TY - JOUR
T1 - Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition
T2 - II. Computational modeling
AU - Breen, Miyuki
AU - Villeneuve, Daniel L.
AU - Ankley, Gerald T.
AU - Bencic, David C.
AU - Breen, Michael S.
AU - Watanabe, Karen H.
AU - Lloyd, Alun L.
AU - Conolly, Rory B.
N1 - Funding Information:
1To whom correspondence should be addressed at U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, 109 T.W. Alexander Dr, Mail B105-03, Research Triangle Park, NC 27711. Fax: 919-541-4284. E-mail: conolly.rory@epa.gov.
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - Biological modeling
KW - Biomarkers
KW - Dose response
KW - Endocrine disruptors
KW - Nonmammalian species
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U2 - 10.1093/toxsci/kft067
DO - 10.1093/toxsci/kft067
M3 - Article
C2 - 23475784
AN - SCOPUS:84878476519
SN - 1096-6080
VL - 133
SP - 234
EP - 247
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -