Case study in 21st century ecotoxicology: using in vitro aromatase inhibition data to predict short term in vivo responses in adult female fish

The current study evaluated whether in vitro measures of aromatase inhibition as inputs into a quantitative adverse outcome pathway (qAOP) construct could effectively predict in vivo effects on 17β-estradiol (E2) and vitellogenin (VTG) concentrations in female fathead minnows. Five chemicals identified as aromatase inhibitors in mammalian-based ToxCast assays were screened for their ability to inhibit fathead minnow aromatase in vitro. Female fathead minnows were then exposed to three of those chemicals, letrozole, epoxiconazole, and imazalil, in concentration response (five concentrations plus control), for 24 h. Consistent with AOP-based expectations, all three chemicals caused significant reductions in plasma E2 and hepatic VTG transcription. Characteristic compensatory up-regulation of aromatase and follicle stimulating hormone receptor (FSHR) transcripts in ovary was observed for letrozole but not the other two compounds. Considering the overall patterns of concentration-response and temporal concordance among endpoints, data from the in vivo experiments strengthen confidence in the qualitative relationships outlined by the AOP. Quantitatively, the qAOP model provided predictions that fell within the standard error of measured data for letrozole, but not for imazalil and epoxiconazole. However, the inclusion of measured plasma concentrations of the test chemicals as inputs improved model predictions, with all predictions falling within the range of measured values. Results highlight both the utility and limitations of the qAOP and its potential use in 21st century ecotoxicology. This article is protected by copyright. All rights reserved.