You are here:
Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: I. Data generation in a small fish model
Citation:
Villeneuve, Dan, M. Breen, D. Bencic, J. Cavallin, K. Jensen, L. Makynen, L. Thomas, L. Wehmas, R. Conolly, AND G. Ankley. Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: I. Data generation in a small fish model. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 133(2):225-233, (2013).
Impact/Purpose:
The manuscript reports on detailed analysis of the time-course of biological responses associated with the reproductive endocrine axis of a small fish following exposure to a model aromatase inhibitor. Aromatase inhibitors are an important class of endocrine active chemicals (EACs) specifically targeted as part of EPA’s endocrine disruptor screening program (EDSP). While existing in vitro and in vivo screening assays are suitable for chemical screening and prioritization, application of these data, particularly in vitro data, in quantitative risk assessments are currently limited by the inability to predict the complex concentration-duration-response relationships that may influence a chemical’s in vivo hazard. This includes feedback and compensatory responses known to occur along the hypothalamic-pituitary-gonadal axis. The current research provides data which supports the development of a dynamic computational model intended to aid such predictions (detailed in a companion paper). As such, it contributes directly to the goals of CSS Task 2.2.3 which focuses on the development of “Virtual Endocrine System” models. Further, the study provides further supporting evidence for an Adverse Outcome Pathway (AOP) linking aromatase inhibition with adverse reproductive effects in fish. Consequently, this work also supports CSS Task 2.1.1 focused on AOP discovery and definition and a complementary effort being conducted under OECD’s AOP workplan, which is intended to support OECD’s test guidelines program, application of IATA (integrated approaches to testing and assessment), and chemical category formation in support of the QSAR toolbox.
Description:
Adaptive or compensatory responses to chemical exposure can significantly influence in vivo concentration-duration-response relationships. The aim of this study was to provide data to support development of a computational dynamic model of the hypothalamic-pituitary-gonadal axis of a model vertebrate and its response to aromatase inhibitors, as a class of endocrine active chemicals. Fathead minnows (Pimephales promelas) were exposed to the aromatase inhibitor fadrozole (0.5 or 30 μg/L) either continuously for 1, 8, 12, 16, 20, 24, and 28 d, or exposed for 8 d and then held in control water (no fadrozole) for an additional 4, 8, 12, 16, or 20 d.The time-course of effects on ovarian steroid production, circulating 17β-estradiol (E2) and vitellogenin concentrations, and expression of steroidogenesis-related genes in the ovary were examined. Exposure to 30 μg fadrozole/L significantly reduced plasma E2 and vitellogenin concentrations after just 1 d and those effects persisted throughout 28 d of exposure. In contrast, ex vivo E2 production was similar to that of controls on d 8-28 of exposure, while transcripts coding for aromatase and follicle-stimulating hormone receptor were elevated, suggesting a compensatory response. Following cessation of fadrozole exposure, ex vivo E2 and plasma E2 concentrations exceeded and then recovered to control levels, but plasma vitellogenin concentrations did not, even after 20 d of depuration. Collectively these data provide several new insights into the nature and time-course of adaptive responses to an aromatase inhibitor which support development of a computational model (see companion article).
