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Targeted pathway-based in vivo testing using thyroperoxidase inhibition to evaluate plasma thyroxine as a surrogate metric of metamorphic success in model amphibian Xenopus laevis
Haselman, Jonathan, J. Olker, P. Kosian, J. Korte, J. Swintek, J. Denny, J. Nichols, J. Tietge, M. Hornung, AND S. Degitz. Targeted pathway-based in vivo testing using thyroperoxidase inhibition to evaluate plasma thyroxine as a surrogate metric of metamorphic success in model amphibian Xenopus laevis. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 175(2):236-250, (2020). https://doi.org/10.1093/toxsci/kfaa036
This work is facilitating the transition away from whole animal toxicity testing by quantitatively characterizing linkages between biochemical (i.e., subapical) endpoints and apical adverse outcomes relevant to ecological risk assessment. These quantitative linkages lay the groundwork for molecular pathway-based hazard assessments that begin with in vitro assays designed to interrogate a single target but can be predictive of downstream effects at higher levels of biological organization. This study serves to demonstrate a means to develop surrogate metrics of apical outcomes using the adverse outcome pathway framework and targeted in vivo testing. These results have the potential to change the strategy for tiered testing related to thyroid disruption and reduce the amount of animal usage in toxicity testing.
Chemical safety evaluation is in the midst of a transition from traditional whole-animal toxicity testing to molecular pathway-based in vitro assays and in silico modeling. However, to facilitate the shift in reliance on apical effects for risk assessment to predictive surrogate metrics having characterized linkages to chemical mechanisms of action, targeted in vivo testing is necessary to establish these predictive relationships. In this study, we demonstrate a means to predict metamorphic success in a model amphibian Xenopus laevis using thyroid-related biochemical measurements during early pro-metamorphosis. The adverse outcome pathway for thyroperoxidase inhibition leading to altered amphibian metamorphosis was used to inform a pathway-based in vivo study design that generated response-response relationships. These causal relationships were used to develop Bayesian probabilistic network models that mathematically determine conditional dependencies between biochemical nodes and support the predictive capability of the biochemical profiles. Plasma thyroxine concentrations were the most predictive of metamorphic success with improved predictivity when thyroid gland sodium-iodide symporter gene expression levels (a compensatory response) were used in conjunction with plasma thyroxine as an additional regressor. Although thyroid-mediated amphibian metamorphosis has been studied for decades, this is the first time a predictive relationship has been characterized between plasma thyroxine and metamorphic success. Linking these types of biochemical surrogate metrics to apical outcomes is vital to facilitate the transition to the new paradigm of chemical safety and ecological risk assessments.