Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|PPARα antagonism leading to body-weight loss||AdverseOutcome|
|Homo sapiens||Homo sapiens||Moderate||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Colinus virginianus||Colinus virginianus||Moderate||NCBI|
Key Event Description
If caloric intake is less than caloric use over time, an individual will lose body weight. This is a basic principle in human dieting as well as an important principle related to individual health and ecological fitness of animal populations. Dynamic energy budget theory has provided useful insights on how organisms take up, assimilate and then allocate energy to various fundamental biological processes including maintenance, growth, development and reproduction (Nisbet et al 2000). Regarding energy allocation, somatic maintenance must first be met before then growth may occur, followed by maturation and then finally, surplus energy is dedicated to reproduction (Nisbet et al 2000). As an example of the importance of energy allocation to ecological fitness, a review by Martin et al (1987) demonstrated that energy availability (availability of food) was the predominant limiting factor in reproductive success and survival for both young and parents in a broad life history review for bird species. This is a likely scenario for many organisms.
Various physiological processes act to maintain and prioritize energy allocations in individuals. The influence of PPARalpha on systemic energy metabolism and energy homeostasis has been broadly established (see reviews by Kersten 2014, Evans et al 2004, Desvergne and Wahli 1999). Inhibition of PPARalpha predominantly impairs lipid metabolism with respect to overall energy metabolism whereby energy release from fatty acid substrates is decreased. PPARalpha has been demonstrated to play a critical role in stimulating fatty acid oxidation and ketogenesis during fasting resulting in increased ketone body levels in plasma (Badman et al 2007, Kersten 2014) a response that is eliminated in PPARalpha knockout mice (Badman et al 2007, Sanderson et al 2010). Reviews by Cahill (2006) and Wang et al (2010) summarize the critical adaptive response of ketogenesis during fasting for maintaining systemic energy homeostasis by providing ketone bodies to energetically fuel a diverse range of tissues, especially the brain. Not only does PPARalpha induce the upstream production of the raw materials for use in ketogenesis through fatty acid beta-oxidation, but also directly induces key enzymes in the ketogenesis pathway including Hmgcs2, Hmgcl and Acat1 (Kersten 2014).
Kersten et al (1999) and Badman et al (2007) demonstrated that PPARalpha-null mice were unable to actively mobilize fatty acid oxidation, and further, Kersten et al (1999) demonstrated that these mice were unable to meet energy demands during fasting and leading to hypoglycemia, hyperlipidemia, hypoketonemia and fatty liver. Observations from toxicological and toxicogenomic research have implicated nitrotoluenes as potential PPAR antagonists in birds (Rawat et al 2010), rats (Deng et al 2011) and mice (Wilbanks et al 2014), an effect that additionally corresponded with weight loss in rats (Wilbanks et al 2014) and weight loss, loss of muscle mass and emaciation in birds (Quinn et al 2007). These combined results indicate that inhibition of PPARalpha signaling and the resultant decrease in fatty acid oxidation and ketogenesis can detrimentally impair systemic energy budgets leading to starvation-like effects and resultant weight loss. As reviewed in the introductory paragraph of this adverse outcome description, impaired energy availability leading to inability to meet somatic maintenance needs and causing negative growth are likely to have detrimental effects on survivorship, reproduction and ecological fitness. Such affects may adversely affect responses of regulatory concern including: individual health, survival, and population sustainability.
How It Is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
Dynamic energy budget model development and validation demonstrated against various parameter values and population studies (Nisbet et al 2000). Food availability, animal weights, brood sizes, adult survival, and juvenile survival measured in Martin et al (1987). Whole body animal weights were measured for mice in Wilbanks et al (2014). Whole body weights, organ weights and breast muscle weights measured in Quinn et al (2007). In vitro human PPARalpha nuclear-receptor activation/inhibition assays have been used to determine if chemicals interfere with PPARalpha nuclear signaling (Wilbanks et al 2014, Gust et al 2015). Transcript Expression of PPARalpha as well as transcript expression for genes in which PPARalpha acts as a transcriptional regulator (Wilbanks et al 2014, Deng et al 2011, Rawat et al 2010, and studies reviewed in Kersten 2014).
Domain of Applicability
Evidence was provided for humans in Kersten (2014), Evans et al (2004), and Desvergne and Wahli (1999). Evidence was provided for mice in Badman et al (2007), Sanderson et al (2010), Wilbanks et al (2014), Xu et al (2012), and Kersten et al (1999). Evidence was provided for birds in Martin et al (1987).
Regulatory Significance of the Adverse Outcome
WWeight loss in wild populations has direct implications on fitness as demonstrated dynamic energy budget modeling (Nisbet et al 2000). Thus weight loss can be used as a metric for populations sustainability. For individuals, rapid weight loss of greater than 20% total body weight is considered indicative of a moribund condition in laboratory animals for many Institutional Animal Care and Use Committees as established by American Association for Laboratory Animal Science (https://www.aalas.org/iacuc#.ViZzMSvaFs).
Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell metabolism 2007, 5(6):426-437.
Cahill GF, Jr.: Fuel metabolism in starvation. Annu Rev Nutr 2006, 26:1-22.
Deng Y, Meyer SA, Guan X, Escalon BL, Ai J, Wilbanks MS, Welti R, Garcia-Reyero N, Perkins EJ (2011) Analysis of common and specific mechanisms of liver function affected by nitrotoluene compounds. PLoS One 6(2): e14662.
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.
Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10(4):355-361.
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W: Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999, 103(11):1489-1498.
Martin TE: Food as a limit on breeding birds: a life-history perspective. Annu Rev Ecol Syst 1987:453-487.
Nisbet R, Muller E, Lika K, Kooijman S: From molecules to ecosystems through dynamic energy budget models. J Anim Ecol 2000, 69(6):913-926.
Quinn MJ Jr, Bazar MA, McFarland CA, Perkins EJ, Gust KA, Gogal Jr RM, Johnson MS (2007) Effects of subchronic exposure to 2,6-dinitrotoluene in the northern bobwhite (Colinus virginianus). Environmental Toxicology and Chemistry 26(10):2202-2207.
Rawat A, Gust KA, Deng Y, Garcia-Reyero N, Quinn MJ, Jr., Johnson MS, Indest KJ, Elasri MO, Perkins EJ (2010) From raw materials to validated system: the construction of a genomic library and microarray to interpret systemic perturbations in Northern bobwhite. Physiological Genomics 42(2):219-235.
Sanderson, L.M., Boekschoten, M.V., Desvergne, B., Muller, M., Kersten, S., 2010. Transcriptional profiling reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver. Physiological Genomics 41:42e52.
Wang YX: PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res 2010, 20(2):124-137.
Wilbanks, M., Gust, K.A., Atwa, S., Sunesara, I., Johnson, D., Ang, C.Y., Meyer., S.A., and Perkins, E.J. 2014. Validation of a genomics-based hypothetical adverse outcome pathway: 2,4-dinitrotoluene perturbs PPAR signaling thus impairing energy metabolism and exercise endurance. Toxicological Sciences. 141(1):44-58.