Application of benchmark dose modeling to protein expression data in the development and analysis of mode of action/adverse outcome pathways for testicular toxicity
- DOI
- Language of the publication
- English
- Date
- 2014-09-22
- Type
- Article
- Author(s)
- Chepelev, Nikolai L.
- Meek, M. E. Bette
- Yauk, Carole Lyn
- Publisher
- Wiley
Abstract
Reliable quantification of gene and protein expression has potential to contribute significantly to the characterization of hypothesized modes of action (MOA) or adverse outcome pathways for critical effects of toxicants. Quantitative analysis of gene expression by benchmark dose (BMD) modeling has been facilitated by the development of effective software tools. In contrast, protein expression is still generally quantified by a less robust effect level (no or lowest [adverse] effect levels) approach, which minimizes its potential utility in the consideration of dose-response and temporal concordance for key events in hypothesized MOAs. BMD modeling is applied here to toxicological data on testicular toxicity to investigate its potential utility in analyzing protein expression relevant to the proposed MOA to inform human health risk assessment. The results illustrate how the BMD analysis of protein expression in animal tissues in response to toxicant exposure: (1) complements other toxicity data, and (2) contributes to consideration of the empirical concordance of dose-response relationships, as part of the weight of evidence for hypothesized MOAs to facilitate consideration and application in regulatory risk assessment. Lack of BMD analysis in proteomics has likely limited its use for these purposes. This paper illustrates the added value of BMD modeling to support and strengthen hypothetical MOAs as a basis to facilitate the translation and uptake of the results of proteomic research into risk assessment.
Plain language summary
Modes of action (MOA) are descriptions of the series of events that occur following a chemical exposure that lead to an adverse outcome (e.g., toxicity). These descriptions enhance human health risk assessment by providing mechanistic information to understand how the toxicant produces these effects. This information can be used to reduce the uncertainties associated with extrapolating results from laboratory animal and cell culture experiments to humans. Proteins are the workhorses of the cell, performing a vast array of functions. Following a toxicant exposure, both the levels and activities of proteins are altered as a first line of defense to cope with the challenge. Changes in protein levels and activity are thus important early indicators of potentially long-term adverse health effects. Effective ways to use knowledge of protein changes in developing and testing MOAs are needed to support regulatory applications. In this study, Health Canada scientists demonstrated how information about changes in protein levels in response to increasing doses of chemical exposure can be used to develop and strengthen MOA models. To this end, protein data reported in the scientific literature from five studies on chemically induced male reproductive toxicity were evaluated. The results illustrated that dose-response analysis of protein expression in animal tissues in response to chemical exposure is instrumental in providing experimental support for hypothesized MOAs. The study also provided insight into the optimal experimental designs that should be used to support human health risk assessment. Finally, this publication provided key considerations for protein data that can now be incorporated by the risk assessment community in the context of regulatory science.
Subject
- Health,
- Health and safety