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Evaluating iodide recycling inhibition as a novel molecular initiating event for thyroid axis disruption
Olker, J., J. Haselman, Pat Kosian, Joe Korte, M. Hornung, AND S. Degitz. Evaluating iodide recycling inhibition as a novel molecular initiating event for thyroid axis disruption. SETAC North America, Minneapolis, MN, November 12 - 16, 2017.
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.
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 low dietary iodine and in low iodine environments, including most freshwater ecosystems. We evaluated the impact of IYD inhibition on the thyroid axis of the model amphibian species Xenopus laevis. Tadpoles were exposed to 3-nitro-L-tyrosine (MNT, a known IYD inhibitor) from premetamorphosis (NF stage 51) to metamorphic climax (NF stage 61-62) in 30-day static renewal waterborne exposure experiments. Under a low iodine diet, exposure to 7.4, 22.2, 66.7, and 200 mg/L MNT was tested with an additional treatment of 200 mg/L MNT with iodide supplementation. IYD inhibition was also tested with three separate diets with different iodine content to exposure of 50, 100, 200, and 400 mg/L MNT. Exposure resulted in markedly delayed metamorphosis and glandular hypertrophy. In tadpoles exposed to the highest concentrations (200 and 400 mg/L), development was completely arrested at NF 58-60, a stage when demand for thyroid hormone dramatically increases. IYD inhibition led to reductions in thyroxine (T4), increased monoiodotyrosine (MIT), and increased diiodotyrosine (DIT) concentrations in the plasma. The dose-response for these effects was dependent on dietary iodine content. Reduced T4, increased MIT and DIT, and thyroid gland compensatory response (sodium/iodide symporter gene expression) were found across the range of concentrations tested, even in treatments where tadpoles reached metamorphic climax. Supplementation with iodide negated the effect of IYD inhibition on metamorphosis and plasma T4, effectively ?‘rescuing’ the exposed tadpoles. In addition, MIT and DIT in the plasma were greatly increased, demonstrating inhibition of iodide recycling. 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, IYD inhibition may be worth further investigation as a molecular initiating event for thyroid axis disruption with cross-species relevance. This abstract does not necessarily reflect US EPA policy.
Record Details:Record Type: DOCUMENT (PRESENTATION/SLIDE)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
MID-CONTINENT ECOLOGY DIVISION