Citation:

Haselman, J., J. Nichols, M. Hornung, Pat Kosian, J. Olker, Joe Korte, AND S. Degitz. Computational modeling of the amphibian thyroid axis supported by targeted in vivo testing to advance quantitative adverse outcome pathway development. National Society of Toxicology Annual Meeting, Baltimore, MD, March 12 - 16, 2017.

Impact/Purpose:

Development of quantitative adverse outcome pathways and predictive models are facilitating the transition away from animal toxicity testing to support chemical risk assessment. This computational model incorporates many of the putative molecular initiating events proposed to lead to thyroid axis disruption and subsequent adverse apical outcomes in amphibians. Demonstration of the consistency between model simulations and empirical data provide confidence in the model’s ability to predict adverse apical effects on amphibian development. This work will result in a model description that can be interfaced with exposure models and/or population models as a predictive tool to support ecological risk assessment.

Description:

In vitro screening of chemicals for bioactivity together with computational modeling are beginning to replace animal toxicity testing in support of chemical risk assessment. To facilitate this transition, an amphibian thyroid axis model has been developed to describe thyroid homeostasis during Xenopus laevis pro-metamorphosis. The model simulates the dynamic relationships of normal thyroid biology throughout this critical period of amphibian development and includes molecular initiating events (MIEs) for thyroid axis disruption to allow in silico simulations of hormone levels following chemical perturbations. One MIE that has been formally described using the adverse outcome pathway (AOP) framework is thyroperoxidase (TPO) inhibition. The goal of this study was to refine the model parameters and validate model predictions by generating dose-response and time-course biochemical data following exposure to three TPO inhibitors, methimazole, 6-propylthiouracil and 2-mercaptobenzothiazole. Key model variables including gland and blood thyroid hormone (TH) levels were compared to empirical values measured in biological samples at 2, 4, 7 and 10 days following initiation of exposure at Nieuwkoop and Faber (NF) stage 54 (onset of pro-metamorphosis). The secondary objective of these studies was to relate depleted blood TH levels to delayed metamorphosis, the adverse apical outcome. Delayed metamorphosis was evaluated by continuing exposure with a subset of larvae until all of the controls reached NF stage 62 (metamorphic climax). All three in vivo studies resulted in dose-dependent reductions in glandular iodinated tyrosine and TH with concomitant dose-dependent reductions in circulating TH levels. Further, all three studies resulted in treatment concentrations exhibiting significantly delayed metamorphosis, providing a basis to predict this adverse apical outcome from early circulating TH levels. This work has advanced quantitative understanding of the amphibian TPO AOP and demonstrated the predictive potential of an amphibian thyroid axis model. This abstract does not necessarily reflect US EPA policy.

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