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.

Widely Used Pesticides with Previously Unknown Endocrine Activity Revealed as in Vitro Antiandrogens

“…There is insufficient evidence to assess the risk of tested pesticides to human health because of a lack of data. However, to our knowledge, all of the pesticides (with the possible exception of fenitrothion; Okahashi et al 2005;Turner et al 2002) identified as in vitro AR antagonists in our study have also been reported to have anti androgenic effects in vivo in animal models (Anway et al 2006;Gray et al 1999;Lambright et al 2000;McIntyre et al 2002;Ostby et al 1999;Sinha et al 2001;Taxvig et al 2007;Uzumcu et al 2004;Vinggaard et al 2005). We also identified 7 compounds that appeared to be androgenic because they stimulated activity in the absence of DHT.…”

“…These compounds are newly formulated fungicides (dimethomorph, 2007; fludioxonil, 2008; fenhexamid, 2001), which are stable on food commodities (> 70% of the parent compound) and remain unchanged on the commodity when reaching the consumer (EFSA 2007(EFSA , 2010a(EFSA , 2010b. Dimethomorph and fenhexamid belong to the fungicide group of sterol bio synthesis inhibitors (Leroux 2004), as do the in vivo anti androgenic conazoles (e.g., Taxvig et al 2007) and imidazoles (Vinggaard et al 2005). A study of the sterol biosynthesis inhibitors imazalil, propi conazole, triadimefon, triadimenol, and prochloraz indicated that all inhibited aromatase in human placental microsomes (Vinggaard et al 2000), but to our knowledge, effects of dimethomorph and fenhexamid on steroido genesis in mammalian cells have not been assessed.…”

“…Similarly, although the National Health and Nutrition Examination Survey (NHANES) in the United States incorporates human biomonitoring of pesticides, exposure concentrations in human target tissues are very poorly understood, because of the almost complete lack of toxico kinetic data, short half-lives of current use pesticides, unspecific urinary metabolites, and unknown metabolic pathways (see Barr 2008) (Table 1). Linuron and tebuconazole are known in vivo anti androgens (Lambright et al 2000;Taxvig et al 2007); however, data on the other pesticides are much more limited. This is especially true of dimethomorph, fludioxonil, and fenhexamid, for which we were unable to identify previous publications regarding endocrine disruption.…”

“…There is a good correlation between androgen receptor (AR) antagonist properties and in vivo anti androgenic effects, and there is also good evidence that androgen-sensitive end points are demasculinized in male rats when exposed in utero to a wide range of pesticides. Antiandrogenic effects both in vitro and via maternal exposure in vivo have been reported in response to the herbicide linuron Lambright et al 2000); the fungicides prochloraz (Vinggaard et al 2005), procymidone (Ostby et al 1999), tebuconazole (Taxvig et al 2007), and vinclozolin (Anway et al 2006;Uzumcu et al 2004); the organochlorine insecticides DDE ) and endosulfan (Sinha et al 2001); the organophosphate dimethoate (Verma and Mohanty 2009); and the pyrethroid insecticide deltamethrin (Andrade et al 2002). However, with the exception of linuron, dimethoate, deltamethrin, and tebuconazole, the pesticides listed above have not been authorized for use in Europe during the past 5 years, which should result in lower occupational, residential, and dietary exposures.…”

Systemic uptake of miconazole during vaginal suppository use and effect on CYP1A2 and CYP3A4 associated enzyme activities in women

“…The developing foetal and infantile endocrine and reproductive systems are particularly 5 susceptible to endocrine disrupting substances [17,18,19]. Other conazoles which like miconazole, have been reported to inhibit CYP19 and testosterone synthesis in vitro, have been shown to disturb steroid synthesis in rat foetuses after prenatal exposure [20,21].…”