ToxSci Advance Access originally published online on January 18, 2007
Toxicological Sciences 2007 97(1):65-74; doi:10.1093/toxsci/kfm004
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Published by Oxford University Press 2007.
Prochloraz Inhibits Testosterone Production at Dosages below Those that Affect Androgen-Dependent Organ Weights or the Onset of Puberty in the Male Sprague Dawley Rat
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* Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695
Reproductive Toxicology Division, Endocrinology Branch, National Human and Environmental Effects Research Laboratories, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599
1 To whom correspondence should be addressed at Reproductive Toxicology Division, Endocrinology Branch, MD-72, National Human and Environmental Effects Research Laboratories, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-4017. E-mail: gray.earl{at}epa.gov.
Received January 3, 2007; accepted January 10, 2007
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Abstract |
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Prochloraz (PCZ) is an imidazole fungicide that inhibits gonadal steroidogenesis and antagonizes the androgen receptor (AR). We hypothesized that pubertal exposure to PCZ would reduce testosterone production and delay male rat reproductive development. Sprague Dawley rats were dosed by gavage with 0, 31.3, 62.5, or 125 mg/kg/day of PCZ from postnatal day (PND) 23 to 42 or 51. There was a significant delay in preputial separation (PPS) at 125 mg/kg/day PCZ and several of the androgen-dependent organ weights were decreased significantly, but the significant organ weight effects were not consistent between the 2 necropsies (PND 42 vs. 51). At both ages, serum testosterone levels and ex vivo testosterone release from the testis were significantly decreased whereas serum progesterone and 17
-hydroxyprogesterone levels were significantly increased at dose levels below those that affected PPS or reproductive organ weights. The hormone results suggested that PCZ was inhibiting CYP17 activity. In a second pubertal study (0, 3.9, 7.8, 15.6, 31.3, or 62.5 mg/kg/day PCZ), serum testosterone levels and ex vivo testosterone production were significantly reduced at 15.6 mg/kg/day PCZ. In order to examine the AR antagonism effects of PCZ, independent of its effects on testosterone synthesis, castrated immature male rats were dosed with androgen and 0, 15.6, 31.3, 62.5, or 125 mg/kg/day PCZ for 10–11 days (Hershberger assay). In this assay, androgen-sensitive organ weights were only significantly decreased at 125 mg/kg/day PCZ. These data from the pubertal assays demonstrate that PCZ decreases testosterone levels and delays rat pubertal development, as hypothesized. However, the fact that hormone levels were affected at dosage eightfold below that which delayed the onset of puberty suggests that rather large reductions in serum testosterone may be required to delay puberty and consistently reduce androgen-dependent tissue weights.
Key Words: prochloraz; testosterone; antiandrogen; puberty; Hershberger; steroidgenesis.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, Office of Research and Development, and U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does the mention of trade names or commercial products constitute endorsement or recommendation for use.
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