Pesticides Research No. 111 2007 – Effects of azole fungicides on the function of sex and thyroid hormones

Effects of azole fungicides on the function of sex and thyroid hormones

5 Conclusion

The main objective of this study was to investigate endocrine disrupting mechanisms and effects of three frequently used triazole fungicides: tebuconazole, propiconazole and epoxiconazole. The background for the study was our previous findings on the imidazole fungicide, prochloraz, which was demonstrated to possess multiple endocrine disrupting mechanisms, to be anti-androgenic in adult male rats, and to disturb reproductive development in the offspring after perinatal exposure.

Overall the results from this study reveal that also other azole fungicides have the abilities to act as endocrine disruptors via a range of different mechanisms. The affinities of tebuconazole, propiconazole, and epoxiconazole for the ER and AhR were less than for prochloraz while the affinities for the AR were similar. Like prochloraz, all three triazoles caused enhanced production of progesterone and reduced synthesis of testosterone and estradiol in vitro in the human adrenocortical carcinoma cell line H295R. Neither prochloraz nor the three triazoles showed convincing interactions with TR. Whether the differences in potencies between prochloraz and the triazole fungicides in some of the in vitro assays are due to the triazole ring compared to the imidazole ring and/or related to the number and placement of halogens in the phenyl ring cannot be concluded from the data in this study.

Unlike prochloraz, tebuconazole and propiconazole did not induce anti-androgenic effects in vivo in adult male rats in the Hershberger assay. However, tebuconazole and epoxiconazole were capable of inducing effects on reproductive development in the offspring after perinatal exposure. Both compounds caused an increased gestational length and virilization of the female offspring evidenced by increased AGD and the effects resemble those previously observed for prochloraz. Like prochloraz, male offspring was feminized by tebuconazole evidenced by increased retention of nipples and reduced testosterone concentration in fetal testis. The effect of tebuconazole on AGD was less than for prochloraz and at birth AGD was not statistically significant shorter than controls. No feminizing effect on male offspring was seen for epoxiconazole. It appeared to be a potent fetotoxic compound and dams dosed with 50 mg/kg were in general unable to deliver their pups. A growth promoting effect on pups was seen with the lowest dose (increased birth weight, increased AGD) which may be related to the marked up-regulation of testosterone levels in the dams.

Overall the profile of action in vitro of the four azole fungicides was relatively similar (except for the AhR response). However, the profile of action in vivo in the developmental toxicity studies varied. Tebuconazole possess a more classical endocrine disrupting effect on male pups like the one seen for prochloraz (increased nipple retention, reduced fetal testosterone and increased progesterone). However, epoxiconazole is first of all markedly fetotoxic and secondly it causes altered sex hormone levels in the dams but not in the fetuses. The common features for all three fungicides are the increased gestational length and the virilizing effect on female pups. The lack of effect from the triazoles in the Hershberger assay, the effect on steroid hormone synthesis in the in vitro assay combined with the enhanced maternal plasma concentration of progesterone and the decreased fetal testicular concentration of testosterone after exposure of pregnant rats strongly indicate that interference with key-enzymes involved in steroid hormone synthesis is one of the major mechanism behind the developmental effects in the offspring.