Abstract
There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17β-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered. In this study, we addressed short-comings of the previous model by incorporating additional details concerning CYP19A (aromatase) protein synthesis. Predictions based on the revised model were evaluated using plasma E2 concentrations and ovarian cytochrome P450 (CYP) 19 A aromatase mRNA data from two fathead minnow time-course experiments with FAD, as well as from a third 4-day study. The extended model provides better fits to measured E2 time-course concentrations, and the model accurately predicts CYP19A mRNA fold changes and plasma E2 dose-response from the 4-d concentration-response study. This study suggests that aromatase protein synthesis is an important process in the biological system to model the effects of FAD exposure.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 36-45 |
| Number of pages | 10 |
| Journal | Comparative Biochemistry and Physiology - C Toxicology and Pharmacology |
| Volume | 183-184 |
| DOIs | |
| State | Published - May 1 2016 |
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Keywords
- Adaptation
- Computational model
- Endocrine disrupting chemicals
- Fadrozole
- Fish
- Hypothalamic-pituitary-gonadal axis
- Protein synthesis
- Toxicology
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Physiology
- Health, Toxicology and Mutagenesis
- Toxicology
Cite this
Computational model of the fathead minnow hypothalamic-pituitary-gonadal axis : Incorporating protein synthesis in improving predictability of responses to endocrine active chemicals. / Breen, Miyuki; Villeneuve, Daniel L.; Ankley, Gerald T.; Bencic, David; Breen, Michael S.; Watanabe-Sailor, Karen; Lloyd, Alun L.; Conolly, Rory B.
In: Comparative Biochemistry and Physiology - C Toxicology and Pharmacology, Vol. 183-184, 01.05.2016, p. 36-45.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Computational model of the fathead minnow hypothalamic-pituitary-gonadal axis
T2 - Incorporating protein synthesis in improving predictability of responses to endocrine active chemicals
AU - Breen, Miyuki
AU - Villeneuve, Daniel L.
AU - Ankley, Gerald T.
AU - Bencic, David
AU - Breen, Michael S.
AU - Watanabe-Sailor, Karen
AU - Lloyd, Alun L.
AU - Conolly, Rory B.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17β-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered. In this study, we addressed short-comings of the previous model by incorporating additional details concerning CYP19A (aromatase) protein synthesis. Predictions based on the revised model were evaluated using plasma E2 concentrations and ovarian cytochrome P450 (CYP) 19 A aromatase mRNA data from two fathead minnow time-course experiments with FAD, as well as from a third 4-day study. The extended model provides better fits to measured E2 time-course concentrations, and the model accurately predicts CYP19A mRNA fold changes and plasma E2 dose-response from the 4-d concentration-response study. This study suggests that aromatase protein synthesis is an important process in the biological system to model the effects of FAD exposure.
AB - There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17β-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered. In this study, we addressed short-comings of the previous model by incorporating additional details concerning CYP19A (aromatase) protein synthesis. Predictions based on the revised model were evaluated using plasma E2 concentrations and ovarian cytochrome P450 (CYP) 19 A aromatase mRNA data from two fathead minnow time-course experiments with FAD, as well as from a third 4-day study. The extended model provides better fits to measured E2 time-course concentrations, and the model accurately predicts CYP19A mRNA fold changes and plasma E2 dose-response from the 4-d concentration-response study. This study suggests that aromatase protein synthesis is an important process in the biological system to model the effects of FAD exposure.
KW - Adaptation
KW - Computational model
KW - Endocrine disrupting chemicals
KW - Fadrozole
KW - Fish
KW - Hypothalamic-pituitary-gonadal axis
KW - Protein synthesis
KW - Toxicology
UR - http://www.scopus.com/inward/record.url?scp=84958787555&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958787555&partnerID=8YFLogxK
U2 - 10.1016/j.cbpc.2016.02.002
DO - 10.1016/j.cbpc.2016.02.002
M3 - Article
C2 - 26875912
AN - SCOPUS:84958787555
VL - 183-184
SP - 36
EP - 45
JO - Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology
JF - Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology
SN - 0742-8413
ER -