What are the Characteristics of Chemical Interference with Thyroid Hormone Metabolizing Enzymes? A Range Finding Study with Iopanoic Acid in the Adult Rat.
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Deiodinases (DIO) are metabolizing enzymes that tightly control thyroid hormone (TH) concentrations in the periphery and the brain. Despite their critical role in TH regulation, the characteristics of interference of DIOs by environmental chemicals remains relatively unexplored. We administered iopanoic acid (IOP) a potent inhibitor of all three deiodinases (DIO1, DIO2, DIO3) to adult female rats (N=7-8/dose gp, 0, 10, 50 mg/kg/day by gavage) for 14 days. Blood collected 24 hr after the 7th and 14th day of dosing revealed increases in serum T4 and rT3 and no changes in T3 or TSH. T4 and rT3 increases are consistent with inhibition of DIO1. IOP did not impact body weight gain but slight reductions in thyroid gland and liver weights were observed. The thyroid gland, liver, and brain were examined for changes in expression of DIO- and TH-regulated genes. Expression of genes involved in TH synthesis (Dio1, Nis, Tg, Tpo, TshR) were unchanged in the thyroid gland with the exception of a decrease in Nis expression. In liver, no changes in gene expression were observed in transporter proteins (Mdr1a, Mct8, Oatp1c1), deiodinases (Dio1, Dio3), or the hormone distributer protein (Ttr). Expression of TH-responsive genes in the cortex (Arc, Bdnf, Camk4, Hr, Klf9, Dio2) were limited to a modest reduction in Dio2 expression at the highest dose level. This change in brain Dio2 expression was likely in response to higher serum T4 rather than any direct action of IOP in brain. The results of this study indicate the chemical interference with DIOs is reflected in serum TH profiles with minimal effects on selected gene transcription in the adult animal. These data provide basis for future studies examining the impact of DIO inhibition on the developing fetal brain. Does not reflect EPA policy