title: Endocrine-disrupting activities in vivo of the fungicides tebuconazole and epoxiconazole.
abstract: The triazole fungicides tebuconazole and epoxiconazole were investigated for reproductive toxic effects after exposure during gestation and lactation. Rats were dosed with epoxiconazole (15 or 50 mg/kg bw/day) or tebuconazole (50 or 100 mg/kg bw/day) during pregnancy from gestational day (GD) 7 and continued during lactation until postnatal day (PND) 16. Some dams were randomly chosen for cesarean section at GD 21 to evaluate effects on sexual differentiation in the fetuses. Other dams delivered normally, and the pups were examined (e.g., anogenital distance [AGD] and hormone levels) at birth, at PND 13 or PND 16, and semen quality was assessed in adults. Both tebuconazole and epoxiconazole affected reproductive development in the offspring after exposure in utero. Both compounds virilized the female offspring as shown by an increased AGD PND 0. Furthermore, tebuconazole had a feminizing effect on male offspring as shown by increased nipple retention. This effect was likely caused by the reduced testosterone levels seen in male fetuses. Tebuconazole increased the testicular concentrations of progesterone and 17alpha-hydroxyprogesterone in male fetuses, indicating a direct impact on the steroid synthesis pathway in the Leydig cells. The high dose of epoxiconazole had marked fetotoxic effects, while the lower dose caused increased birth weights. The increased birth weights may be explained by a marked increase in testosterone levels in dams during gestation. Common features for azole fungicides are that they increase gestational length, virilize female pups, and affect steroid hormone levels in fetuses and/or dams. These effects strongly indicate that one major underlying mechanism for the endocrine-disrupting effects of azole fungicides is disturbance of key enzymes like CYP17 involved in the synthesis of steroid hormones.
authors.affiliation: Department of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860, Søborg, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Taxvig
authors.forename: Ulla
authors.initials: U
authors.lastname: Hass
authors.forename: Marta
authors.initials: M
authors.lastname: Axelstad
authors.forename: Majken
authors.initials: M
authors.lastname: Dalgaard
authors.forename: Julie
authors.initials: J
authors.lastname: Boberg
authors.forename: Helle Raun
authors.initials: HR
authors.lastname: Andeasen
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Vinggaard
mesh_terms: D019326:17-alpha-Hydroxyprogesterone; D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001724:Birth Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity*; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D005836:Genitalia, Female / Q000002:abnormalities / Q000187:drug effects; D007774:Lactation / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D009558:Nipples / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011374:Progesterone; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*; D013076:Sperm Count; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000502:physiology; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013739:Testosterone; D014230:Triazoles / Q000633:toxicity*