A Computational Model of the Hypothalamic-Pituitary-Gonadal Axis in Male Fathead Minnows Exposed to 17α-Ethinylestradiol and 17β-Estradiol

• DOI: 10.1093/toxsci/kfp069
• Publication Date: 2009-04-08T20:13:09Z
• Authors: Karen H. Watanabe; Zhenhong Li; Kevin J. Kroll; Daniel L. Villeneuve; Natàlia Garcia-Re...; Edward F. Orlando; Maria S. Sepúlveda; Timothy W. Collette; Drew R. Ekman; Gerald T. Ankley; Nancy D. Denslow
• Keywords: Male; Hypothalamo-Hypophyseal System; Principal Component Analysis; 0303 health sciences; Estradiol; Cyprinidae; Pituitary-Adrenal System; Ethinyl Estradiol; Lipid Metabolism; Models, Biological; Markov Chains; 6. Clean water; Vitellogenins; 03 medical and health sciences; Calibration; Animals; Computer Simulation; Gonadal Steroid Hormones; Monte Carlo Method; Water Pollutants, Chemical; Signal Transduction

Estrogenic chemicals in the aquatic environment have been shown to cause a variety of reproductive anomalies in fish including full sex reversal, intersex, and altered population sex ratios. Two estrogens found in the aquatic environment, 17alpha-ethinylestradiol (EE(2)) and 17beta-estradiol (E(2)), have been measured in wastewater treatment effluents and have been shown to cause adverse effects in fish. To further our understanding of how estrogen exposure affects reproductive endpoints in the male fathead minnow (FHM, Pimephales promelas), a physiologically based computational model was developed of the hypothalamic-pituitary-gonadal (HPG) axis. Apical reproductive endpoints in the model include plasma steroid hormone and vitellogenin concentrations. Using Markov chain Monte Carlo simulation, the model was calibrated with data from unexposed FHM, and FHM exposed to EE(2) and E(2). Independent experimental data sets were used to evaluate model predictions. We found good agreement between our model predictions and a variety of measured reproductive endpoints, although the model underpredicts unexposed FHM reproductive endpoint variances, and overpredicts variances in estrogen-exposed FHM. We conclude that this model provides a robust representation of the HPG axis in male FHM.