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A Network of AOPs for reduced thyroid hormone synthesis derived from inhibition of Thyroperoxidase - A common Molecular Initiating Event Leading to Species-Specific Indices of Adversity.
Gilbert, M., K. Crofton, K. Paul-Friedman, J. Haselman, S. Degitz, M. Hornung, D. Knapen, L. Vergauwen, E. Stinckens, S. Marty, R. Zoeller, AND B. Demeniex. A Network of AOPs for reduced thyroid hormone synthesis derived from inhibition of Thyroperoxidase - A common Molecular Initiating Event Leading to Species-Specific Indices of Adversity. US EPA Office of Research and Development, Washington, DC, 2016.
EPA has adopted 'Adverse Outcome Pathway (AOP) framework to provide a biological context for the integration information available from disparate data sources at many different levels of biological organization in a manner that is meaningful and suitable for regulatory decision-making. AOP describes a progression of events for which evidence-based biological linkages can be described between key events that span the to cellular to organ to system to organism level at which an adverse phenotypic change is observable in vivo. This AOP describes the biological pathway of thyroid hormone synthesis inhibition that leads to brain dysfunction in the mammals, delayed metamorphosis in amphibians, and reduced swim bladder inflation fish. Together they describe an AOP network stemming from a common 'Molecular Initiating Event, MIE' across species with species-specific outcomes.
This collection of 3 AOPs describe varying outcomes of adversity dependent upon species in response to inhibition of thyroperoxidase (TPO) during development. Chemical inhibition of TPO, the molecular-initiating event (MIE), results in decreased thyroid hormone (TH) synthesis, and subsequent reduction in circulating concentrations of THs. THs are essential for normal human brain development, metamorphorfic change from tadpole to frog in amphibians, and deficits in inflation of the anterior swim bladder in young fishes. Chemicals that interfere with TH synthesis have the potential to cause TH insufficiency that may result in adverse neurodevelopmental effects in offspring. The biochemistry of TPO and its essentiality for TH synthesis is well known across species. Although quantitative information at all levels of KERs is limited a number of applications of this AOP have been identified.