Antiandrogenic effects in vitro and in vivo of the fungicide prochloraz.
The commonly used imidazole fungicide prochloraz was tested for antiandrogenic effects in vitro and in vivo. Prochloraz, but not the metabolites 2,4,6-trichlorophenoxyacetic acid or 2,4,6-trichlorophenol, inhibited the R1881-induced response in an androgen receptor reporter gene assay. In the Hershberger assay, prochloraz exposure at all dose levels (50, 100, and 200 mg/kg) given orally to castrated testosterone (T)-treated males markedly reduced weights of ventral prostate, seminal vesicles, musc. levator ani/bulbocavernosus, and bulbourethral gland. These effects were accompanied by an increase in LH and a reduction of the T(4) and TSH level. The effects on seminal vesicles, LH, T(4), and TSH were also evident in intact prochloraz-exposed young adult rats. Body weights were unaffected whereas liver weights were increased in prochloraz-treated animals. Changes in androgen-regulated gene expression were determined in ventral prostates by real-time RT-PCR. A pronounced decrease of ornithin decarboxylase and PBP C3 mRNA levels was observed for both prochloraz and flutamide. These results indicate that prochloraz antagonizes the peripheral androgen receptors resulting in decreased growth of androgen-dependent tissues and that it antagonizes central androgen receptors blocking the negative feed-back mechanism of testosterone resulting in increased LH secretion from the pituitary. The antiandrogenic effects of prochloraz were in many ways qualitatively comparable, although weaker, to the effects of flutamide. However, differential effects on levels of FSH, T(4), and TSH indicate that other modes of action apart from the pure AR antagonism might play a role in vivo.
Vinggaard
Anne Marie
AM
Institute of Food Safety and Nutrition, Danish Veterinary and Food Administration, Mørkhøj Bygade 19, Dk-2860 Søborg, Denmark. amv@fdir.dk
Nellemann
Christine
C
Dalgaard
Majken
M
Jørgensen
Eva Bonefeld
EB
Andersen
Helle Raun
HR
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005485:Flutamide / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects; D005837:Genitalia, Male / Q000187:drug effects / Q000254:growth & development; D007093:Imidazoles / Q000633:toxicity*; D007150:Immunohistochemistry; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000235:genetics; D013739:Testosterone / Q000494:pharmacology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D018076:DNA, Complementary; D005659:Fungicides, Industrial; D007093:Imidazoles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013739:Testosterone; D005485:Flutamide; D007986:Luteinizing Hormone; D013972:Thyrotropin; C045362:prochloraz; D009955:Ornithine Decarboxylase; D013974:Thyroxine