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Adverse outcome pathway network-based assessment of the interactive effects of an androgen receptor agonist and an aromatase inhibitor on fish endocrine function
Citation:
Ankley, G., B. Blackwell, J. Cavallin, J. Doering, D. Feifarek, K. Jensen, M. Kahl, C. Lalone, S. Poole, E. Randolph, T. Saari, AND D. Villeneuve. Adverse outcome pathway network-based assessment of the interactive effects of an androgen receptor agonist and an aromatase inhibitor on fish endocrine function. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, 39(4):913-922, (2020). https://doi.org/10.1073/pnas
Impact/Purpose:
Adverse outcome pathway (AOP) networks potentially provide a basis for predictive approaches to assess the toxicity of chemical mixtures. This study evaluated the utility of a simple AOP network to predict the interactive effects of a binary chemical mixture comprised of an inhibitor of the aromatase enzyme (fadrozole, a human pharmaceutical) and an agonist of the androgen receptor (trenbolone, a veterinary drug). Overall, prediction of interactive effects of the two chemicals based on the AOP network di not match actual observed effects. Rather, the two compounds seemed to interact in an independent manner in terms of their effects on the hypothalamic-pituitary-gonadal axis in the fish.
Description:
Predictive, mechanism-based approaches to assessing the toxicity of contaminant mixtures have been largely limited to chemicals that exert effects through the same biological target/molecular initiating event (MIE). However, through understanding specific pathways through which chemicals exert their effects it might be possible to identify shared “downstream” nodes that could serve as the basis for forecasting the interactive effects of chemicals that act via different MIEs. Adverse outcome pathway (AOP) networks are constructs that conceptually support this type of analysis. In the present study we assessed the utility of a simple AOP network for predicting the effects of mixtures of an aromatase inhibitor (fadrozole; FAD) and an androgen receptor (AR) agonist (17â-trenbolone; TRB) on aspects of reproductive endocrine function in female fathead minnows. The fish were exposed to multiple concentrations of FAD and TRB singly or in combination in a complete matrix design for 48- or 96-h. Effects on two shared nodes in the AOP network, plasma 17â-estradiol concentration and vitellogenin (VTG) production (measured as hepatic VTG transcripts) responded as anticipated to FAD but were only minimally impacted by TRB. There was no seeming interaction between the two chemicals on either endpoint, or on expression of two ovarian steroidogenic genes coding for proteins known to be affected in a compensatory manner by FAD and TRB (cytochrome P450 aromatase, cytochrome P450 side-chain-cleavage). Failure to observed predicted interactions between FAD and TRB on endocrine function could be attributed to several factors, including an incomplete understanding of direct and compensatory responses associated with perturbation of AR signaling.
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DOI: Adverse outcome pathway network-based assessment of the interactive effects of an androgen receptor agonist and an aromatase inhibitor on fish endocrine function