Over
the past decade, there has been increased concern for environmental
chemicals that can target various sites within the hypothalamic–pituitary–thyroid
axis to potentially disrupt thyroid synthesis, transport, metabolism,
and/or function. One well-known thyroid target in both humans and
wildlife is the sodium iodide symporter (NIS) that regulates iodide
uptake into the thyroid gland, the first step of thyroid hormone synthesis.
Our laboratory previously developed and validated a radioactive iodide
uptake (RAIU) high-throughput assay in a stably transduced human NIS
cell line (hNIS-HEK293T-EPA) to identify chemicals with potential
for NIS inhibition. So far, we have tested over 2000 chemicals (US
EPA’s ToxCast chemical libraries PI_v2, PII, and e1K) and discovered
a subset of chemicals that significantly inhibit iodide uptake in
the hNIS assay. Here, we utilized this screening assay to test a set
of 149 unique per- and polyfluoroalkyl substances (PFAS) (ToxCast
PFAS library) for potential NIS inhibition. For this evaluation, the
149 blinded samples were screened in a tiered approach, first in an
initial single-concentration (≤100 μM) RAIU assay and
subsequent evaluation of the chemicals that produced ≥20% inhibition
using multiconcentration (MC) response (0.001–100 μM)
testing in parallel RAIU and cell viability assays. Of this set, 38
of the PFAS chemicals inhibited iodide uptake ≥20% in the MC
testing with 25 displaying inhibition ≥50%. To prioritize the
most potent PFAS NIS inhibitors in this set, chemicals were ranked
based on outcomes of both iodide uptake and cytotoxicity and normalized
to perchlorate, a known positive control. Consistent with previous
findings, PFOS and PFHxS were again found to be potent NIS inhibitors,
yet significant inhibition was also observed for several other screened
PFAS chemicals. Although further studies are clearly warranted, this
initial screening effort identifies NIS as a molecular target for
potential thyroid disruption by this persistent and structurally diverse
class of chemicals.