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Computational Modeling to Evaluate Alternative Hypotheses for the Linkage of Aromatase Inhibition to Vitellogenin Levels in Fathead Minnows
Citation:
Cheng, W., Q. Zhang, A. Schroeder, Dan Villeneuve, G. Ankley, AND R. Conolly. Computational Modeling to Evaluate Alternative Hypotheses for the Linkage of Aromatase Inhibition to Vitellogenin Levels in Fathead Minnows. The Society of Toxicology 55th Annual Meeting and ToxExpo, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
Endocrine disruption in fish can affect reproduction and population trajectories. This abstract describes quantitative modeling as part of a larger EPA research project focusing on understanding effects of an aromatase inhibitor on vitellogenin levels in fish. Aromatase inhibition and vitellogenin production are key events in an adverse outcome pathway (AOP) linking exposure of fish to certain endocrine disrupters with adverse effects on reproduction.
Description:
Aromatase converts testosterone to estradiol (E2). In fish, E2 concentrations control hepatic synthesis of the glycolipoprotein vitellogenin (VTG), an egg yolk precursor protein essential to oocyte development and larval survival. Fathead minnows were exposed to the aromatase inhibitor, fadrozole, for 8 days and held in control water for an additional 20 days. We observed dose-dependent reductions in plasma E2 and VTG during exposure to fadrozole. While VTG concentrations dropped as the E2 level declined at the onset of exposure, the recovery of VTG during depuration was delayed relative to that of E2. An existing computational model of the hypothalamic-pituitary-gonadal axis was modified to evaluate three alternative hypotheses regarding the regulation of VTG. The first hypothesis, describing the rate of VTG synthesis as proportional to hepatic E2, failed to describe the VTG data. In the second hypothesis, using a type I coherent feed-forward motif, hepatic synthesis of VTG involves both direct E2 signaling and an intermediate transcription factor induced by E2. The third hypothesis involves a negative feedback loop operating in the ovary where the synthesis of the ovarian VTG transporter used for uptake of VTG from the blood is negatively regulated by VTG in the ovary. For both the feedforward and feedback loops, ultrasensitivity, allowing signal amplification and threshold, was implemented using Hill equations. Both the feed-forward and feedback motifs were able to recapitulate the observed VTG dynamics, suggesting that one or both may operate in fathead minnows. While computational modeling cannot reveal the actual biological identity of the regulatory circuits, it can identify hypotheses worth of laboratory investigation. This abstract does not necessarily reflect the policy of the US EPA.