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In vivo deiodinase inhibition by iopanoic acid causes thyroid axis disruption and dysmorphogenesis in model amphibian species Xenopus laevis
Citation:
Haselman, J., Pat Kosian, K. Donnay, M. Hornung, Joe Korte, J. Denny, J. Olker, R. Schulte, C. Knutsen, AND S. Degitz. In vivo deiodinase inhibition by iopanoic acid causes thyroid axis disruption and dysmorphogenesis in model amphibian species Xenopus laevis. Society of Toxicology Meeting, San Antonio, TX, March 11 - 15, 2018.
Impact/Purpose:
The Agency is in the process of identifying biological targets susceptible to chemical interaction leading to endocrine toxicity, then developing assays to include those targets in the battery of in vitro high-throughput screening tests to evaluate chemical safety. Deiodinase enzymes have been identified as potential targets for thyroid endocrine disruption, therefore high-throughput assays have been developed and the ToxCast chemical inventory is in the process of being screened for bioactivity. However, there is a paucity of in vivo data characterizing potential thyroid disruption via deiodinase inhibition, leaving great uncertainty regarding the predictive linkage between in vitro deiodinase inhibition and in vivo organismal adverse outcomes following chemical exposure. This work begins to characterize that gap and advance the capability of the Agency to predict adverse organismal outcomes based on high-throughput in vitro data supporting streamlined chemical risk evaluations.
Description:
Deiodinase (DIO) enzymes activate, deactivate and catabolize thyroid hormones (THs) and play an important role in thyroid-mediated amphibian metamorphosis. DIOs have been implicated as putative targets of xenobiotics leading to thyroid disruption. In an effort to characterize biochemical and apical effects on the thyroid axis following in vivo DIO inhibition, a 40 day waterborne iopanoic acid (IOP) exposure was conducted with model amphibian species Xenopus laevis. Stage-matched pro-metamorphic larvae were exposed to 0, 1.5, 3.0 or 6.0 mg/L IOP until 2 weeks after the median time control larvae completed metamorphosis. Blood and thyroid glands were collected from random sub-samples at 7 and 11 d to evaluate levels of circulating and glandular TH and mono- and di-iodotyrosine (MIT, DIT). Time to complete metamorphosis, growth and somatic development were evaluated as larvae completed metamorphosis or at test termination. There were treatment-related increases in both circulating and glandular thyroxine (T4), suggesting inhibition of negative feedback in the hypothalamus-pituitary by IOP. TH precursors, MIT and DIT, were also increased in thyroid glands by IOP treatment whereas glandular triiodothyronine (T3) was decreased, suggesting inhibition of T4-to-T3 conversion by type II DIO. IOP treatment also caused decreased sodium iodide symporter gene expression in thyroid glands, contrary to what would be expected in hyperthyroid conditions. Approximately 37% of the 6.0 mg/L treatment did not complete metamorphosis prior to test termination, of which all were developmentally asynchronous with many abnormally retaining gill structure. Of the individuals in the 3.0 and 6.0 mg/L treatments that completed metamorphosis, ~40 and ~70%, respectively, had observable minute tail remnants at test termination, indicating inhibition of full tail resorption. Interestingly, tail resorption began earlier in IOP-exposed larvae as compared to control while final resorption was delayed. Taken together, IOP exposure caused systemic hyperthyroid conditions while disrupting metamorphic processes in the peripheral tissues due to inhibition of proper biochemical conversions of TH. This study provides precedent for thyroid axis disruption and adverse apical outcomes mediated by deiodinase inhibition.