title: Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: II. Computational modeling.
abstract: Endocrine-disrupting chemicals can affect reproduction and development in humans and wildlife. We developed a computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC) behaviors for endocrine effects of the aromatase inhibitor, fadrozole (FAD). The model describes adaptive responses to endocrine stress involving regulated secretion of a generic gonadotropin (LH/FSH) from the hypothalamic-pituitary complex. For model development, we used plasma 17β-estradiol (E2) concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two time-course experiments, each of which included both an exposure and a depuration phase, and plasma E2 data from a third 4-day study. Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 µg/l FAD exposure concentrations, and good fits to these data were obtained. The model accurately predicted CYP19A mRNA fold changes for controls and three FAD doses (0, 0.5, and 3 µg/l) and plasma E2 dose response from the 4-day study. Comparing the model-predicted DRTC with experimental data provided insight into how the feedback control mechanisms in the HPG axis mediate these changes: specifically, adaptive changes in plasma E2 levels occurring during exposure and "overshoot" occurring postexposure. This study demonstrates the value of mechanistic modeling to examine and predict dynamic behaviors in perturbed systems. As this work progresses, we will obtain a refined understanding of how adaptive responses within the vertebrate HPG axis affect DRTC behaviors for aromatase inhibitors and other types of endocrine-active chemicals and apply that knowledge in support of risk assessments.
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Breen
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
authors.forename: David C
authors.initials: DC
authors.lastname: Bencic
authors.forename: Michael S
authors.initials: MS
authors.lastname: Breen
authors.forename: Karen H
authors.initials: KH
authors.lastname: Watanabe
authors.forename: Alun L
authors.initials: AL
authors.lastname: Lloyd
authors.forename: Rory B
authors.initials: RB
authors.lastname: Conolly
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000826:Animal Testing Alternatives; D000818:Animals; D047072:Aromatase Inhibitors / Q000633:toxicity*; D003198:Computer Simulation; D003530:Cyprinidae / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D004965:Estrogen Antagonists / Q000633:toxicity*; D017316:Fadrozole / Q000633:toxicity*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010053:Ovary / Q000187:drug effects* / Q000201:enzymology; D011237:Predictive Value of Tests; D013997:Time Factors
chemical_list: D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D004958:Estradiol; D017316:Fadrozole
keywords: biological modeling; biomarkers.; dose response; endocrine disruptors; non-mammalian species