Comparison of the Sensitivity of Histopathological and Immunohistochemical Analyses With That of Serum Hormone Measurements for Early Detection of Antithyroid Effects in Rats Treated With Iodide Uptake Inhibitors

ABSTRACT Serum thyroxine (T4), triiodothyronine (T3), and thyroid‐stimulating hormone (TSH) measurements are widely used to detect antithyroid effects in rodent toxicity studies. However, the assays used to measure these hormones are costly and highly variable depending on the blood sampling and measurement conditions. We previously demonstrated that histopathological evaluation detects the effects of thyroid peroxidase (TPO) inhibitors and thyroid hormone metabolism promoters more sensitively than serum hormone measurements. Here, we examined whether this approach can also improve early detection of antithyroid chemicals that inhibit iodide uptake, an essential step in thyroid hormone synthesis. We compared histopathological and immunohistochemical findings with serum hormone measurements in 6‐week‐old male Sprague–Dawley rats (five per group) administered ammonium perchlorate (APC) or potassium thiocyanate (PTC) in drinking water for 28 days. Serum T4 decreased at 1000 ppm APC and 5000 ppm PTC, T3 decreased at 1000 ppm APC, and TSH increased at ≥ 100 ppm APC. In contrast, follicular cell hypertrophy was detected at ≥ 10 ppm APC and 5000 ppm PTC, indicating greater sensitivity compared with serum hormone measurements. Decreased T3 and T4 immunostaining showed a sensitivity comparable with that of serum hormone changes, whereas thyroid sodium/iodide symporter (NIS)‐immunopositive areas increased at doses that produced no detectable changes in serum hormone levels, suggesting that NIS immunostaining represents the most sensitive marker of iodide uptake inhibition. These results suggest that combining histopathological and immunohistochemical analyses enables sensitive detection of antithyroid effects and provides mechanistic information that cannot be obtained from serum hormone measurements alone.