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Adverse Outcome Pathway (AOP) Network Development for Fatty Liver
Citation:
Angrish, M., Jonathan-Phillip Kaiser, C. McQueen, AND B. Chorley. Adverse Outcome Pathway (AOP) Network Development for Fatty Liver. Society of Toxicology 55th Annual Meeting and ToxExpo, New Orleans, LA, March 13 - 16, 2016.
Impact/Purpose:
Fatty liver (FL) disease is a growing epidemic and currently affects 20–30% of the U.S. population, making it the most common liver disease in the U.S. Furthermore, FL is associated with obesity, diabetes, metabolic syndrome, cardiovascular disease, and certain types of cancer, making FL a major public health concern and a target for preventive strategies. One approach to reduce FL risk is to restrict exposure to environmental chemicals. Data linking chemicals to FL etiology have been used by the U.S. EPA’s Integrated Risk Information System (IRIS) database to derive reference values that help characterize public health risks and support risk management decisions. The challenge is to develop a testing paradigm that is predictive of hepatic steatosis. Here, we assembled an AOP network (AOPnet) that captures the biological complexity of FL disease. This AOPnet consists of interconnected AOPs that are defined by four apical KEs; hepatic fatty acid uptake, de novo fatty acid and lipid synthesis, fatty acid oxidation, and lipid efflux, that branch into interconnected, proximal key events (KEs), key event relationships, and molecular initiating events. This AOPnet will aid biological target identification and assay development initiatives while providing a framework for chemical prioritization based on the likelihood to induce steatosis. Further, we assessed AOPnet KE activation in vitro using a HepaRG human hepatocyte cell model treated with reference chemicals known to cause steatosis in vivo.
Description:
Adverse outcome pathways (AOPs) are descriptive biological sequences that start from a molecular initiating event (MIE) and end with an adverse health outcome. AOPs provide biological context for high throughput chemical testing and further prioritize environmental health risk research. According to the Organization for Economic Co-operation and Development guidelines, AOPs are pathways with one MIE anchored to an adverse outcome (AO) by key events (KEs) and key event relationships (KERs). However, this approach does not always capture the cumulative impacts of multiple MIEs on the AO. For example, hepatic lipid flux due to chemical-induced toxicity initiates from multiple ligand-activated receptors and signaling pathways that cascade across biology to converge upon a common fatty liver (FL, also known as steatosis) outcome. To capture this complexity, a top-down strategy was used to develop a FL AOP network (AOPnet). Literature was queried based on the terms steatosis, fatty liver, cirrhosis, and hepatocellular carcinoma. Search results were analyzed for physiological and pathophysiological organ level, cellular and molecular processes, as well as pathway intermediates, to identify potential KEs and MIEs that are key for hepatic lipid metabolism, maintenance, and dysregulation. The analysis identified four apical KE nodes (hepatic fatty acid uptake, de novo fatty acid and lipid synthesis, fatty acid oxidation, and lipid efflux) juxtaposed to the FL AO. The apical KEs were further linked through lower levels of biological organization to potential MIEs. A putative fatty liver AOPnet was constructed from MIE, KE, and AO nodes connected by KER edges that contained supporting evidence to infer that an upstream event caused a downstream event. This integrative AOPnet provided an evidence-based framework used to identify a minimal number of in vitro-based assays for KEs to infer chemical-induced effects predictive of a fatty liver outcome. From a public health standpoint, limiting chemical exposures that contribute to the etiology of fatty liver is important to prevent serious and potentially progressive liver disease, as well as extra-hepatic effects related to metabolic syndrome and systemic metabolism. This work does not necessarily reflect the policies of the U.S. EPA.