Toxicokinetic insights into distinct mechanisms of action of two thyroid toxicants: Propylthiouracil and pregnenolone 16α-carbonitrile

Thyroid hormones (THs) are critical for metabolic regulation and brain development. Disruptions in TH homeostasis, especially during fetal development, can lead to irreversible neurodevelopmental impairments. Thyroid hormone system-disrupting chemicals (THSDCs), are of growing concern for human health due to their potential to interfere with TH signaling. This study investigates the toxicokinetic properties of two THSDCs: propylthiouracil (PTU), which inhibits TH synthesis, and pregnenolone-16 alpha-carbonitrile (PCN), which enhances the TH hepatic metabolism. Using in vitro approaches and in vivo models involving pregnant, fetal, and neonatal rats, we aimed to characterize the absorption, distribution, metabolism, and excretion (ADME) profiles of these compounds. Liver metabolism, fraction unbound, plasma concentrations, and tissue distribution of PTU and PCN were assessed. Our investigation demonstrated that PCN underwent quick liver metabolism, resulting in undetectable PCN levels in adult and newborn rat tissues as well as in maternal milk. In contrast, PTU exhibited high permeability through the intestinal barrier and was slowly metabolized by the liver, leading to high PTU concentrations in the maternal milk, thyroid gland, and the brain of fetuses and newborns. These latter results raise concerns regarding the potential direct effect of PTU on neonatal brain development. Especially, the hypothesis that PTU can interact with brain peroxidases involved in detoxification processes warrants further investigation. These findings highlight the intricate relationship between THSDC exposure, altered TH synthesis and metabolism, and subsequent impacts on neurodevelopment.