Suggestions for applications of toxicogenomic approaches in the adverse outcome pathway of 2,4-dinitrotoluene

Abstract

Objective and methods The risks of harmful chemicals are actively investigated with diverse toxicological in vitro and in vivo models, although such approaches may have critical problems, such as ethical issues or difficulties extrapolating between animal and human data. Adverse outcome pathways (AOP), in which a conceptually constructed pathway describes the sequential linkage between a molecular initiating event and its final adverse outcome, are actively studied in chemical risk assessment as an alternative prediction tool for understanding the mode of action induced by exposure to a certain chemical. Researchers have recently suggested integrated forms of toxicogenomic approaches and presented general draft AOPs for chemical risk assessment. In this review, we introduce the concept and application status of AOP and suggest possible complementary points for AOP frameworks using the toxicogenomic data analysis of 2,4-dinitrotoluene (2,4-DNT) as an example, considering the high risk of environmental pollution and chemical explosion. To explore the biological events induced by 2,4-DNT, a literature-based pathway analysis was conducted using selected animal genomic data relating to 2,4-DNT retrieved from public databases. Results and conclusion Biological network connections among the retrieved genes provided additional knowledge on possible occurrences of inflammation, diabetes mellitus, and carcinogenesis mediated by alteration of cellular processes (oxidative stress, autophagy, and inflammatory responses) and protein functions (NF-kB family, proteasome endopeptidase complex, and Jun/Fos) derived from gene expression changes by 2,4-DNT exposure. This review provides a novel approach using large-scale toxicological literature-based biological pathway analysis to improve confidence in the existing putative AOPs.