1 research outputs found
High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase I Chemical Library
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 using an initial single-concentration
(100 μM) radioactive-iodide uptake (RAIU) assay, followed by
169 samples further evaluated in multi-concentration (0.001 μM–100
μM) 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 potential 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)