Citation:

Haselman, Jonathan, J. Nichols, K. Mattingly, M. Hornung, AND S. Degitz. A biologically based computational model for the hypothalamic-pituitary-thyroid (HPT) axis in Xenopus laevis larvae. MATHEMATICAL BIOSCIENCES. Elsevier Science Ltd, New York, NY, 362:109021, (2023). https://doi.org/10.1016/j.mbs.2023.109021

Impact/Purpose:

This sub-product provides computational tools for interpretation of mechanisms of thyroid axis disruption in support of the OCSPP Endocrine Disruptor Screening Program. The computational model of the amphibian thyroid axis includes a number of molecular mechanisms that are known to lead to thyroid disruption and are also represented among the suite of ToxCast in vitro screening assays. The current version of the model simulates normal Xenopus laevis developmental biology throughout a critical window of metamorphic development, which provides the foundation for future integration of exposure toxicokinetics and in vitro screening data to predict thyroid axis status and apical outcomes. Future versions of the model will aim to simulate the Tier 1 Amphibian Metamorphosis Assay in an effort to prioritize testing and reduce animal usage for chemical safety assessment. 

Description:

A biologically based computational model was developed to describe the hypothalamic-pituitary-thyroid (HPT) axis in developing Xenopus laevis larvae. The goal of this effort was to develop a tool that can be used to better understand mechanisms of thyroid hormone-mediated metamorphosis in X. laevis and predict organismal outcomes when those mechanisms are perturbed by chemical toxicants. In this report, we describe efforts to simulate the normal biology of control organisms. The structure of the model borrows from established models of HPT axis function in mammals. Additional features specific to X. laevis account for the effects of organism growth, growth of the thyroid gland, and developmental changes in regulation of thyroid stimulating hormone (TSH) by circulating thyroid hormones (THs). Calibration was achieved by simulating observed changes in stored and circulating levels of THs during a critical developmental window (Nieuwkoop and Faber stages 54–57) that encompasses widely used in vivo chemical testing protocols. The resulting model predicts that multiple homeostatic processes, operating in concert, can act to preserve circulating levels of THs despite profound impairments in TH synthesis. Represented in the model are several biochemical processes for which there are high-throughput in vitro chemical screening assays. By linking the HPT axis model to a toxicokinetic model of chemical uptake and distribution, it may be possible to use this in vitro effects information to predict chemical effects in X. laevis larvae resulting from defined chemical exposures.

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