The Thyroperoxidase Inhibiting Pesticide Amitrole Causes Developmental Hypothyroidism and Alters Brain Development: Heterotopia Form in the Brain of Perinatally Exposed Rat Offspring

Thyroid hormones (TH) are essential for brain development, and their synthesis is dependent on thyroperoxidase activity in the thyroid follicles. The U.S. Environmental Protection Agency’s ToxCast program has identified a number of environmental chemicals that are thyroperoxidase inhibitors in vitro and therefore potential thyroid hormone system disruptors. However, what effects these chemicals can have on in vivo serum TH concentrations or on brain development remain unknown. Here, we exposed pregnant rat dams by oral gavage to 2-mercaptobenzimidazole (MBI), amitrole or cyanamide; three environmental chemicals that are in vitro inhibitors of thyroperoxidase. MBI and cyanamide had only minor, sporadic effects on TH concentrations in dams but caused reproductive toxicity such as dystocia and reduced postnatal body weights. In contrast, amitrole, a triazole pesticide, reduced circulating thyroxine (T4) concentrations and caused abnormal brain development in the offspring. A congenital malformation were observed in the brain of the offspring, with large clusters of ectopic neurons in the corpus callosum; so called periventricular heterotopia, which can form after developmental TH insufficiency. Since the irreversibly formed heterotopia appears to manifest after exposure to amitrole, this pesticide joins the two classical thyroperoxidase inhibiting anti-thyroid drugs propylthiouracil and methimazole. We propose heterotopia formation as a relevant effect endpoint for developmental thyroid hormone system disruption caused by exposure to thyroperoxidase inhibiting chemicals.