Thyroid hormone (TH) system-disrupting chemicals can cause adverse effects, including neurodevelopmental deficits. While current in vivo test methods reliably detect disruptions from potent antithyroid drugs such as propylthiouracil (PTU) and methimazole (MMI) through thyroid gland histopathology, they may lack sensitivity for less potent chemicals or those acting through alternative mechanisms. A more systemic, mechanism-based approach may therefore be needed to identify TH system-disrupting capacity. Here, we assessed the effects of the environmental chemicals perfluorooctane sulfonate (PFOS) and tetrabromobisphenol A (TBBPA) on the TH system using in vitro and in vivo approaches. PFOS inhibited the TH transmembrane transporter monocarboxylate transporter 8 (MCT8) and the sodium-iodide symporter (NIS). TBBPA inhibited MCT8, the enzyme activity of all three iodothyronine deiodinases (DIO1/2/3), and thyroperoxidase (TPO). In time-mated rats, in utero and early postnatal exposure to PFOS (0.4 or 0.8 mg/kg bw/day) or TBBPA (250 or 500 mg/kg bw/day) reduced serum TH concentrations in dams and offspring, but neither chemical altered thyroid stimulating hormone (TSH) in offspring. We observed no, or only modest, effects on thyroid gland histology. Both chemicals altered TH metabolism by deiodinase and dehalogenase enzymes and reduced iodine content in the thyroid. In the fetal brain, PFOS increased T3, while TBBPA decreased T4 in the postnatal brain. These findings demonstrate distinct TH-disrupting profiles of PFOS and TBBPA, differing from classic antithyroid compounds PTU and MMI. Our results highlight the need for more comprehensive systems-approaches to capture TH disrupting chemicals acting through diverse mechanisms.
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