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Computational Modeling of Hypothalamic-Pituitary-Gonadal Axis to Predict Adaptive Responses in Female Fathead Minnows Exposed to an Aromatase Inhibitor
Citation:
Breen, M., D. Villeneuve, G. T. ANKLEY, D. C. BENCIC, M. BREEN, K. WATANABE, A. Lloyd, AND R. Conolly. Computational Modeling of Hypothalamic-Pituitary-Gonadal Axis to Predict Adaptive Responses in Female Fathead Minnows Exposed to an Aromatase Inhibitor. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
Weare developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict doseresponse and time-course (DRTC) behaviors for endocrine effects of the aromatase inhibitor, fadrozole (FAD).
Description:
Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic 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 includes two feedback regulatory loops within the HPG axis that mediate adaptive responses to endocrine stress. One regulatory loop controls the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the brain, and the other regulates LH and FSH receptor recycling in the ovary. Data on plasma E2 and ovarian CYP19A mRNA from two experiments with a post-exposure recovery phase were used to develop and evaluate the model. In the experiments, fathead minnows were exposed to FAD at 0, 3, or 30 ug/L for 8 days followed by an 8-day recovery phase (experiment 1) or to FAD at 0,0.5, or 30 ug/L for 8 days followed by a 20-day recovery phase (experiment 2). Adaptive changes in plasma E2 levels occurred during exposure and overshoot occurred post-exposure. Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 ug/L FAD doses. The model predicted dynamic E2 concentrations for 0, 0.5, and 3 ug/L fit closely to timecourse measurements. This abstract does not necessarily reflect US Environmental Protection Agency policy.