University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln U.S. Environmental Protection Agency Papers U.S. Environmental Protection Agency 2011 Use of comparative genomics approaches to characterize interspecies differences in response to environmental chemicals: Challenges, opportunities, and research needs Sarah L. Burgess-Herbert U.S. EPA, [email protected] Susan Y. Euling U.S. EPA Follow this and additional works at: https://digitalcommons.unl.edu/usepapapers Burgess-Herbert, Sarah L. and Euling, Susan Y., "Use of comparative genomics approaches to characterize interspecies differences in response to environmental chemicals: Challenges, opportunities, and research needs" (2011). U.S. Environmental Protection Agency Papers. 160. https://digitalcommons.unl.edu/usepapapers/160 This Article is brought to you for free and open access by the U.S. Environmental Protection Agency at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in U.S. Environmental Protection Agency Papers by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. YTAAP-12265; No. of pages: 14; 4C: Toxicology and Applied Pharmacology xxx (2011) xxx–xxx Contents lists available at SciVerse ScienceDirect Toxicology and Applied Pharmacology journal homepage: www.elsevier.com/locate/ytaap Contemporary Issues in Toxicology Use of comparative genomics approaches to characterize interspecies differences in response to environmental chemicals: Challenges, opportunities, and research needs☆ Sarah L. Burgess-Herbert a,⁎, Susan Y. Euling b a American Association for the Advancement of Science (AAAS) Science and Technology Policy Fellow at the US Environmental Protection Agency (EPA), 2009–10, USA b National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Washington, DC 20460, USA article info abstract Article history: A critical challenge for environmental chemical risk assessment is the characterization and reduction of Received 8 June 2011 uncertainties introduced when extrapolating inferences from one species to another. The purpose of this Revised 11 November 2011 article is to explore the challenges, opportunities, and research needs surrounding the issue of how genomics Accepted 16 November 2011 data and computational and systems level approaches can be applied to inform differences in response to Available online xxxx environmental chemical exposure across species. We propose that the data, tools, and evolutionary frame- work of comparative genomics be adapted to inform interspecies differences in chemical mechanisms of Keywords: Cross-species action. We compare and contrast existing approaches, from disciplines as varied as evolutionary biology, sys- Molecular network tems biology, mathematics, and computer science, that can be used, modified, and combined in new ways to Biological pathway discover and characterize interspecies differences in chemical mechanism of action which, in turn, can be Selective constraints explored for application to risk assessment. We consider how genetic, protein, pathway, and network infor- -omics mation can be interrogated from an evolutionary biology perspective to effectively characterize variations in Human health risk assessment biological processes of toxicological relevance among organisms. We conclude that comparative genomics Systems biology approaches show promise for characterizing interspecies differences in mechanisms of action, and further, for improving our understanding of the uncertainties inherent in extrapolating inferences across species in both ecological and human health risk assessment. To achieve long-term relevance and consistent use in environmental chemical risk assessment, improved bioinformatics tools, computational methods robust to data gaps, and quantitative approaches for conducting extrapolations across species are critically needed. Specific areas ripe for research to address these needs are recommended. © 2011 Elsevier Inc. All rights reserved. Contents Introduction ................................................................. 0 Approaches to comparing species at the molecular level............................................. 0 Gene/protein level approaches ...................................................... 0 Chemical examples ........................................................ 0 Pathway level approaches ........................................................ 0 Chemical example ......................................................... 0 Network level approaches ........................................................ 0 Discussion .................................................................. 0 Strengths and weaknesses of approaches ................................................. 0 Challenges and recommendations for risk assessment ........................................... 0 Abbreviations: AhR, aryl hydrocarbon receptor; ADME, absorption, distribution, metabolism, and excretion; APAP, N-acetyl-p-aminophenol; EGBE, ethylene glycol monobutyl ether; MYC, myelocytomatosis oncogene; MOA, mode of action; DRE, dioxin response element; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial); IRIS, Integrated Risk Information System; JUN, jun proto-oncogene; PPARα, peroxisome proliferator activated receptor alpha; RfC, reference concentration; RfD, reference dose; NOAEL, no-observed-adverse-effect-level; LOAEL, lowest-observed-adverse-effect-level; DBP, dibutyl phthalate; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TD, toxicodynamic; TK, toxicokinetic; NRC, National Research Council; EPA, Environmental Protection Agency; DNA, deoxyribonucleic acid; RNA, ribonucleic acid; PID, percent identity; PXR, pregnane X receptor. ☆ Disclaimer: This manuscript has been reviewed by the U.S. Environmental Protection Agency and approved for publication. The views expressed in this manuscript are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. ⁎ Corresponding author at: 2151 Jamieson Ave #1504, Alexandria, VA, 22314, USA. Tel.: +1 703 624 1989. E-mail address: [email protected] (S.L. Burgess-Herbert). 0041-008X/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2011.11.011 Please cite this article as: Burgess-Herbert, S.L., Euling, S.Y., Use of comparative genomics approaches to characterize interspecies differences in response to environmental ..., Toxicol. Appl. Pharmacol. (2011), doi:10.1016/j.taap.2011.11.011 2 S.L. Burgess-Herbert, S.Y. Euling / Toxicology and Applied Pharmacology xxx (2011) xxx–xxx Conflict of interest statement ......................................................... 0 Acknowledgments .............................................................. 0 References .................................................................. 0 Introduction inferences from animal models to humans challenging in the context of human health risk assessment, and inferences across species chal- In the National Research Council's (NRC) 2007 report, Toxicity lenging in the context of ecological risk assessment. These differences Testing in the 21st Century: A Vision and a Strategy, they provided can be in dosimetry, exposure, metabolic pathways, and in homology a general plan for a transition to a new “pathway-based” paradigm of genes, proteins, biochemistry, and physiology (National Research for toxicity testing and risk assessment (National Research Council, Council, 2006). Because of these challenges, there is a need for 2007). This strategy envisions the replacement of in vivo animal tox- approaches to identify, understand, and, ideally, quantify interspecies icology studies with in vitro molecular studies, and the use of these in differences in chemical mechanism of action. A chemical's mechanism vitro studies in combination with computational models as the basis of action is defined here as the complete molecular sequence of events for regulatory decision making. In response, the U.S. Environmental between the interaction of the chemical with its target site(s) and Protection Agency (EPA) has developed its own strategic plan for observation of the outcome(s) (Fig. 1). The mechanism of action can moving towards a toxicity pathway-based risk assessment paradigm include both toxicokinetic (e.g., chemical absorption, distribution, (U.S. EPA, 2009; www.epa.gov/spc/toxicitytesting). Genomics data, metabolism, or excretion) and toxicodynamic events (e.g., changes at resources, and tools are central to the execution of this future risk the molecular, cellular, tissue, or organ level). Because a chemical's assessment paradigm. In addition, they are also useful within the cur- mechanism of action has rarely been fully understood due to data limi- rent paradigm of risk assessment, especially in the context of formu- tations, the “mode of action” concept was developed for and applied to lating evidence-based extrapolations from one population to another human health risk assessment. A chemical's mode of action, or “MOA,” and from one species to another. Indeed, one of the three key areas has been functionally defined as a key event, or a sequence of key identified by a Health and Environmental Sciences Institute (HESI) events, that a particular toxicity outcome is dependent upon (i.e., part survey in which genomics is perceived as having the greatest rele- of the causal pathway and not a coincident event) (U.S. EPA, 2006). vance and impact