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Androgen and estrogen stimulation of ornithine decarboxylase activity in mouse kidney
K Svechnikov1, E M Ritzén, M Holst
1Department of Women and Child Health, Pediatric Endocrinology Unit (Q2:08), Karolinska Institute and Astrid Lindgren Childrens Hospital, S-171 76, Stockholm, Sweden.
Abstract:
In the present work, the activity of mouse renal ornithine decarboxylase (ODC) from CBA female mice was used as a biological marker to detect (anti)androgenic activity of different groups of endocrine disruptors and steroids. Daily injections of testosterone or dihydrotestosterone (DHT) into 60 day old female mice for 4 days increased renal ODC activity in a dose-dependent manner that reached up to 100-fold (testosterone) or 250-fold (DHT) above the baseline when the highest dose, 200 microg/mouse, was used. Administration of flutamide concurrently with testosterone (75 microg/mouse) caused a potent decrease of ODC induction in a dose-dependent manner, suppressing the enzyme activity at the doses of 0.1 and 0.5 mg/mouse by about 88 and 95%, respectively. In contrast, estradiol at the doses of 0.5 and 1 mg/mouse induced a significant stimulation of renal ODC activity in a dose-dependent manner when it was given alone or in combination with testosterone. Using a sensitive increase in ODC activity in response to androgens as an end point, we did not detect an antiandrogenic effect of several antiandrogens, such as cyproterone acetate, spironolactone, p,p'DDE and vinclozolin. Also, none of these antiandrogens were able to change the basal level of renal ODC activity, with the exception of cyproterone acetate that at a dose of 0.1 mg/mouse stimulated ODC activity. The data obtained suggest that mouse renal ODC from CBA females is not strictly androgen-specific and cannot be used for estimation of antiandrogenic effects of compounds having an affinity to different types of receptors.
Insights
Mouse kidney ornithine decarboxylase (ODC) activity is a sensitive marker for androgenic compounds but not reliable for detecting anti-androgenic effects of certain chemicals.
Area of Science:
- Endocrinology
- Biochemistry
- Toxicology
Background:
- Ornithine decarboxylase (ODC) is an enzyme involved in polyamine synthesis.
- ODC activity can be modulated by androgens and anti-androgens.
- Investigating ODC as a biomarker for endocrine disruptor activity is crucial.
Purpose of the Study:
- To evaluate mouse renal ornithine decarboxylase (ODC) as a biomarker for detecting androgenic and anti-androgenic activities.
- To assess the dose-dependent effects of testosterone, dihydrotestosterone (DHT), estradiol, and anti-androgens on renal ODC activity in female mice.
Main Methods:
- Female CBA mice were injected daily with varying doses of testosterone, DHT, estradiol, flutamide, cyproterone acetate, spironolactone, p,p'DDE, and vinclozolin.
- Renal ODC activity was measured as a biological response to the administered compounds.
- The impact of co-administration of flutamide with testosterone was also analyzed.
Main Results:
- Testosterone and DHT significantly increased renal ODC activity in a dose-dependent manner.
- Flutamide potently suppressed testosterone-induced ODC activity.
- Estradiol stimulated ODC activity, and several tested anti-androgens did not show anti-androgenic effects on ODC induction, with cyproterone acetate showing a stimulatory effect at a low dose.
Conclusions:
- Mouse renal ODC activity is a sensitive indicator of androgenic effects.
- Renal ODC activity in female mice is not a reliable biomarker for detecting the anti-androgenic effects of all tested compounds.
- The specificity of ODC activity for androgen action is limited, especially for compounds with diverse receptor affinities.