ToxSci Advance Access originally published online on April 8, 2009
Toxicological Sciences 2009 109(2):180-192; doi:10.1093/toxsci/kfp069
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A Computational Model of the Hypothalamic-Pituitary-Gonadal Axis in Male Fathead Minnows Exposed to 17
-Ethinylestradiol and 17β-Estradiol
* Division of Environmental and Biomolecular Systems, Department of Science and Engineering, Oregon Health & Science University, West Campus, Beaverton, Oregon 97006
Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, Florida 32611
Mid-Continent Ecology Division, U.S. EPA, Duluth, Minnesota 55804
Animal & Avian Sciences Department, University of Maryland, College Park, Maryland 20742
¶ Department of Forestry & Natural Resources, Purdue University, West Lafayette, Indiana 47907
|| Ecosystems Research Division, U.S. EPA, Athens, Georgia 30605
1 To whom correspondence should be addressed at Division of Environmental and Biomolecular Systems, Oregon Health & Science University, West Campus, 20000 NW Walker Road, Beaverton, OR 97006. Fax: (503)-748-1464. E-mail: watanabe{at}ebs.ogi.edu.
Received December 10, 2008; accepted March 28, 2009
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Abstract |
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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, 17
-ethinylestradiol (EE2) and 17β-estradiol (E2), 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 EE2 and E2. 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.
Key Words: EE2; E2; fish; steroid hormones; environmental estrogen; Markov chain Monte Carlo simulation; predictive toxicology; system model.