Toxicological Profile of Chemical Interference of Thyroid Hormone Metabolism via Deiodinase Enzymes In a Rodent Model.

Abstract

Thyroid hormones (TH) are highly iodinated molecules that regulate many aspects of mammalian physiology and are essential for normal growth and development. Deiodinases (Dio) are a family of metabolizing enzymes controlling systemic and local availability of the major TH secreted from the thyroid gland. Despite their critical role in TH regulation, the toxicological characterization of the effects of chemical interference of Dios in mammalian models has remained relatively underexplored. Here we investigated the effects of exposure to iopanoic acid (IOP), a potent in vitro inhibitor of Dio enzymes. Adult rats administered IOP (0, 1, 5, 10 and 50 mg/kg/day, oral gavage) for 14 days exhibited an increase in serum thyroxine (T4) and reverse T3 (rT3), consistent with an inhibition of deiodinase 1 (Dio1). To verify these serum TH effects were induced by IOP action on deiodination pathways, we examined Dio activity ex-vivo in liver from exposed animals. TH metabolites quantified by liquid chromatography mass spectrometry (LC-MS/MS) were used as the readout of Dio activity. Dose-dependent reductions in Dio1 and Dio3 activity were confirmed in hepatic microsomes prepared from IOP-exposed animals. The findings provide a signature pattern for serum TH change to assist translation of in vitro assays for this mode of action of environmental contaminants and interpretation of regulatory reports of serum TH profiles. By elucidating the mechanistic underpinning of chemical-induced perturbations of this critical TH metabolic pathway, the findings may inform risk-based decision making and serve to help to refine regulatory strategies for TH system disrupting compounds.