Antiandrogenic effects in short-term in vivo studies of the fungicide fenarimol.
The fungicide fenarimol has estrogenic and antiandrogenic activity and inhibits aromatase activity in vitro. We tested, whether fenarimol had antiandrogenic effects in vivo. In a Hershberger assay, fenarimol given orally to castrated testosterone-treated male rats caused markedly reduced weights of ventral prostate, seminal vesicles, musc. levator ani/bulbocavernosus, and bulbourethral glands. Qualitatively similar, but weaker, effects were also evident in intact fenarimol-exposed young adult males, except that prostates were not significantly affected. Changes in androgen-regulated gene expression were determined by real-time RT-PCR in ventral prostates and fenarimol caused a pronounced decrease of prostate binding protein C3 (PBP C3), ornithin decarboxylase (ODC), and insulin-like-growth factor 1 (IGF-1) mRNA levels. The antiandogenic drug flutamide, included as a positive control, caused down-regulation of PBP C3 mRNA and up-regulation of TRPM-2 mRNA levels. Serum T4 levels were reduced after fenarimol treatment and a tendency towards increased LH levels was seen. However, no effects on testosterone levels or testosterone production ex vivo could be revealed. Taken together these results indicate that fenarimol acts as an antiandrogen in vivo having effects qualitatively comparable to those of flutamide on organ level, whereas differential effects on gene expression were observed. In an additional Hershberger test, the effects of fenarimol were compared to those of estradiol benzoate, prochloraz and the aromatase inhibitor fadrozole. The data indicate a similar mode of action of fenarimol and prochloraz in the males, whereas no indications were found that the estrogenic or aromatase inhibitory properties had important impact on the effects observed in the males. Thus, it is suggested that fenarimol mediates its antiandrogenic effects at least partly via antagonism of androgen receptors.
Vinggaard
Anne Marie
AM
Department of Toxicology and Risk Assessment, Danish Institute for Food and Veterinary Research, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark. amv@dfvf.dk
Jacobsen
Helene
H
Metzdorff
Stine Broeng
SB
Andersen
Helle Raun
HR
Nellemann
Christine
C
D000726:Androgen Antagonists / Q000633:toxicity*; D000727:Androgen-Binding Protein / Q000235:genetics; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D002369:Castration; D006224:Cricetinae; D003412:Cricetulus; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005659:Fungicides, Industrial / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000235:genetics; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D060789:Prostatein; D011743:Pyrimidines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism*; D060765:Secretoglobins; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D043343:Testosterone Propionate / Q000494:pharmacology; D014598:Uteroglobin; D060788:Mammaglobin B
D000726:Androgen Antagonists; D000727:Androgen-Binding Protein; D000728:Androgens; D005659:Fungicides, Industrial; D007334:Insulin-Like Growth Factor I; D009955:Ornithine Decarboxylase; D060789:Prostatein; D011743:Pyrimidines; D012333:RNA, Messenger; D011944:Receptors, Androgen; D060765:Secretoglobins; D043343:Testosterone Propionate; D014598:Uteroglobin; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C033789:fenarimol; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B