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Quantitative Adverse Outcome Pathway for Neurodevelopmental Effects of Thyroid Peroxidase-Induced Thyroid Hormone Synthesis Inhibition
Hassan, I., H. El-Masri, Pat Kosian, J. Ford, R. Ford, M. Jasper, S. Degitz, AND M. Gilbert. Quantitative Adverse Outcome Pathway for Neurodevelopmental Effects of Thyroid Peroxidase-Induced Thyroid Hormone Synthesis Inhibition. Society of Toxicology, Baltimore, MD, March 12 - 16, 2017.
Present data at SOT from progress in quantitative adverse outcome pathway development for thyroid hormone disruption -
Adequate levels of thyroid hormones (TH) are needed for proper brain development and deficiencies lead to adverse neurological outcomes in humans and in animal models. Environmental chemicals have been shown to disrupt TH levels, yet the relationship between developmental exposures and decline in serum TH leading to neurodevelopmental impairments is poorly understood. In this study, we assembled experimental and literature data to empirically describe a quantitative adverse outcome pathway (qAOP) for TH insufficiency and impaired neurodevelopmental outcome. Specifically, we quantitatively linked, reductions in TH synthesis from inhibition of thyroperoxidase (TPO) and resulting decreases in serum TH in the dam and fetus. We also mathematically linked deficits in the fetal brain hormone levels to structural defect or heterotopias in the brain of offspring. Pregnant dams were exposed to the prototypic TPO inhibitor, 6-propylthiouracil (PTU 0, 0.1, 0.5, 1, 2, or 3 ppm) from gestational day (GD) 6-20. On GD20, PTU concentrations were increased in maternal and fetal serum with the levels in the dams being 2-fold higher than the fetus. Serum T4 levels in the dam were decreased by 55% and 81% at 2 and 3 ppm, and fetal serum T4 was reduced by 35%, 60%, 83%, and 90% with exposure to 0.5, 1, 2, and 3 ppm doses of PTU. Exposure to 2 and 3 ppm PTU decreased fetal serum T3 with no change observed in the dam at any dose level. Increases in maternal and fetal serum PTU and decreases in maternal and fetal serum T4 levels were highly correlated. Fetal brain T4, estimated from published literature sources, were quantitatively linked to increases in heterotopia size in the brains of offspring. Taken together, these data show the potential of in vivo assessments and quantitative modeling to predict the development of a structural brain malformation and demonstrate the utility of qAOP approach to evaluate brain deficits that may result from exposure to other TH disruptors. Does not reflect EPA policy.