Detection and mechanistic estimation of antithyroid chemicals in repeated-dose oral toxicity studies in rats

Abstract

We aim to establish a more efficient method for detecting antithyroid chemicals. Ten chemicals with 5 types of antithyroid mechanisms (inhibitors of thyroid peroxidase (TPO), iodine uptake, deiodinase (DIO), and TSH production and promoters of hormone metabolism in the liver) were orally administered to 6-week-old male SD rats for 28 days. Serum T3, T4, and TSH levels were measured, and histopathological and immunohistochemical analyses were performed. For the 4 mechanisms except for TSH production inhibition, follicular cell hypertrophy in the thyroid gland increased from low doses compared to changes in blood hormone levels, and was the most sensitive indicator. Immunohistochemistry showed that thyroid T3/T4 staining was decreased by TPO and iodine uptake inhibitors, which was thought to reflect a direct inhibition. Thyroid NIS expression was increased by iodine uptake inhibitors, but in contrast, it was decreased by DIO inhibitors. In addition, hepatic UGT1A6 expression was increased by hormone metabolism promoters. For TSH production inhibitors, decreases in TSH-producing cells in the pituitary gland could be detected by immunostaining. These results demonstrated that histopathology of the thyroid gland is a useful indicator for detecting antithyroid chemicals, and that the mechanism can be estimated by immunohistochemistry. These methods can be easily performed in 28-day repeated-dose studies, which are commonly used in safety evaluation of chemicals, and it is expected that combining them with blood hormone levels will lead to faster and more precise evaluations.