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Abstract - In vitro approaches to risk assess chemical mediated changes in thyroid function.

Authors: Larry G. Higgins, Corinne Haines, A. Kenneth McLeod, Lynsey Chatham, Graeme Clark and Marc Princivalle.
Concept Life Sciences, 2 James Lynsey Place, Dundee, UK KY157NF
Keywords: Thyroxine, Thyroid peroxidase, Endocrine Disruption.

The hypothalamic-pituitary-thyroid axis (HPT axis) is conserved across vertebrate evolution. Perturbation of thyroid hormone homeostasis (THH) can lead to adverse effects in thyroid function affecting growth, metabolism and cognitive function.  In utero, appropriate thyroid hormone concentrations are absolutely required for normal nervous system development. Chemical disruption of THH can occur via a number of mechanisms, including increased hepatic thyroid hormone clearance, inhibition of iodide transport into the thyroid (sodium/iodide symporter), inhibition of iodide oxidation (thyroid peroxidase) and inhibition of thyroid hormone deiodination (deiodinases). To understand the effect of chemicals on these functions the following assays are utilised. 1. in vitro primary hepatic thyroid hormone metabolism (multiple species), 2. thyroid peroxidase inhibition (multiple species), 3. deiodinase inhibition (rat and human), 4. sodium/iodide symporter inhibition (rat). Rat sodium iodide symporter inhibition and rat and human deiodinase 1,2 and 3 inhibition assays are currently being validated. Here we report the validation of in vitro rat, dog, pig and human TPO inhibition and in vitro primary hepatocyte metabolism of thyroxine (T4).  In concurrence with the literature, TPO inhibition by 6-propyl-2-thiouracil (PTU) shows broad sensitivity across the species tested. in rat (IC50 2.2 µM ) Dog (IC50 17.7 µM ) pig (IC50 7.6 µM) and human (IC50 50.9 µM ). T4 metabolism by primary cultures of human and rat hepatocytes show a consistent dose response induction (approximately 2 fold over vehicle control) in response to reference item administration.

These assays form part of an in vitro screen used to generate data to study chemical endocrine disruption hazard.

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