Maternal exposure to iopanoic acid disrupts thyroid hormone metabolism and impairs development of the rodent brain

Thyroid hormones (THs) regulate development, growth, and metabolism. Integral to the regulation of their action are the deiodinases (Dios), metabolizing enzymes that activate (Dio1 and Dio2) and deactivate (Dio3) THs, exerting precise control over local TH action. We examined the effect of chemical interference with Dios on brain development in a rodent pregnancy model using iopanoic acid (IOP). Pregnant rat dams were exposed to 0, 5, or 10 mg/kg IOP daily by gavage from gestational day 6 to postnatal (PN) day 15. Pups were euthanized at PN0, 2, 6, and 14. Serum and brain TH and Dio activity in cortical microsomes were measured, and 2 neuroanatomical defects emblematic of TH insufficiency were examined in the brains of offspring. IOP increased serum total T4 and rT3 in dams and pups. IOP decreased Dio2 and Dio3 activity in the dam cortex and forebrain of PN0 and PN2 pups, with no effect seen on PN14. On PN2, brain T4 was increased, brain T3 was reduced, and TH-responsive genes were downregulated. A periventricular heterotopia was present in the brains of IOP-treated pups on PN14, whereas no change was seen in the numbers of parvalbumin-expressing neurons. The observation that IOP induced changes in serum THs that were not predictive of brain effects has profound implications for the interpretation of altered serum TH profiles in a chemical regulatory context as well as in a clinical setting.