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ToxSci Advance Access published online on March 31, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh125
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received December 4, 2003; accepted March 1, 2004
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.

Endocrine Toxicology

The Characterization and Hormonal Regulation of Kidney Androgen-Regulated Protein (Kap)-Luciferase Transgenic Mice

S. E. Malstrom 1*, O. Tornavaca 2, A. Meseguer 2, A. F. Purchio 1, and D. B. West 1

1 Xenogen Corporation, Alameda, California
2 Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Barcelona, Spain

* To whom correspondence should be addressed. E-mail: Scott.Malstrom{at}xenogen.com.


  Abstract

The androgen-dependent regulation for the gene encoding the kidney androgen regulated protein (Kap) was examined in transgenic mice expressing luciferase (luc) under the control of the murine Kap promoter. Biophotonic imaging was used to visualize luciferase expression from the kidneys and various organs that were confirmed using luminometer assays. Kap-luc expression was observed at high levels in kidneys, epididymides, testes and seminal vesicles in male mice, and in kidneys, ovaries and uterus in female mice. Kap-luc expression was modulated by androgen and anti-androgen treatment in both male and female mice. Male mice were treated daily with the anti-androgenic compounds, cyproterone acetate (50 and 100mg/kg/day) and flutamide (50 and 100mg/kg/day), or vehicle for 16 days. Endpoints evaluated included in vivo biophotonic imaging, body weights, organ weights (liver, kidney, testes, epididymides, preputial gland and seminal vesicles), protein luciferase assays and western blot analysis. Biophotonic imaging was used to follow Kap-luc expression from each animal throughout the experiment using a sensitive imaging system. These imaging results correlated well with western blot analysis and traditional endpoints of body and organ weights. Following treatment with anti-androgens, the luciferase signal was found to significantly decrease in the intact male mouse using in vivo biophotonic imaging and correlated with measurements of luciferase activity in homogenized organ extracts. The decrease in epididymal and seminal vesicle weight confirmed the action of the anti-androgens. In vivo imaging documented significant changes in luciferase expression within the first few days of the experiment indicative of the anti-androgenic activity of the drugs. Testosterone treatment significantly increased the Kap-luc bioluminescent signal in female mice. This increased luciferase induction was shown to be inhibited by co-administration of cyproterone (100mg/kg/day). Our results indicate that biophotonic imaging may provide a useful approach for noninvasively tracking the effects of endocrine disruptors in specific tissues.

Key Words: Kidney androgen-regulated protein, bioluminescent imaging, in vivo .


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