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ToxSci Advance Access published online on October 3, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl124
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Published by Oxford University Press 2006.
Received September 6, 2006
Accepted September 29, 2006

Reproductive and Developmental Toxicology

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

Amber K. Goetz 1, Hongzu Ren 2, Judith E. Schmid 2, Chad R. Blystone 3, Inthirany Thillainadarajah 2, Deborah S. Best 2, Harriette P. Nichols 2, Lillian F. Strader 2, Douglas C. Wolf 2, Michael G. Narotsky 2, John C. Rockett 2, and David J. Dix 4 *

1 Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695, USA; National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
2 National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
3 Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695, USA; National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
4 National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA

* To whom correspondence should be addressed.
David J. Dix, E-mail: dix.david{at}epa.gov


  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 (100, 500, or 2000 ppm), propiconazole (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.

Keywords: myclobutanil; propiconazole; triadimefon; development; steroidogenesis.
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