Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals.
Widely used conazole antifungals were tested for endocrine disruptive effects using a panel of in vitro assays. They all showed endocrine disrupting potential and ability to act via several different mechanisms. Overall the imidazoles (econazole, ketoconazole, miconazole, prochloraz) were more potent than the triazoles (epoxiconazole, propiconazole, tebuconazole). The critical mechanism seems to be disturbance of steroid biosynthesis. In the H295R cell assay, the conazoles decreased the formation of estradiol and testosterone, and increased the concentration of progesterone, indicating inhibition of enzymes involved in the conversion of progesterone to testosterone. Prochloraz was most potent followed by econazole~miconazole>ketoconazole>tebuconazole>epoxiconazole>propiconazole. In the MCF-7 cell proliferation assay, the conazoles showed anti-estrogenic effect, including aromatase inhibition, since they inhibited the response induced by both 17β-estradiol (miconazole>econazole~ketoconazole>prochloraz>tebuconazole>epoxiconazole>propiconazole) and testosterone (econazole>miconazole>prochloraz>ketoconazole>tebuconazole>epoxiconazole>propiconazole). The triazoles were anti-androgenic in an androgen receptor reporter gene assay (epoxiconazole∼tebuconazole>propiconazole). This effect could not be evaluated for the pharmaceutical imidazoles due to cytotoxicity.
Kjærstad
Mia B
MB
Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, JB Winsløwsvej 17, Odense C, Denmark.
Taxvig
Camilla
C
Nellemann
Christine
C
Vinggaard
Anne Marie
AM
Andersen
Helle R
HR
D059002:Androgen Receptor Antagonists / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D065729:Cytochrome P-450 CYP2C9; D052244:Endocrine Disruptors / Q000633:toxicity*; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000633:toxicity; D005659:Fungicides, Industrial / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D011374:Progesterone / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014230:Triazoles / Q000633:toxicity*
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000935:Antifungal Agents; D047072:Aromatase Inhibitors; D052244:Endocrine Disruptors; D004965:Estrogen Antagonists; D005659:Fungicides, Industrial; D007093:Imidazoles; D011944:Receptors, Androgen; D014230:Triazoles; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases