Tissue biomarkers of thyroid status as correlates of neurodevelopmental impairment following gestational and lactational exposure to thyroid disruptor propylthiouracil
Taylor, Matthew Aaron
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From its influence on mitochondrial activity and basal metabolic rate to its complex interplay with other endocrine organs, the thyroid gland is vital for proper development and operation of the mammalian body. Neurological development is a special concern due to the relative sensitivity of gestating females and neonates to thyroid disruption. The studies described within investigate the effects of developmental exposure to antithyroid compounds on the neurodevelopment of rats. As peripheral tissues including the brain are capable of partial compensation in response to declining availability of thyroid hormones from serum, we hypothesized that measuring thyroid-responsive parameters such as tissue- 5dei¶odinase enzyme activity thyroid hormone concentrations, and mRNA expression would provide data which would more closely correlate to neurological endpoints than serum thyroid hormone or thyrotropin (TSH) concentrations. We further hypothesized that younger animals would be more sensitive to thyroid disruption than older animals, due to diminished reserve of the compensatory mechanisms in the hypothalamic-pituitary-thyroid axis. We used two antithyroid compounds to test these hypotheses. Propylthiouracil (PTU) at 0, 0.3, 1, 3, and 10 ppm in drinking water, and perchlorate at 150ppm in drinking water were administered from gestational day 2 until weaning. Serum and cerebrocortical thyroid hormone concentrations were measured at postnatal days 4, 14, and 21-32, as well as in dams and pups allowed to recover for 60 days post-weaning. Hippocampal in vitro electrophysiological measurements were performed on pups and adults. Open field behavioral testing was performed on adults. Overall, we found that the chosen thyroid-responsive biomarkers were insufficient to consistently predict the presence of electrophysiological alterations. A severe reduction in serum total T4 concentration in developing pups was found to be a necessary condition for neurological impairment. Reductions in cortical T3 concentrations were not found to perfectly correlate with neurological outcomes.