You are here:
Case study in 21st century ecotoxicology: Using in vitro aromatase inhibition data to predict short term in vivo responses in adult female fish
Citation:
Villeneuve, Dan, B. Blackwell, J. Cavallin, W. Cheng, R. Conolly, D. Feifarek, K. Jensen, M. Kahl, R. Milsk, S. Poole, E. Randolph, T. Saari, AND G. Ankley. Case study in 21st century ecotoxicology: Using in vitro aromatase inhibition data to predict short term in vivo responses in adult female fish. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 40(4):1155-1170, (2021). https://doi.org/10.1002/etc.4968
Impact/Purpose:
EPA has committed to reducing the use of animals in chemical safety assessment. This research was designed to evaluate whether a biologically-based computational model aligned with an adverse outcome pathway (AOP) could effectively predict animal (in vivo) responses to chemicals shown to inhibit the enzyme aromatase in a non-animal (in vitro) screening assays. Aromatase is an enzyme that plays a critical role in the synthesis of estrogens, an important class of hormones, and chemicals that inhibit aromatase are viewed as probable endocrine disrupting compounds. Although the model was not able to accurately predict the average in vivo responses observed for all chemicals tested, there was strong qualitative to semi-quantitative agreement with the proposed AOP and predictions did fall within the distribution of measured values. Consequently, this “new approach methodology” likely has utility for screening-level assessments. This work helps to establish the confidence and limitations of this approach, allowing for EPA’s program offices to define suitable fit-for-purpose relative to applications related to endocrine disruptor screening and chemical safety assessment.
Description:
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 17â-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, for 24 h. Consistent with the AOP, all three chemicals caused significant reductions in plasma E2 and hepatic VTG transcription within 24 h. 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 strengthens confidence in the qualitative relationships outlined by the AOP. Quantitively, the qAOP model provided predictions that fell within the standard error of measured data for letrozole, but not for imazalil and epoxiconazole. However, use of measured plasma concentrations of test chemical as inputs improved model predictions and all predictions fell within the range of measured values. Results highlight both the utility and limitations of the qAOP and its potential use in 21st century ecotoxicology.
URLs/Downloads:
DOI: Case study in 21st century ecotoxicology: Using in vitro aromatase inhibition data to predict short term in vivo responses in adult female fish