Abstract
Causal biological network models consisting of multiple biological pathways involved in a given biological process can serve to contextualize gene expression changes and unravel key mechanisms responsible for those changes. The transcriptomic data from the respiratory nasal epithelium (RNE) of rats exposed to formaldehyde have been investigated using such causal biological network models. The resulting association between the biological impact assessed by network perturbation and the squamous cell carcinoma rate in the RNE after two years has been further investigated to gain mechanistic insights. A detailed node-level investigation revealed that while similar network models were impacted across exposure doses, the directionality of the effect was opposite for the lowest doses compared to high doses. In particular, NF-κB was inferred to be upregulated in response to the two higher doses and downregulated in response to the lower doses in the context of the epithelial innate immune activation network model. This highlighted a dose threshold indicative of a long-term biphasic effect of formaldehyde exposure leading to carcinogenicity. The presented approach could be used to establish the mechanism of action or grouping of compounds based on impacted regions in the network models.
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References
Council NR. Toxicity testing in the 21st century: a vision and a strategy. National Academies Press, 2007
Sturla, S.J., Boobis, A.R., FitzGerald, R.E., et al.: Systems toxicology: from basic research to risk assessment. Chem. Res. Toxicol. 27, 314–329 (2014)
Alexander-Dann, B., Pruteanu, L.L., Oerton, E., et al.: Developments in toxicogenomics: understanding and predicting compound-induced toxicity from gene expression data. Mol. Omics 14, 218–236 (2018)
Emmert-Streib, F., Dehmer, M., Haibe-Kains, B.: Gene regulatory networks and their applications: understanding biological and medical problems in terms of networks. Front. Cell Dev. Biol. 2, 38 (2014)
Szostak, J., Ansari, S., Madan, S., et al.: Construction of biological networks from unstructured information based on a semi-automated curation workflow. Database 2015, bav057 (2015)
Martin, F., Sewer, A., Talikka, M., Xiang, Y., Hoeng, J., Peitsch, M.C.: Quantification of biological network perturbations for mechanistic insight and diagnostics using two-layer causal models. BMC Bioinform. 15, 238 (2014)
Talikka, M., Bukharov, N., Hayes, W.S., et al.: Novel approaches to develop community-built biological network models for potential drug discovery. Expert Opin. Drug Discov. 12, 849–857 (2017)
Hoeng, J., Talikka, M., Martin, F., et al.: Toxicopanomics: applications of genomics, transcriptomics, proteomics, and lipidomics in predictive mechanistic toxicology. In: Hayes’ Principles and Methods of Toxicology, p. 322–359. CRC Press (2014)
Andersen, M.E., Clewell 3rd, H.J., Bermudez, E., et al.: Formaldehyde: integrating dosimetry, cytotoxicity, and genomics to understand dose-dependent transitions for an endogenous compound. Toxicol. Sci. 118, 716–731 (2010)
Bernstein, R.S., Stayner, L.T., Elliott, L.J., Kimbrough, R., Falk, H., Blade, L.: Inhalation exposure to formaldehyde: an overview of its toxicology, epidemiology, monitoring, and control. Am. Ind. Hyg. Assoc. J. 45, 778–785 (1984)
Kerns, W.D., Pavkov, K.L., Donofrio, D.J., Gralla, E.J., Swenberg, J.A.: Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res. 43, 4382–4392 (1983)
Monticello, T.M., Swenberg, J.A., Gross, E.A., et al.: Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations of cells. Cancer Res. 56, 1012–1022 (1996)
Boué, S., Talikka, M., Westra, J.W., et al.: Causal biological network database: a comprehensive platform of causal biological network models focused on the pulmonary and vascular systems. Database 2015, bav030 (2015)
Hoeng, J., Talikka, M., Martin, F., et al.: Case study: the role of mechanistic network models in systems toxicology. Drug Discov. Today 19, 183–192 (2014)
Kogel, U., Titz, B., Schlage, W.K., et al.: Evaluation of the tobacco heating system 2.2. Part 7: systems toxicological assessment of a mentholated version revealed reduced cellular and molecular exposure effects compared with mentholated and non-mentholated cigarette smoke. Regul. Toxicol. Pharmacol. 81, S123–S138 (2016)
Phillips, B., Veljkovic, E., Boué, S., et al.: An 8-month systems toxicology inhalation/cessation study in Apoe−/− mice to investigate cardiovascular and respiratory exposure effects of a candidate modified risk tobacco product, THS 2.2, compared with conventional cigarettes. Toxicol. Sci. 149, 411–432 (2015)
Talikka, M., Boue, S., Schlage, W.K.: Causal biological network database: a comprehensive platform of causal biological network models focused on the pulmonary and vascular systems. In: Hoeng, J., Peitsch, M.C. (eds.) Computational Systems Toxicology. MPT, pp. 65–93. Springer, New York (2015). https://doi.org/10.1007/978-1-4939-2778-4_3
Wong, E.T., Kogel, U., Veljkovic, E., et al.: Evaluation of the Tobacco Heating System 2.2. Part 4: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects compared with cigarette smoke. Regul. Toxicol. Pharmacol. 81, S59–S81 (2016)
Zanetti, F., Sewer, A., Scotti, E., et al.: Assessment of the impact of aerosol from a potential modified risk tobacco product compared with cigarette smoke on human organotypic oral epithelial cultures under different exposure regimens. Food Chem. Toxicol. 115, 148–169 (2018)
Dai, M., Wang, P., Boyd, A.D., et al.: Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucl. Acids Res. 33, e175 (2005)
McCall, M.N., Bolstad, B.M., Irizarry, R.A.: Frozen robust multiarray analysis (fRMA). Biostatistics 11, 242–253 (2010)
Bolstad, B.M., Irizarry, R.A., Åstrand, M., Speed, T.P.: A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003)
Thomson, T.M., Sewer, A., Martin, F., et al.: Quantitative assessment of biological impact using transcriptomic data and mechanistic network models. Toxicol. Appl. Pharmacol. 272, 863–878 (2013)
Park, J., Schlage, W., Frushour, B., Talikka, M., Toedter, G.: Construction of a computable network model of tissue repair and angiogenesis in the lung. J. Clin. Toxicol. S12, 002 (2013). https://doi.org/10.4172/2161-0495.S12-002
Frey, B.J., Dueck, D.: Clustering by passing messages between data points. Science 315, 972–976 (2007)
Karin, M.: NF-κB as a critical link between inflammation and cancer. Cold Spring Harb. Persp. Biol. 1, a000141 (2009)
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Martin, F., Talikka, M., Hoeng, J., Peitsch, M.C. (2020). Systems Toxicology Approach to Unravel Early Indicators of Squamous Cell Carcinoma Rate in Rat Nasal Epithelium Induced by Formaldehyde Exposure. In: Fdez-Riverola, F., Rocha, M., Mohamad, M., Zaki, N., Castellanos-Garzón, J. (eds) Practical Applications of Computational Biology and Bioinformatics, 13th International Conference. PACBB 2019. Advances in Intelligent Systems and Computing, vol 1005 . Springer, Cham. https://doi.org/10.1007/978-3-030-23873-5_3
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