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Title: Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals

Abstract

Dysfunction of the enzyme aromatase (CYP19) is associated with endocrine pathologies such as osteoporosis, impaired fertility and development of hormone-dependent cancers. Certain endocrine disrupting chemicals affect aromatase expression and activity in vitro, but little is known about their ability to do so in vivo. We evaluated a bioluminescent mouse model (LPTA (registered)) CD-1-Tg(Cyp19-luc)-Xen) expressing luciferase under control of the gonadal aromatase pII promoter as an in vivo screening tool for chemicals that may affect aromatase expression. We studied the effects of forskolin, pregnant mare serum gonadotropin and atrazine in this model (atrazine was previously shown to induced pII-promoter-driven aromatase expression in H295R human adrenocortical carcinoma cells). About 2-4 out of every group of 10 male or female Cyp19-luc mice injected i.p. with 10 mg/kg forskolin had increased gonadal bioluminescence after 3-5 days compared to controls; the others appeared non-responsive. Similarly, about 4 per group of 9 individual females injected with pregnant mare serum gonadotropin had increased ovarian bioluminescence after 24 h. There was a statistically significant correlation between ovarian bioluminescence and plasma estradiol concentrations (n = 14; p = 0.022). Males exposed to a single dose of 100 mg/kg or males and females exposed to 5 daily injections of 30more » mg/kg atrazine showed no change in gonadal bioluminescence over a 7 day period, but a significant interaction was found between atrazine (100 mg/kg) and time in female mice (p < 0.05; two-way ANOVA). Ex vivo luciferase activity in dissected organs was increased by forskolin in testis, epididymis and ovaries. Atrazine (30 mg/kg/day) increased (30%) luciferase activity significantly in epididymis only. In conclusion, certain individual Cyp19-luc mice are highly responsive to aromatase inducers, suggesting this model, with further optimization, may have potential as an in vivo screening tool for environmental contaminants.« less

Authors:
Publication Date:
OSTI Identifier:
21460237
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 249; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2010.08.011; PII: S0041-008X(10)00284-X; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLUMINESCENCE; ENDOCRINE GLANDS; LUCIFERASE; MICE; PROMOTERS; ANIMALS; BODY; EMISSION; ENZYMES; GLANDS; LUMINESCENCE; MAMMALS; ORGANIC COMPOUNDS; ORGANS; OXIDASES; OXIDOREDUCTASES; PHOTON EMISSION; PROTEINS; RODENTS; VERTEBRATES

Citation Formats

Rivest, Patricia, Devine, Patrick J., E-mail: patrick.devine@iaf.inrs.ca, and Sanderson, J. Thomas, E-mail: thomas.sanderson@iaf.inrs.c. Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals. United States: N. p., 2010. Web. doi:10.1016/j.taap.2010.08.011.
Rivest, Patricia, Devine, Patrick J., E-mail: patrick.devine@iaf.inrs.ca, & Sanderson, J. Thomas, E-mail: thomas.sanderson@iaf.inrs.c. Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals. United States. https://doi.org/10.1016/j.taap.2010.08.011
Rivest, Patricia, Devine, Patrick J., E-mail: patrick.devine@iaf.inrs.ca, and Sanderson, J. Thomas, E-mail: thomas.sanderson@iaf.inrs.c. 2010. "Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals". United States. https://doi.org/10.1016/j.taap.2010.08.011.
@article{osti_21460237,
title = {Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals},
author = {Rivest, Patricia and Devine, Patrick J., E-mail: patrick.devine@iaf.inrs.ca and Sanderson, J. Thomas, E-mail: thomas.sanderson@iaf.inrs.c},
abstractNote = {Dysfunction of the enzyme aromatase (CYP19) is associated with endocrine pathologies such as osteoporosis, impaired fertility and development of hormone-dependent cancers. Certain endocrine disrupting chemicals affect aromatase expression and activity in vitro, but little is known about their ability to do so in vivo. We evaluated a bioluminescent mouse model (LPTA (registered)) CD-1-Tg(Cyp19-luc)-Xen) expressing luciferase under control of the gonadal aromatase pII promoter as an in vivo screening tool for chemicals that may affect aromatase expression. We studied the effects of forskolin, pregnant mare serum gonadotropin and atrazine in this model (atrazine was previously shown to induced pII-promoter-driven aromatase expression in H295R human adrenocortical carcinoma cells). About 2-4 out of every group of 10 male or female Cyp19-luc mice injected i.p. with 10 mg/kg forskolin had increased gonadal bioluminescence after 3-5 days compared to controls; the others appeared non-responsive. Similarly, about 4 per group of 9 individual females injected with pregnant mare serum gonadotropin had increased ovarian bioluminescence after 24 h. There was a statistically significant correlation between ovarian bioluminescence and plasma estradiol concentrations (n = 14; p = 0.022). Males exposed to a single dose of 100 mg/kg or males and females exposed to 5 daily injections of 30 mg/kg atrazine showed no change in gonadal bioluminescence over a 7 day period, but a significant interaction was found between atrazine (100 mg/kg) and time in female mice (p < 0.05; two-way ANOVA). Ex vivo luciferase activity in dissected organs was increased by forskolin in testis, epididymis and ovaries. Atrazine (30 mg/kg/day) increased (30%) luciferase activity significantly in epididymis only. In conclusion, certain individual Cyp19-luc mice are highly responsive to aromatase inducers, suggesting this model, with further optimization, may have potential as an in vivo screening tool for environmental contaminants.},
doi = {10.1016/j.taap.2010.08.011},
url = {https://www.osti.gov/biblio/21460237}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 249,
place = {United States},
year = {Mon Nov 15 00:00:00 EST 2010},
month = {Mon Nov 15 00:00:00 EST 2010}
}