Publications : 2020

Ankley GT, Blackwell BR, Cavallin JE, Doering JA, Feifarek DJ, Jensen KM, Kahl MD, LaLone CA, Poole ST, Randolph EC, Saari TW, Villeneuve DL. 2020. Adverse outcome pathway network-based assessment of the interactive effects of an androgen receptor agonist and an aromatase inhibitor on fish endocrine function. Environ Toxicol Chem 39:913–922.


Predictive approaches to assessing the toxicity of contaminant mixtures have been largely limited to chemicals that exert effects through the same biological molecular initiating event (MIE). However, by understanding specific pathways through which chemicals exert effects it may be possible to identify shared “downstream” nodes as the basis for forecasting interactive effects of chemicals with different MIEs. Adverse outcome pathway (AOP) networks conceptually support this type of analysis. Herein we assess 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 (17β-trenbolone; TRB) on aspects of reproductive endocrine function in female fathead minnows. The fish were exposed to multiple concentrations of FAD and TRB individually or in combination for 48- or 96-h. Effects on two shared nodes in the AOP network, plasma 17β-estradiol (E2) concentration and vitellogenin (VTG) production (measured as hepatic vtg transcripts) responded as anticipated to FAD alone but were minimally impacted by TRB alone. Overall, there were indications that TRB enhanced decreases in E2 and vtg in FAD-exposed fish but results often were not statistically-significant. Failure to consistently observe hypothesized interactions between FAD and TRB could be due to several factors, including lack of impact of TRB, inherent biological variability in the endpoints assessed, and/or an incomplete understanding of interactions (including feedback) between different pathways within the hypothalamic-pituitary-gonadal axis.