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Identification of Modulators of the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα) in a Mouse Liver Gene Expression Compendium
Oshida, K., N. Vasani, W. Ward, R. Thomas, D. Applegate, Mitch Rosen, B. Abbott, C. Lau, G. Guo, L. Aleksunes, C. Klaassen, AND C. Corton. Identification of Modulators of the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα) in a Mouse Liver Gene Expression Compendium. PLoS ONE . Public Library of Science, San Francisco, CA, 10(2):e0112655, (2015).
A number of agencies that regulate chemicals have initiated programs to define the universe of AOPs affected by chemical exposure. These effo11s are to place data from high throughput screens (e.g., EPA ToxCast screening program) into the context of AOP key events. The computational strategy described in this paper, i.e., using the Running Fisher's test to find biosets with similarity to transcription factor signatures will be useful in future screens to characterize chemicals, diets, infections, etc. that impact key events in AOPs and in building cumulative risk models including those that predict liver cancer and steatosis.
The nuclear receptor family member peroxisome proliferator-activated receptor α (PPARα) is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPARα in rodents increases in liver cancer incidence, whereas suppression of PPARα activity can lead to hepatocellular steatosis. Analytical approaches were developed to identify biosets (i.e., gene expression differences between two conditions) in a genomic database in which PPARα activity was altered. A gene expression signature of 131 PPARα-dependent genes was built using profiles from the livers of wild-type and PPARα-null mice after exposure to three structurally diverse PPARα activators (WY-14,643, fenofibrate and perfluorohexane sulfonate). A rank-based test (Running Fisher’s test (p-value ≤ 10-4)) was used to evaluate the similarity between the PPARα signature and a test set of 48 and 31 biosets positive or negative, respectively for PPARα activation; the test resulted in a balanced accuracy of 98%. The signature was used to identify factors that activate or suppress PPARα in an annotated mouse liver/primary hepatocyte gene expression database of ~1850 biosets. In addition to the expected activation of PPARα by fibrate drugs, di(2-ethylhexyl) phthalate, and perfluorinated compounds, PPARα was activated by benzofuran, galactosamine and TCDD and suppressed by hepatotoxins acetaminophen, lipopolysaccharide, silicon dioxide nanoparticles and trovafloxacin. Additional factors that activate (fasting, caloric restriction) or suppress (infections) PPARα were also identified. This study 1) developed methods useful for future screening of environmental chemicals, 2) identified novel chemicals that activate or suppress PPARα, and 3) identified factors including diet and infection that modulate PPARα activity and would be hypothesized to affect chemical-induced PPARα activity. (265 words)
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
SYSTEMS BIOLOGY BRANCH