Disruption of Testosterone Homeostasis as a Mode of Action for the Reproductive Toxicity of Triazole Fungicides in the Male Rat

Abstract

Triazole fungicides associated with a range of reported male reproductive effects in experimental animals were selected to assess potential toxic modes of action. Wistar Han rats were fed myclobutanil (M: 100, 500, or 2000 ppm), propiconazole (P: 100, 500, or 2500 ppm), or triadimefon (T: 100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 120. One male per litter was necropsied on PND1, 22, 50, or 92. Measurements included anogenital distance (AGD) at PND0, body and organ weights, serum hormone levels, age at preputial separation (PPS), sperm morphology and motility, and fertility and fecundity. AGD was increased by the high dose of all three triazoles, indicating hypervirilization. Triadimefon delayed PPS, consistent with delayed puberty, at 1800 ppm. Relative liver weights were increased at PND1, 50, and 92 by all three triazoles. Hepatocellular hypertrophy was present at PND50 from propiconazole and triadimefon and at PND92 from all three high-dose triazole treatments. Relative pituitary weights were decreased at PND92 by middle- and high-dose myclobutanil treatment. Absolute testis weights were increased at PND1 by myclobutanil, at PND22 by myclobutanil and triadimefon, and at PND50 by propiconazole and triadimefon treatment. Relative ventral prostate weights were increased at PND92 by myclobutanil and triadimefon treatment. Serum testosterone was increased at PND50 by triadimefon and at PND92/99 by all three triazole treatments. Insemination and fertility were impaired by myclobutanil and triadimefon treatment. In addition to the reproductive system effects, total serum thyroxine levels were decreased at PND92 by high-dose triadimefon. These reproductive effects are consistent with the disruption of testosterone homeostasis as a key event in the mode of action for triazole-induced reproductive toxicity.

Zebrafish as an Alternative Vertebrate Model for Investigating Developmental Toxicity—The Triadimefon Example

“…In rodents, triadimefon causes hepatocyte hypertrophy in a dose dependent manner [8] whereas in rats it has been found to act as a thyroid tumorigen [9]. In addition, triadimefon treated rats exhibited reduced fertility and decrease in size in two generation reproduction studies [10]. It has also be shown to elicit a neurotoxic syndrome in rats characterized by increased motor activity [11].…”

Tebuconazole disrupts steroidogenesis in Xenopus laevis

“…The capacity of azole fungicides to cause endocrine disruption has been demonstrated (Brande-Lavridsen et al, 2008;Goetz et al, 2007;Jacobsen et al, 2012;Kjaerstad et al, 2010;Mnif et al, 2011;Taxvig et al, 2007;Yu et al, 2013). These fungicides inhibit fungal growth by specifically inhibiting the cytochrome P450-mediated C 14 ␣-de-methylation step in the biosynthesis of ergosterol, a biomolecule unique in fungi.…”

A Review on Microextraction Techniques for Selected Triazole Fungicides Determination in Water and Food Samples

“…Many studies have been carried out concerning these pesticides effects in animals. Tumorigenic effects [4], endocrine disrupting effects [5] and disturbances in reproductive systems have been shown in rats [6]. Those fungicides can also induce some tumors in mice livers [7].…”