High-Throughput Screening and Quantitative Chemical Ranking for Sodium Iodide Symporter (NIS) Inhibitors in ToxCast Phase I Chemical Library

摘要

Thyroid uptake of iodide via the sodium-iodide symporter (NIS) is the first step in the biosynthesis of thyroid hormones that are critical for health and development in humans and wildlife. Despite having long been a known target of endocrine disrupting chemicals such as perchlorate, information regarding NIS inhibition activity is still unavailable for the vast majority of environmental chemicals. This study applied a previously validated high-throughput approach to screen for NIS inhibitors in the ToxCast phase I library, representing 293 important environmental chemicals. Here 310 blinded samples were screened in a tiered-approach by an initial single-concentration (100μM) radioactive-iodide uptake (RAIU) assay, followed with 169 samples further evaluated in multi-concentration (0.001μM-100μM) testing in parallel RAIU and cell viability assays. A novel chemical ranking system that incorporates multi-concentration RAIU and cytotoxicity responses was also developed as a standardized method for chemical prioritization in current and future screenings. Representative chemical responses and thyroid effects of high-ranking chemicals are further discussed. This study significantly expands current knowledge of NIS inhibition potentials in environmental chemicals, and provides critical support to U.S.EPA’s Endocrine Disruptor Screening Program (EDSP) initiative to expand coverage of thyroid molecular targets as well as the development of thyroid adverse outcome pathways (AOPs).