You are here:
Inhibition of Rat and Human Steroidogenesis by Triazole Antifungals
Citation:
GOETZ, A., J. C. ROCKETT, H. REN, I. THILLAINADARAJAH, AND D. J. DIX. Inhibition of Rat and Human Steroidogenesis by Triazole Antifungals. Systems Biology in Reproductive Medicine. Informa Healthcare USA, New York, NY, 55(5-6):214-26, (2009).
Impact/Purpose:
In summary, triadimefon, myclobutanil and propiconazole show weak inhibition of testosterone production in vitro in rat testis cultures, and the hormone data suggests inhibition of CYP17A1. However, in vivo triadimefon increased rat testis testosterone production and serum 16 testosterone levels. The mechanism of action for increased testis testosterone levels in vivo is unresolved, but may possibly involve a disruption of the HPG axis. Further studies into the effects of triadimefon and other triazoles on the pituitary, hypothalamus, testis, and steroidogenesis will be needed to fully elucidate the dose-response of mechanisms relevant to human health risk assessments.
Description:
Environmental chemicals that alter steroid production could interfere with male reproductive development and function. Three agricultural antifungal triazoles (myclobutanil, propiconazole and triadimefon) that are known to modulate expression of cytochrome P450 (CYP) genes and enzymatic activities were tested for effects on steroidogenesis in rat and human 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 μM 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 adenocarcima) cell line. Following 48 hour exposure to myclobutanil, propiconazole or triadimefon at 1, 3, 10, 30, or 100 μM, 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 very high concentrations in vitro, operating on a model system without neuroendocrine control, as is the case in vivo.
