Given the tremendous advances in omics technologies and approaches to provide truly global assessment of biological functions, we are able to provide a top-down method for mechanism of action (MoA) screening that requires no prior knowledge of chemical effects.Specifically, we provide a frame-work to apply global expression methods (typically transcriptomics) to identify enriched responses within the biological signaling networks and metabolic pathways that underlie critical biological functions affected by chemical exposures. These functional enrichment results are integrated with resultant adverse toxicological outcomes to develop hypothetical MoAs. The hypothetical MoAs are then validated in subsequent experiments that directly test the involvement of the chemical of interest in the implicated biological signaling networks and/or metabolic pathways, typically using biochemical or in vitro assays. Specific examples of our work in MoA discovery include discovery of MoAs for two specific material types of concern to the US Army (Gust et al. 2009, Gust et al. 2011, Gust et al. 2015, Rawat et al. 2010), each of which have been validated in directed investigations (Wilbanks et al. 2014, Williams et al. 2011) and transitioned to adverse outcome pathways (AOPs) for use in regulatory assessment applications (Collier et al. 2016, Gong et al. 2015).
- Collier, Z.A., Gust, K.A., Gonzalez-Morales, B., Gong, P., Wilbanks, M.S., Linkov, I., Perkins, E.J., 2016. A weight of evidence assessment approach for adverse outcome pathways. Regul. Toxicol. Pharmacol. 75, 46-57.
- Gong, P., Hong, H., Perkins, E.J., 2015. Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers. Biomark. Med. 9, 1225-1239.
- Gust, K.A., Nanduri, B., Rawat, A., Wilbanks, M.S., Ang, C.Y., Johnson, D.R., Pendarvis, K., Chen, X., Quinn, M.J., Jr., Johnson, M.S., Burgess, S.C., Perkins, E.J., 2015. Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite. BMC Genomics 16, 587.
- Gust, K.A., Pirooznia, M., Quinn, M.J., Jr., Johnson, M.S., Escalon, L., Indest, K.J., Guan, X., Clarke, J., Deng, Y., Gong, P., Perkins, E.J., 2009. Neurotoxicogenomic investigations to assess mechanisms of action of the munitions constituents RDX and 2,6-DNT in Northern bobwhite (Colinus virginianus). Toxicol. Sci. 110, 168-180.
- Gust, K.A., Wilbanks, M.S., Guan, X., Pirooznia, M., Habib, T., Yoo, L., Wintz, H., Vulpe, C.D., Perkins, E.J., 2011. Investigations of transcript expression in fathead minnow (Pimephales promelas) brain tissue reveal toxicological impacts of RDX exposure. Aquat. Toxicol. 101, 135-145.
- Rawat, A., Gust, K.A., Deng, Y., Garcia-Reyero, N., Quinn, M.J., Jr., Johnson, M.S., Indest, K.J., Elasri, M.O., Perkins, E.J., 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, 219-235.
- Wilbanks, M.S., Gust, K.A., Atwa, S., Sunesara, I., Johnson, D., Ang, C.Y., Meyer, S.A., 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. Toxicol. Sci. 141, 44-58.
- Williams, L.R., Aroniadou-Anderjaska, V., Qashu, F., Finne, H., Pidoplichko, V., Bannon, D.I., Braga, M.F., 2011. RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures. Environ. Health Perspect. 119, 357-363.