Comparisons of the Sensitivity of Histopathological and Immunohistochemical Analyses With Blood Hormone Levels for Early Detection of Antithyroid Effects in Rats Treated With Promoters of Thyroid Hormone Metabolism

Although blood triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels are useful for detecting antithyroid compounds in rodent toxicity studies, there are challenges with high variability due to sampling conditions. Here, we compared histopathological and immunohistochemical findings with blood hormone levels in rats treated with promoters of thyroid hormone metabolism to explore useful markers for hypothyroidism. Six-week-old male and female Sprague-Dawley rats (5/group) were administered phenobarbital sodium salt (NaPB) or nicardipine hydrochloride (NCD) by gavage for 28 days. Decreased serum T4 and increased TSH levels were detected at 100 mg/kg NaPB and 150 mg/kg NCD, whereas follicular cell hypertrophy occurred at lower doses of ≥ 30 mg/kg NaPB and ≥ 50 mg/kg NCD. There was no obvious change in T3 or T4 immunostaining in the thyroid unlike thyroid peroxidase (TPO) inhibitors, and uridine diphosphate-glucuronosyltransferase 1A6-positive area in the liver increased at doses lower than those affecting the serum T4 levels and generally the same as those at which hepatocellular hypertrophy and follicular cell hypertrophy were observed, indicating its usefulness in detecting thyroid hormone metabolism promoters. These results indicate that histopathology is useful for sensitive detection of hormone metabolism promoters and can be distinguished from TPO inhibitors by immunohistochemistry.