Iopanoic acid alters thyroid hormone-related gene expression, thyroid hormone levels, swim bladder inflation, and swimming performance in Japanese medaka.

Disruption of the thyroid hormone system by synthetic chemicals is gaining attention owing to its potential negative effects on organisms. In this study, the effects of the dio-inhibitor iopanoic acid (IOP) on the levels of thyroid hormone and related gene expression, swim bladder inflation, and swimming performance were investigated in Japanese medaka. Iopanoic acid exposure suppressed thyroid-stimulating hormone ß (tshß), tshß-like, iodotyronin deiodinase 1 (dio1), and dio2 expression, and increased T4 and T3 levels. In addition, IOP exposure inhibited swim bladder inflation, reducing swimming performance. Although adverse outcome pathways of thyroid hormone disruption have been developed using zebrafish, no adverse outcome pathways have been developed using Japanese medaka. This study confirmed that IOP inhibits dio expression (a molecular initiating event), affects T3 and T4 levels (a key event), and reduces swim bladder inflation (a key event) and swimming performance (an adverse outcome) in Japanese medaka.

Impaired swim bladder inflation in early life stage fathead minnows exposed to a deiodinase inhibitor, iopanoic acid.

Inflation of the posterior and/or anterior swim bladder is a process previously demonstrated to be regulated by thyroid hormones. We investigated whether inhibition of deiodinases, which convert thyroxine (T4) to the more biologically active form, 3,5,3'-triiodothyronine (T3), would impact swim bladder inflation. Two experiments were conducted using a model deiodinase inhibitor, iopanoic acid (IOP). First, fathead minnow embryos were exposed to 0.6, 1.9, or 6.0 mg/L or control water until 6 d postfertilization (dpf), at which time posterior swim bladder inflation was assessed. To examine anterior swim bladder inflation, a second study was conducted with 6-dpf larvae exposed to the same IOP concentrations until 21 dpf. Fish from both studies were sampled for T4/T3 measurements and gene transcription analyses. Incidence and length of inflated posterior swim bladders were significantly reduced in the 6.0 mg/L treatment at 6 dpf. Incidence of inflation and length of anterior swim bladder were significantly reduced in all IOP treatments at 14 dpf, but inflation recovered by 18 dpf. Throughout the larval study, whole-body T4 concentrations increased and T3 concentrations decreased in all IOP treatments. Consistent with hypothesized compensatory responses, deiodinase-2 messenger ribonucleic acid (mRNA) was up-regulated in the larval study, and thyroperoxidase mRNA was down-regulated in all IOP treatments in both studies. These results support the hypothesized adverse outcome pathways linking inhibition of deiodinase activity to impaired swim bladder inflation. Environ Toxicol Chem 2017;36:2942-2952. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

Gastrointestinal radiology. A study of iopanoate metabolism and toxicity in isolated cell cultures.

Radiologists are familiar with certain toxic manifestations of biliary and urinary contrast media (ie, acute tubular necrosis in dehydrated patients with diabetes or multiple myeloma), and with the specific effects of contrast media on other diagnostic tests (ie, I uptake, PBI, etc). These have been studied because of their clinical and diagnostic impact upon patient management. It has become apparent that many subtle, though perhaps predictable, drug interactions occur. Some of these are of obvious clinical and therapeutic significance and have been studied and described in detail. The authors have tried to establish the effects of clinically used drugs on the contrast medium iopanoic acid. The fact that both drugs thus far studied - aspirin and cholestyramine - have profound laboratory effects on iopanoic acid suggests that some systematic approach to the study of the clinical pharmacology of contrast agents is desirable. Others have also observed effects of contrast media on various clinical and laboratory parameters, but most observations are isolated empirical observations, and our basic understanding of the mechanisms involved are crude at best. How might this problem be approached? Although in vivo pharmacokinetic studies in unanesthetized animals allow identification of possible drug-drug interactions in the absence of multiple clinical variables and let us do crossover studies with each animal acting as its own control, such studies are difficult, expensive, and do little to establish the mechanism of the interaction. The authors are currently approaching this problem with a more basic technique. In conjunction with colleagues in gastroenterology and pharmacy, they are studying iopanoate metabolism and aspirin-iopanoate interaction in isolated hepatocyte monolayer cultures. The preliminary data from these experiments will be presented, and the significance of these results and the potential usefulness of this model will be discussed.

Use of tissue culture to examine neurotoxicity of contrast media.

The effect of small concentrations of diatrizoate, ioglycamate, and iopanoate salts on cultured sympathetic ganglia was studied. Biliary contrast media in clinical blood concentrations caused severe degeneration of cultured neurons, but similar concentrations of diatrizoate caused no effect. This technique may be used to measure the direct neurotoxicity or general cytotoxicity of contrast media.