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ToxSci Advance Access originally published online on March 15, 2007
Toxicological Sciences 2007 97(2):512-519; doi:10.1093/toxsci/kfm055
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Published by Oxford University Press 2007.

Sensitivity of Fetal Rat Testicular Steroidogenesis to Maternal Prochloraz Exposure and the Underlying Mechanism of Inhibition

Chad R. Blystone*,{dagger}, Christy S. Lambright{dagger}, Kembra L. Howdeshell{dagger}, Johnathan Furr{dagger}, Robin M. Sternberg*, Brian C. Butterworth{ddagger}, Elizabeth J. Durhan{ddagger}, Elizabeth A. Makynen{ddagger}, Gerald T. Ankley{ddagger}, Vickie S. Wilson{dagger}, Gerald A. LeBlanc* and L. Earl Gray, Jr{dagger},1

* Department of Environmental and Molecular Toxicology, NC State University, Raleigh, North Carolina 27695 {dagger} U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, Research Triangle Park, North Carolina 27711 {ddagger} U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota, 55804

1 To whom correspondence should be addressed. Fax: 919-541-4017. E-mail: gray.earl{at}epa.gov.

Received January 23, 2007; accepted March 12, 2007


  Abstract

The fungicide prochloraz (PCZ) induces malformations in androgen-dependent tissues in male rats when administered during sex differentiation. The sensitivity of fetal testicular steroidogenesis to PCZ was investigated to test the hypothesis that the reported morphological effects from maternal exposure were associated with reduced testosterone synthesis. Pregnant Sprague-Dawley rats were dosed by gavage with 0, 7.8, 15.6, 31.3, 62.5, and 125 mg PCZ/kg/day (n = 8) from gestational day (GD) 14 to 18. On GD 18, the effects of PCZ on fetal steroidogenesis were assessed by measuring hormone production from ex vivo fetal testes after a 3-h incubation. Lastly, PCZ levels in amniotic fluid and maternal serum were measured using liquid chromatography/mass spectroscopy and correlated to the inhibition of steroidogenesis. Fetal progesterone and 17{alpha}-hydroxyprogesterone production levels were increased significantly at every PCZ dose, whereas testosterone levels were significantly decreased only at the two high doses. These results suggest that PCZ inhibits the conversion of progesterone to testosterone through the inhibition of CYP17. To test this hypothesis, PCZ effects on CYP17 gene expression and in vitro CYP17 hydroxylase activity were evaluated. PCZ had no effect on testicular CYP17 mRNA levels as measured by quantitative real-time polymersase chain reaction. However, microsomal CYP17 hydroxylase activity was significantly inhibited by the fungicide (Ki = 865nM). Amniotic fluid PCZ concentrations ranged from 78 to 1512 ppb (207–4014nM) and testosterone production was reduced when PCZ reached ~500 ppb, which compares favorably with the determined CYP17 hydroxylase Ki (326 ppb). These results demonstrate that PCZ lowers testicular testosterone synthesis by inhibiting CYP17 activity which likely contributes to the induced malformations in androgen-dependent tissues of male offspring.

Key Words: prochloraz; testosterone; CYP17; steroidogenesis; fetal testis.

Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, ORD, 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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