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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
Author(s) -
Ankley Gerald T.,
Blackwell Brett R.,
Cavallin Jenna E.,
Doering Jon A.,
Feifarek David J.,
Jensen Kathleen M.,
Kahl Michael D.,
LaLone Carlie A.,
Poole Shane T.,
Randolph Eric C.,
Saari Travis W.,
Villeneuve Daniel L.
Publication year - 2020
Publication title -
environmental toxicology and chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.1
H-Index - 171
eISSN - 1552-8618
pISSN - 0730-7268
DOI - 10.1002/etc.4668
Subject(s) - aromatase , biology , aromatase inhibitor , adverse outcome pathway , agonist , androgen , androgen receptor , endocrine disruptor , vitellogenin , endocrine system , medicine , endocrinology , pharmacology , receptor , hormone , fish <actinopterygii> , computational biology , genetics , fishery , prostate cancer , cancer , breast cancer
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. 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 molecular initiating events. Adverse outcome pathway (AOP) networks conceptually support this type of analysis. We assessed the utility of a simple AOP network for predicting the effects of mixtures of an aromatase inhibitor (fadrozole) and an androgen receptor agonist (17β‐trenbolone) on aspects of reproductive endocrine function in female fathead minnows. The fish were exposed to multiple concentrations of fadrozole and 17β‐trenbolone individually or in combination for 48 or 96 h. Effects on 2 shared nodes in the AOP network, plasma 17β‐estradiol (E2) concentration and vitellogenin (VTG) production (measured as hepatic vtg transcripts) responded as anticipated to fadrozole alone but were minimally impacted by 17β‐trenbolone alone. Overall, there were indications that 17β‐trenbolone enhanced decreases in E2 and vtg in fadrozole‐exposed fish, as anticipated, but the results often were not statistically significant. Failure to consistently observe hypothesized interactions between fadrozole and 17β‐trenbolone could be due to several factors, including lack of impact of 17β‐trenbolone, 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. Environ Toxicol Chem 2020;39:913–922. © 2020 SETAC