Inhibition of rat and human steroidogenesis by triazole antifungals.
Environmental chemicals that alter steroid production could interfere with male reproductive development and function. Three agricultural antifungal triazoles that are known to modulate expression of cytochrome P450 (CYP) genes and enzymatic activities were tested for effects on steroidogenesis using rat in vivo (triadimefon), rat in vitro (myclobutanil and triadimefon), and human in vitro (myclobutanil, propiconazole, and triadimefon) model systems. Hormone production was measured in testis organ cultures from untreated adult and neonatal rats, following in vitro exposure to 1, 10, or 100 muM of myclobutanil or triadimefon. Myclobutanil and triadimefon reduced media levels of testosterone by 40-68% in the adult and neonatal testis culture, and altered steroid production in a manner that indicated CYP17-hydroxylase/17,20 lyase (CYP17A1) inhibition at the highest concentration tested. Rat to human comparison was explored using the H295R (human adrenal adenocarcinoma) cell line. Following 48 h exposure to myclobutanil, propiconazole, or triadimefon at 1, 3, 10, 30, or 100 muM, there was an overall decrease in estradiol, progesterone, and testosterone by all three triazoles. These data indicate that myclobutanil, propiconazole, and triadimefon are weak inhibitors of testosterone production in vitro. However, in vivo exposure of rats to triazoles resulted in increased serum and intra-testicular testosterone levels. This discordance could be due to higher concentrations of triazoles tested in vitro, and differences within an in vitro model system lacking hepatic metabolism and neuroendocrine control.
Goetz
Amber K
AK
Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Rockett
John C
JC
Ren
Hongzu
H
Thillainadarajah
Inthirany
I
Dix
David J
DJ
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D013739:Testosterone / Q000096:biosynthesis; D014230:Triazoles / Q000494:pharmacology*
D000935:Antifungal Agents; D009570:Nitriles; D013256:Steroids; D014230:Triazoles; C045950:propiconazole; C032910:triadimefon; D013739:Testosterone; C446685:systhane; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase