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BRAIN, LIVER AND THYROID BIOMARKERS REFLECT ENHANCED SENSITIVITY OF THE DEVELOPING RAT TO THYROID HORMONE DEPLETION.
Citation:
TAYLOR, M., M. STRAMIELLO, N. PAOLINO, N. JENNINGS, J. SWANT, J. FISHER, J. WAGNER, M. E. GILBERT, AND D. FERGUSON. BRAIN, LIVER AND THYROID BIOMARKERS REFLECT ENHANCED SENSITIVITY OF THE DEVELOPING RAT TO THYROID HORMONE DEPLETION. Presented at Society of Toxicology, Charlotte, NC, March 25 - 29, 2007.
Description:
Many developmental events are regulated at least in part by thyroid hormones. It was hypothesized that tissue biomarkers of thyroid status would be more accurate predictors of neurotoxicity than serum biomarkers in rats treated with the goitrogen propylthiouracil (PTU). Over several studies, timed pregnant rats were dosed 0, 0.3, 1, 3 or 10 ppm PTU solutions in drinking water from day 2 of gestation until weaning. Dams and pups were studied at 21-30 days after birth for thyroid status and hippocampal electrophysiology,
focusing on synaptic potential and weak and strong long term potentiation (LTP). Brain tissue from animals dosed with 0, 1, 2, or 3 ppm PTU at the USEPA was studied. Cerebrocortical Type 2 5'-deiodinase (D2), which converts thyroxine(T4) into the metabolically active 3',3,5-Triiodothyronine (T3), was found to be a very sensitive
indicator of T4 depletion, and provided robust protection of brain T3 levels. Cortical T3 concentrations were reduced further in pups than in dams. Serum T3 concentrations were better protected than serum T4 concentrations. Serum T4 was more affected by doses >0.3ppm in PND4 and 14 pups than older animals. Serum T4 and cortical D2 activity
correlated strongly, and results from two rat strains were nearly identical, strengthening the utility of D2 as a biomarker of thyroid disruption in the brain. In our first study, effects on synaptic potential in PND 21 pups showed a strong linear correlation to
cerebrocortical D2(R=.75, p<.0001). In that study, synaptic potential decreased with increasing D2 and decreasing serum T4, and LTP was impaired in PND100 animals. Overall, exposure to PTU doses >0.3ppm had effects on at least serum T4 at PND4-21. This data will assist researchers developing a biologically based pharmacokinetic model of thyroid disruption in the developing rat. Funding was provided by USEPA STAR cooperative agreement #R832134. (Does not reflect USEPA policy)