title: Computational model of the fathead minnow hypothalamic-pituitary-gonadal axis: Incorporating protein synthesis in improving predictability of responses to endocrine active chemicals.
abstract: There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17β-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered. In this study, we addressed short-comings of the previous model by incorporating additional details concerning CYP19A (aromatase) protein synthesis. Predictions based on the revised model were evaluated using plasma E2 concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two fathead minnow time-course experiments with FAD, as well as from a third 4-day study. The extended model provides better fits to measured E2 time-course concentrations, and the model accurately predicts CYP19A mRNA fold changes and plasma E2 dose-response from the 4-d concentration-response study. This study suggests that aromatase protein synthesis is an important process in the biological system to model the effects of FAD exposure.
authors.affiliation: Biomathematics Graduate Program, Department of Mathematics, North Carolina State University, Box 8203, Raleigh, NC 27695, USA. Electronic address: mbreen@ncsu.edu.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Breen
authors.affiliation: Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, 6201 Congdon Blvd, Duluth, MN 55804, USA. Electronic address: villeneuve.dan@epa.gov.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.affiliation: Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, 6201 Congdon Blvd, Duluth, MN 55804, USA. Electronic address: ankley.gerald@epa.gov.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
authors.affiliation: Ecological Exposure Research Division, National Exposure Research Laboratory, U.S. Environmental Protection Agency, Cincinnati, OH, USA. Electronic address: bencic.david@epa.gov.
authors.forename: David
authors.initials: D
authors.lastname: Bencic
authors.affiliation: National Exposure Research Laboratory, U.S. Environmental Protection Agency, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA. Electronic address: breen.michael@epa.gov.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Breen
authors.affiliation: Division of Environmental and Biomolecular Systems, Institute of Environmental Health, Oregon Health & Science University, 3181 SW Sam Jackson Park Road HRC3, Portland, OR 97239, USA. Electronic address: watanabk@ohsu.edu.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Watanabe
authors.affiliation: Biomathematics Graduate Program, Department of Mathematics, North Carolina State University, Box 8203, Raleigh, NC 27695, USA. Electronic address: alun_lloyd@ncsu.edu.
authors.forename: Alun L
authors.initials: AL
authors.lastname: Lloyd
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA. Electronic address: conolly.rory@epa.gov.
authors.forename: Rory B
authors.initials: RB
authors.lastname: Conolly
mesh_terms: D000818:Animals; D001141:Aromatase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D019295:Computational Biology; D003530:Cyprinidae / Q000097:blood / Q000254:growth & development / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity*; D004958:Estradiol / Q000097:blood; D017316:Fadrozole / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D029941:Fish Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010053:Ovary / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D015203:Reproducibility of Results; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D047072:Aromatase Inhibitors; D052244:Endocrine Disruptors; D029941:Fish Proteins; D012333:RNA, Messenger; D014874:Water Pollutants, Chemical; D004958:Estradiol; D001141:Aromatase; D017316:Fadrozole
keywords: Adaptation; Computational model; Endocrine disrupting chemicals; Fadrozole; Fish; Hypothalamic–pituitary–gonadal axis; Protein synthesis; Toxicology