Species-specific sensitivity to in vitro inhibition of the thyroperoxidase (TPO) enzyme by environmental pollutants for five fishes

Abstract Chemicals released into aquatic environments are detected in surface waters globally, and some can disrupt thyroid hormone (TH) signaling in fishes. A key protein in this pathway is thyroperoxidase (TPO), which catalyzes synthesis of THs. Inhibition of TPO is associated with decreased THs, leading to a variety of adverse outcomes. However, there is uncertainty regarding species-specific sensitivities to inhibition of TPO among fishes and whether inhibitors in mammals share that activity in fishes. Therefore, the present study applied the Amplex UltraRed TPO assay to compare in vitro sensitivities across five phylogenetically diverse fishes, namely red drum (Sciaenops ocellatus), sheepshead minnow (Cyprinodon variegatus), American eel (Anguilla rostrata), southern flounder (Paralichthys lethostigma), and spotted gar (Lepisosteus oculatus). The reference inhibitor, methimazole, and five environmentally relevant chemicals were evaluated to represent a range of potencies reported in the ToxCast mammalian-based assays. Methimazole inhibited TPO activity in all five species, with sensitivities within an order of magnitude. All evaluated chemicals, except dichlorvos, inhibited TPO activity, with all five species having similar sensitivities. Potency relative to methimazole varied across the tested chemicals, with the average potency ranking across species being methimazole > bisphenol A > chlorophene > chlorpyrifos > triclocarban > dichlorvos. Chemicals identified as TPO inhibitors in mammalian-based assays shared inhibitory activity across fishes, and relative potencies were conserved between mammals and fishes. This sensitivity was consistent across phylogenetically diverse species and is supported by the high level of conservation of TPO structure and function across vertebrate taxa. Taken together, these findings suggest that toxicity data from model fishes can be extrapolated to native species and mammalian-based ToxCast data can confidently be used as a source for predicting relative potencies of chemicals for inhibiting TPO of fishes in support of more objective ecological risk assessments.