Citation:

Angrish, M. AND B. Chorley. Epigenomic Applications in an Adverse Outcome Pathway for Obesity. Toxicoepigenetics, Tysons, VA, November 02 - 04, 2016.

Impact/Purpose:

This work describes toxicoepigenetics applications in AOP-based high throughput toxicity testing. Specifically, there are gaps in the existing methods used to capture epigenetic toxicity. These gaps are highlighted and along with future approaches that may fill those gaps. Furthermore, epigenetic events are framed in an AOP network. The flexibility of the AOP framework may proivide an ideal scaffold for mapping epigenetic endpoints to biology, from the molecular to the population level.

Description:

Epigenomic Applications in an Adverse Outcome Pathway (AOP) for ObesityMichelle M. Angrish1 and Brian N. Chorley 11National Health and Environmental Effects Research Laboratory, ORD, US EPA, Research Triangle Park, North Carolina 27709, United StatesAbstractExogenous chemical exposures may modify the epigenome to increase susceptibility to different life-stage and life-long diseases including obesity. Specifically, evidence suggests epigenetic modifications enhance adipogenesis during critical developmental windows leading to obesity later in life. The challenge is demonstrating a causal linkage between those epigenetic changes (such as histone modification, DNA methylation, noncoding RNA, or chromatin structure) and an adverse outcome. Adverse Outcome Pathways (AOP) may provide the framework needed to organize epigenetic information so that causal relationships can be identified. In this work an AOP was constructed to understand and anchor epigenetic modifications leading to an obesity adverse outcome. AOP construction began by a literature search. PubMed was queried by the terms obesity and epigenetic and obesogenic. 35 search results were returned and reviewed for physical and molecular data. That data were organized into an AOP for obesity using a top-down approach outlined by Villeneuve et al., “Adverse Outcome Pathway Development I: Strategies and Principles” as well as the Organisation for Economic Co-operation and Development’s Guidance Document on Developing and Assessing AOPs. A result was that environmental factors such as maternal nutrition, diet, and exposures to endocrine disrupting chemicals (tributyltin, brominated diphenyl ether 47, and polycyclic aromatic hydrocarbons) affected DNA methylation and the expression of key developmental, adipogenic, and lipogenic genes, including the peroxisome proliferator activated receptor gamma (PPARγ) and its targets. This information was organized into an AOP network and used to exemplify the diverse ways that epigenetic modification can adversely impact obesity. This work is a critical step towards applying epigenetic information in chemical prioritization and risk assessment applications. This abstract does not reflect official Agency policy.

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