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Empirical testing AOP network-based hazard prediction combined effect of aromatase inhibition & androgen receptor agonism
Citation:
Poole, S., G. Ankley, B. Blackwell, J. Cavallin, J. Doering, D. Feifarek, K. Jensen, M. Kahl, E. Randolph, T. Saari, AND Dan Villeneuve. Empirical testing AOP network-based hazard prediction combined effect of aromatase inhibition & androgen receptor agonism. SETAC North America, Minneapolis, MN, November 12 - 16, 2017.
Impact/Purpose:
EPA program offices, Regions, and states are faced with the challenge of conducting risk assessments for real-world exposure scenarios. These typically involve concurrent exposure to mixture or to chemicals that may have more than one mode of action. The present research begins to test how effectively the adverse outcome pathway (AOP) framework can be used to predict the integrated outcome of simultaneous exposure to more than one stressor. In this case, fish were exposed to a mixture of two endocrine-active chemicals, and an AOP network was applied to the effects. Results of this study yield insights into how the AOP framework can be applied to assessing mixture toxicity and more complex exposure scenarios. This work supports out year products of CSS Project 17.01, Adverse Outcome Pathway Discovery and Development.
Description:
Adverse outcome pathways (AOPs) describe linkages between a specific molecular perturbation resulting from interaction of a chemical with a biomolecule in an organism and one possible adverse outcome of regulatory significance. While individual AOPs have utility, it is recognized that real-world exposures are likely to involve concurrent activation of multiple AOPs either as a result of exposure to mixtures, or exposure to single chemicals with multiple modes of action. Consequently, it is important to evaluate how effectively toxicological outcomes may be predicted from consideration of AOPs as networks. As an initial test of this concept, fathead minnows (Pimephales promelas) were exposed to one of two concentrations of fadrozole (FAD; 0.5 or 5 µg/L), a model aromatase inhibitor, one of three concentrations of 17â-trenbolone (TRB; 5, 15, or 50 ng/L), a model androgen, or a mixture of the two in a complete matrix (12 treatment conditions total including controls). Experimental concentrations of TRB were measured at 4.21, 11.45, and 45.23ng/L (84%,76%,90% nominal respectively) and FAD at 0.53 and 5.22 µg/L (107% and 104% of nominal). Specific AOP-based hypotheses regarding effects on circulating steroid and vitellogenin concentrations as well as expression of mRNAs coding for vtg, esr1, cyp19a1a, and cyp11a following 48 or 96 h of exposure were tested. Preliminary results suggest that exposure to FAD resulted in concentration-dependent decreases in both vtg and esr1 mRNA abundance in liver, regardless of co-exposure with TRB. Analysis and comparison of multiple endpoints corresponding to key events associated with two separate AOPs as well as some well-established compensatory responses should yield new insights into the interactions between these two pathways. The contents of this abstract neither constitute, nor necessarily reflect, official US EPA policy.