Endocrine‐disrupting properties in vivo of widely used azole fungicides

Abstract

The endocrine-disrupting potential of four commonly used azole fungicides, propiconazole, tebuconazole, epoxiconazole and ketoconazole, were tested in two short-term in vivo studies. Initially, the antiandrogenic effects of propiconazole and tebuconazole (50, 100 and 150 mg/kg body weight/day each) were examined in the Hershberger assay. In the second study, pregnant Wistar rats were dosed with propiconazole, tebuconazole, epoxiconazole or ketoconazole (50 mg/kg/day each) from gestational day (GD) 7 to GD 21. Caesarian sections were performed on dams at GD 21. Tebuconazole and propiconazole demonstrated no antiandrogenic effects at doses between 50 and 150 mg/kg body weight/day in the Hershberger assay. In the in utero exposure toxicity study, ketoconazole, a pharmaceutical to treat human fungal infections, decreased anogenital distance and reduced testicular testosterone levels, demonstrating a demasculinizing effect on male fetuses. Tebuconazole, epoxiconazole and ketoconazole induced a high-frequency of post-implantation loss, and both ketoconazole and epoxiconazole caused a marked increase in late and very late resorptions. Overall the results show that many of the commonly used azole fungicides act as endocrine disruptors in vivo, although the profile of action in vivo varies. As ketoconazole is known to implicate numerous endocrine-disrupting effects in humans, the concern for the effects of the other tested azole fungicides in humans is growing.

Predictive value of cell assays for developmental toxicity and embryotoxicity of conazole fungicides

“…Taxvig et al (2007Taxvig et al ( , 2008 found that epoxiconazole had several adverse embryotoxic outcomes such as increased post-implantation loss and late resorptions in Wistar rats (tab. 2).…”

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

“…Besides concerns over the influence of agricultural azoles on resistance development in the clinic, concern has arisen in Europe over endocrine disruption effects of agricultural azoles in mammals (23,24) and the hepatotoxicity of these fungicides (25). Azole antifungals cause hepatotoxicity by inducing the expression of liver cytochrome P450 enzymes (CYP1, CYP2, and CYP3 families), which in turn increases the abundance of reactive oxygen species in liver cells, resulting in lipid peroxidation and DNA damage (25).…”

“…Disruption of the endocrine system can lead to impaired reproduction, alterations in sexual differentiation, impaired growth and development, and the formation of hormone-dependent cancers (24). Ketoconazole causes the demasculinizing of male fetuses in rats (23) and decreased levels of testosterone and cortisol in the plasma of humans (29,30), leading to gynecomastia and oligospermia in men and menstrual irregularities in women (31). Azole antifungals disrupt the endocrine system by inhibiting several highly substrate-selective cytochrome P450 enzymes involved in mammalian steroid hormone biosynthesis (24).…”

Simultaneous determination of 24 personal care products in fish muscle and liver tissues using QuEChERS extraction coupled with ultra pressure liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometer analyses

“…Although biocides, synthetic musks, Electronic supplementary material The online version of this article (doi:10.1007/s00216-016-9924-y) contains supplementary material, which is available to authorized users. and benzotriazoles show weak acute toxicity to aquatic organisms, their chronic toxicity and endocrine-disrupting effects cannot be neglected [15,16], such as pathological damage to tissues [17], estrogenic activities [18], and anti-estrogenic effect [19].…”