The non-aromatizable androgen, dihydrotestosterone, induces antiestrogenic responses in the rainbow trout.
In order to satisfy government mandates, numerous studies have been performed categorizing potential endocrine disrupting chemicals as (anti)estrogens or (anti)androgens. We report here that dihydrotestosterone (DHT), a potent, non-aromatizable androgen receptor agonist, induces antiestrogenic responses through direct and/or indirect modulation of vitellogenin (Vg), steroid hormone and total cytochrome P450 levels. DHT and two weak, aromatizable androgens, DHEA and androstenedione (0.05-50 mg/kg per day), were fed to juvenile trout for 2 weeks. DHEA and androstenedione significantly increased blood plasma Vg by up to 30- and 45-fold, respectively (P<0.05, t-test). 17beta-Estradiol (E2) increases were also observed with both androgens, albeit with lower sensitivity. DHT markedly decreased Vg and E2 levels, suggesting that DHEA and androstenedione increased Vg and E2 via conversion to E2 and not by estrogen receptor agonism. DHEA and androstenedione had no effect on total cytochrome P450 content, while DHT significantly decreased P450 content in a dose dependent fashion. These results indicate that alterations in metabolism mediated by androgen receptor binding may be responsible for the Vg and E2 decreases by DHT. In an attempt to decipher between receptor and non-receptor androgenic mechanisms of the observed DHT effects, DHT (0, 50 or 100 mg/kg per day) and flutamide (0-1250 mg/kg per day), an androgen receptor antagonist, were fed to juvenile rainbow trout for 2 weeks. Flutamide alone was as effective as DHT in decreasing E2 and Vg levels in males but did not significantly reverse DHT induced Vg decreases in either sex (P>0.05, F-test). DHT decreases in total P450 content were partially attenuated in males by flutamide co-treatment, but not females, suggesting a partial androgenic mechanism to the P450 decreases as well as a fundamental sex difference responding to androgen receptor binding. Moreover, flutamide alone decreased P450 content by up to 30% in males and 40% in females. These effects may be mediated through direct androgen receptor binding irrespective of whether the binding is agonistic or antagonistic. This study indicates that androgen receptor agonists/antagonists can elicit significant antiestrogenic effects that may not necessarily be mediated through classic receptor binding mechanisms and signal transduction pathways.
Shilling
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Department of Environmental and Molecular Toxicology and Marine/Freshwater Biomedical Sciences Center, Agricultural and Life Sciences Building, room 1007, Oregon State University, Corvallis, OR 97331, USA.
Williams
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D000726:Androgen Antagonists / Q000494:pharmacology; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000097:blood*; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D017686:Oncorhynchus mykiss; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D014819:Vitellogenins / Q000187:drug effects / Q000378:metabolism*
D000726:Androgen Antagonists; D011944:Receptors, Androgen; D014819:Vitellogenins; D013196:Dihydrotestosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D004958:Estradiol; D005485:Flutamide; D003577:Cytochrome P-450 Enzyme System