Disruption of testosterone homeostasis as a mode of action for the reproductive toxicity of triazole fungicides in the male rat

Triazole function 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) 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 pereputial seperatin (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, consistant with delayed puberty, at 1800 ppm. Relative liver weights were increased at PND1, 50 and 92 by all three triazoles. Heptocellular 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, at PND22 by myclobutanil and traidimefon, and at PND50 by propiconazole and traidimefon 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 consistant with the disruption of testosterone homeostasis as a key event in the mode of action for traizole-induced reproductive toxicity.