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Computational modeling of dynamic alteration of plasma vitellogenin in response to aromatase CYP19 inhibition in fathead minnows
Citation:
Cheng, W., Q. Zhang, A. Schroeder, Dan Villeneuve, G. Ankley, AND R. Conolly. Computational modeling of dynamic alteration of plasma vitellogenin in response to aromatase CYP19 inhibition in fathead minnows. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 154(1):78-89, (2016).
Impact/Purpose:
The computational model we have described links aromatase inhibition in female FHM to changes in hepatic and plasma VTG and VTG uptake into the ovary. Linking this model with computational descriptions of FHM oogenesis (Li et al., 2011)and of FHM population dynamics (Miller and Ankley, 2004) will provide a complete quantitative version of the FHM aromatase inhibition AOP. This qAOP will have the capability to predict dose-response and time-course for fecundity and population trajectory for various degrees and durations of experimentally and environmentally relevant aromatase inhibition. Aromatase inhibition can be measured experimentally or predicted using suitable models of exposure and pharmacokinetics for specific chemicals. The use of this approach to support regulatory decision-making will require careful evaluation of model uncertainty and comparison of this uncertainty with the uncertainty of the decision support process used in the absence of the qAOP.
Description:
In vertebrates, conversion of testosterone into 17β-estradiol (E2) is catalyzed by cytochrome P450 (CYP) 19A aromatase. An important role of E2 in oviparous vertebrates such as fish is stimulation of hepatic synthesis of the glycolipoprotein vitellogenin (VTG), an egg yolk precursor essential to oocyte development and larval survival. In fathead minnows (Pimephales promelas) exposed to the aromatase inhibitor fadrozole, plasma VTG levels do not uniformly change in concert with plasma E2 levels. Specifically, while plasma VTG and E2 levels both decrease relatively quickly when aromatase is first inhibited, the recovery of plasma VTG upon cessation of aromatase inhibition is substantially delayed relative to the recovery of plasma E2. We modified an existing computational model of the fathead minnow hypothalamic-pituitary-gonadal axis to evaluate alternative hypotheses that might explain this delay. In the first hypothesis, a feedback loop involving active transport of VTG from the blood into the ovary is used. The activity of the transporter is negatively regulated by ovarian VTG. In the second hypothesis, a Type 1 coherent feed-forward loop is implemented in the liver. This loop has two major components. The first describes canonical E2 signaling involving E2-dependent activation of the E2 receptor (ER), while the second component describes non-classical E2 signaling involving E2-dependent but ER independent VTG gene activation. Both hypotheses include Hill functions, which generate hypersensitive responses. This computational modeling exercise has identified hypothetical regulatory motifs that accurately describe the observed VTG dynamics. These motifs could be used to guide design of laboratory experiments intended to determine if either of the motifs, or perhaps even both of them, actually do control VTG dynamics in fathead minnows exposed to aromatase inhibitors.
