Maternal exposure to the thyroperoxidase-inhibiting pesticide amitrole induces hypothyroidism and developmental neurotoxicity in the rat brain

Thyroid hormone (TH) system-disrupting chemicals pose significant risks to human health and the environment, highlighting the urgent need for improved toxicological testing methods. A major concern is that environmental chemicals may induce developmental neurotoxicity by compromising TH signaling during critical life stages. In this study, we evaluated the thyroidal and neurotoxic effects of two compounds that interfere with TH signaling by inhibiting TH synthesis in the thyroid gland. Methimazole (MMI) is a pharmaceutical specifically designed to treat hyperthyroidism by inhibiting thyroperoxidase (TPO), while the herbicide amitrole has unintentional TPO-inhibiting properties. Pregnant and lactating rat dams were exposed to control (corn oil), 8 or 16 mg/kg body weight/day MMI, or 25 or 50 mg/kg body weight/day amitrole from gestation day 7 to postnatal day 16. MMI and amitrole induced fetal and postnatal hypothyroidism in offspring. Both compounds induced similar reductions in serum and brain TH concentrations and induced a brain malformation, periventricular heterotopia, tied to compromised TH signaling. Our results reinforce concerns over the potential for exposure to environmental chemicals with TH system-disrupting properties to negatively impact the developing brain in vertebrates.