal blood collected for thyroid hormone analysis. Cerebellum, medulla, hippocampus, cortex, olfactory bulbs were separated from dissected brain and relative expression of BDNF gene transcripts known to play critical roles in developing rat brain, were determined by RT-PCR. Daily body weight in dams and pups, the number of pups at birth, the eye –closure opening day and BDNF expression in brain extract was determined in the preweaning rats as a function of MMI exposure. The results indicate that genes driving important developmental processes during early brain development are sensitive to perturbations of the thyroid axis function.
Highlights
Thyroid hormones are essential for brain development through specific time windows influencing neurogenesis, neuronal migration, neuronal and glial cell differentiation, myelination, and synaptogenesis (Bernal, 2007)
Exposure of pregnant rat to 50ppm, 75 ppm an 100 ppm from gestation day (GD) 3 to PN20 significantly reduced in dose-dependent manner circulating total T3, total T4, free T4 and thyroid stimulating hormone (TSH) levels in the dams at developmental stage, but these reductions reversed in hypothyroid with T4-replacement group
A number of observations resulted from this investigation were 1) decreased brain-derived neurotrophic factor (BDNF) expression in the neonate of hypothyroid group, 2) but surprisingly, increased BDNF mRNA in the male and female offspring, 3) neurotrophin mRNA expression varies by sex, brain region and dose of MMI, 4) in hypothyroid groups the number of pups at birth was decreased, 5) infant body weight was decreased and 6) the eye closure opening day was delayed
Summary
Thyroid hormones are essential for brain development through specific time windows influencing neurogenesis, neuronal migration, neuronal and glial cell differentiation, myelination, and synaptogenesis (Bernal, 2007). Thyroid hormone action in CNS development is mediated through nuclear receptors (TRs) and integrin α β (Stenzel et al, 2014) that regulates gene expression. Many genes in developing rat brain have been reported to be altered by hypothyroidism (Royland et al, 2008) but the impact of severe degrees of perturbation of the thyroid axis function on specific target gene expression known to play critical roles in developing rat brain, has not been detected. Even modest reductions in thyroid hormones during critical period of brain development produce morphological alterations, synaptic dysfunction, and behavioral impairments (Gilbert & Zoeller, 2010; Ghassabian et al, 2011; Gilbert et al, 2015). Studies examining the effect of thyroid hormone reduction on gene expression have not produced consistent results
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