TY - JOUR
T1 - A computational model of the hypothalamic-pituitary-gonadal axis in male fathead minnows exposed to 17α-ethinylestradiol and 17β-estradiol
AU - Watanabe, Karen H.
AU - Li, Zhenhong
AU - Kroll, Kevin J.
AU - Villeneuve, Daniel L.
AU - Garcia-Reyero, Natàlia
AU - Orlando, Edward F.
AU - Sepúlveda, Maria S.
AU - Collette, Timothy W.
AU - Ekman, Drew R.
AU - Ankley, Gerald T.
AU - Denslow, Nancy D.
N1 - Funding Information:
Although the research described in this article has been funded in part by the U.S. Environmental Protection Agency, it has not been subjected to any formal Environmental Protection Agency review and does not necessarily reflect the views of the Agency. No official endorsement should be inferred.
PY - 2009
Y1 - 2009
N2 - 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, 17α-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.
AB - 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, 17α-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.
KW - E
KW - EE
KW - Environmental estrogen
KW - Fish
KW - Markov chain Monte Carlo simulation
KW - Predictive toxicology
KW - Steroid hormones
KW - System model
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U2 - 10.1093/toxsci/kfp069
DO - 10.1093/toxsci/kfp069
M3 - Article
C2 - 19357070
AN - SCOPUS:66149129169
SN - 1096-6080
VL - 109
SP - 180
EP - 192
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -