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Evaluating iodide recycling inhibition as a novel molecular initiating event for thyroid axis disruption in amphibians
Citation:
Olker, J., J. Haselman, Pat Kosian, K. Donnay, Joe Korte, C. Blanksma, M. Hornung, AND S. Degitz. Evaluating iodide recycling inhibition as a novel molecular initiating event for thyroid axis disruption in amphibians. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 166(2):318-331, (2018). https://doi.org/10.1093/toxsci/kfy203
Impact/Purpose:
Iodotyrosine deiodinase is the enzyme that catalyzes iodide recycling. This enzyme protects against excretion of critical iodide and promotes accumulation of iodide in the thyroid follicular cells for thyroid hormone synthesis. This iodide recycling is especially critical for low iodine diets and low iodine environments, including most freshwater ecosystems. Evaluating iodotyrosine deiodinase inhibition with in vivo assays will establish biological relevance, susceptibility to chemical inhibition, and validate this novel molecular initiating event for thyroid axis disruption.
Description:
The enzyme iodotyrosine deiodinase (dehalogenase, IYD) catalyzes iodide recycling and promotes iodide retention in thyroid follicular cells. Loss of function or chemical inhibition of IYD reduces available iodide for thyroid hormone synthesis, which leads to hormone insufficiency in tissues and subsequent negative developmental consequences. Iodide recycling by IYD is especially critical under conditions of lower dietary iodine and in low iodine environments. We characterized IYD ontogeny and evaluated the effect of IYD inhibition on the thyroid axis in the model amphibian species, Xenopus laevis. IYD mRNA expression was quantified in multiple tissues in normal development. To test IYD inhibition, X. laevis tadpoles were exposed to 3-nitro-L-tyrosine (MNT) from premetamorphosis (NF stage 50) to metamorphic climax (NF stage 62) in 42-day static renewal waterborne exposure experiment, with MNT concentrations from 7.4 to 200 mg/L and an additional ?‘rescue’ treatment in which 200 mg/L MNT was supplemented with iodide. IYD was expressed in thyroid glands, kidneys, liver, and intestine, but minimally in the tail. Chemical inhibition of IYD resulted in markedly delayed development, with tadpoles in the highest MNT concentrations stalled at NF60-61. This effect was linked to altered biochemical measurements, with reduced circulating triiodothyronine (T3), reduced glandular and circulating thyroxine (T4), and increased monoiodotyrosine (MIT) and diiodotyrosine (DIT) in the plasma. Iodide supplementation negated these effects, ?‘rescuing’ exposed tadpoles. These results establish toxicological relevance of IYD inhibition and validate this novel molecular initiating event in amphibians. Given the highly conserved nature of the IYD protein sequence and scarcity of iodine in the environment, IYD inhibition should be further investigated as a molecular initiating event for thyroid axis disruption in freshwater organisms.
URLs/Downloads:
DOI: Evaluating iodide recycling inhibition as a novel molecular initiating event for thyroid axis disruption in amphibians