title: Editor's Highlight: Computational Modeling of Plasma Vitellogenin Alterations in Response to Aromatase Inhibition in Fathead Minnows.
abstract: 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 (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.
authors: *Oak Ridge Institute for Science and Education; Tennessee.|Integrated Systems Toxicology Division, National Health and Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
authors: Wan-Yun
authors: WY
authors: Cheng
authors: Department of Environmental Health, Rollins School of Public Health, Emory University, Georgia.
authors: Qiang
authors: Q
authors: Zhang
authors: Math, Science & Technology Department, University of Minnesota Crookston, Minnesota.
authors: Anthony
authors: A
authors: Schroeder
authors: Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Minnesota.
authors: Daniel L
authors: DL
authors: Villeneuve
authors: Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Minnesota.
authors: Gerald T
authors: GT
authors: Ankley
authors: Integrated Systems Toxicology Division, National Health and Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; conolly.rory@epa.gov.
authors: Rory
authors: R
authors: Conolly
mesh_terms: D000818:Animals; D001141:Aromatase; D047072:Aromatase Inhibitors / Q000633:toxicity*; D003198:Computer Simulation; D003530:Cyprinidae / Q000097:blood*; D004958:Estradiol / Q000097:blood*; D017316:Fadrozole / Q000633:toxicity*; D005260:Female; D010053:Ovary; D014819:Vitellogenins / Q000097:blood*
chemical_list: D047072:Aromatase Inhibitors; D014819:Vitellogenins; D004958:Estradiol; D001141:Aromatase; D017316:Fadrozole
keywords: adverse outcome pathway; aquatic toxicology; computational toxicology.; endocrine toxicology; environmental toxicology; in vitro and altenatives; predictive toxicology