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The adverse outcome pathway for uncoupling of oxidative phosphorylation leading to growth inhibition
Citation:
Song, Y. AND Dan Villeneuve. The adverse outcome pathway for uncoupling of oxidative phosphorylation leading to growth inhibition. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, , 1-9, (2021). https://doi.org/10.1002/etc.5197
Impact/Purpose:
The adverse outcome pathway (AOP) framework provides a systematic means to organize scientific knowledge and data, often scattered across a wide variety of sources, in a format that supports extrapolation from biological responses and endpoints that are easily and cost-effectively measured to predicted impacts on those that a meaningful from a risk management perspective. The present AOP links measures or modeled predictions of chemical-mediated uncoupling of oxidative phosphorylation, the key process for generating energy to support cell growth and division, to the ecologically-relevant apical endpoint of growth inhibition. As such, the AOP provides weight of evidence that helps support the use of non-animal alternative data as a basis for ecological hazard identification. This AOP is highly relevant as the Tox21 high throughput screening program has identified over 2000 compounds with potential to uncouple mitochondrial oxidative phosphorylation.
Description:
Uncoupling of oxidative phosphorylation (OXPHOS) is a well-known mechanism of action of many chemicals. Mitochondrial uncoupler-mediated energetic dysfunction is known to affect growth, a critical process in most organisms and a chronic toxicity endpoint included in many OECD test guidelines. This adverse outcome pathway (AOP) causally links uncoupling of OXPHOS to growth inhibition, through ATP depletion and reduced cell proliferation as the intermediate key events (KEs), with strong weight of evidence support. The AOP is generalized to reflect its expected applicability to a broad range of taxa, ranging from microalga to human. Three out of four KEs included can be quantified using high-throughput methods, making this AOP particularly useful for screening, prioritization and hazard assessment of mitochondrial uncouplers as potential growth inhibiting chemicals. This AOP is therefore considered to be of regulatory and ecological relevance. The AOP also forms the core of a larger AOP network addressing uncoupling of OXPHOS mediated growth inhibition (AOP 263-268).
URLs/Downloads:
DOI: The adverse outcome pathway for uncoupling of oxidative phosphorylation leading to growth inhibition
VILLENEUVE-AOP-REVISED MS.PDF (PDF, NA pp, 592.642 KB, about PDF)