Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows

Wan Yun Cheng, Qiang Zhang, Anthony Schroeder, Daniel L. Villeneuve, Gerald T. Ankley, Rory Conolly

    Research output: Contribution to journalArticlepeer-review

    8 Scopus citations

    Abstract

    In vertebrates, conversion of testosterone into 17b-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 (FHMs) (Pimephales promelas) exposed to the aromatase inhibitor fadrozole, plasma VTG levels do not change in concert with plasma E2 levels. Specifically, while plasma VTG and E2 levels both drop 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 FHM 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 2 arms, both requiring E2 activation. The first arm describes direct, canonical E2-driven transcriptional induction of VTG, and the second describes an E2-driven intermediate transcriptional regulator that is also required for VTG synthesis. Both hypotheses accurately described the observed VTG dynamics. This result 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 FHMs exposed to aromatase inhibitors. Published by Oxford University Press on behalf of the Society of Toxicology 2016.

    Original languageEnglish (US)
    Pages (from-to)78-89
    Number of pages12
    JournalToxicological Sciences
    Volume154
    Issue number1
    DOIs
    StatePublished - Nov 1 2016

    Keywords

    • Adverse outcome pathway
    • Aquatic toxicology
    • Computational toxicology
    • Endocrine toxicology
    • Environmental toxicology
    • In vitro and altenatives
    • Predictive toxicology

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