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ToxSci Advance Access published online on May 18, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi202
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Published by Oxford University Press 2005.
Received March 30, 2005
Accepted May 6, 2005

Environmental Toxicology

Effects of two fungicides with multiple modes of action on reproductive endocrine function in the fathead minnow (Pimephales promelas)

Gerald T. Ankley 1*, Kathleen M. Jensen 1, Elizabeth J. Durhan 1, Elizabeth A. Makynen 1, Brian C. Butterworth 1, Michael D. Kahl 1, Daniel L. Villeneuve 1, Ann Linnum 1, L. Earl Gray 2, Mary Cardon 2, and Vickie S. Wilson 2

1 U.S. Environmental Protection Agency, ORD, NHEERL, Mid-Continent Ecology Division, 6201 Congdon Boulevard, Duluth, MN 55804 USA
2 U.S. Environmental Protection Agency, ORD, NHEERL, Reproductive Toxicology Division, RTP, NC 27711 USA

* To whom correspondence should be addressed.
Gerald T. Ankley, E-mail: ankley.gerald{at}epa.gov


  Abstract

Many chemicals that adversely affect reproduction and/or development do so through multiple pathways within the reproductive tract and hypothalamic-pituitary-gonadal axis. Notable in this regard are fungicides, such as prochloraz or fenarimol, which in mammals have the potential to impact endocrine function through inhibition of CYP enzymes involved in steroid metabolism as well as through antagonism of the androgen receptor(s). The objective of our studies was to assess the effects of prochloraz and fenarimol on reproductive endocrine function in a model small fish species, the fathead minnow (Pimephales promelas), using both in vitro and in vivo assays. The two fungicides inhibited in vitro CYP19 aromatase activity in brain and ovarian homogenates from the fish, with prochloraz exhibiting a greater potency than fenarimol. Prochloraz and fenarimol also bound competitively to the cloned fathead minnow androgen receptor expressed in COS-1 cells. The two fungicides significantly reduced fecundity of the fish in a 21-d reproduction assay at water concentrations of 0.1 (prochloraz) and 1.0 (fenarimol) mg/L. The in vivo effects of prochloraz on plasma steroid (17{beta}-estradiol, testosterone, 11- ketotestosterone) and vitellogenin (an estrogen-responsive protein) concentrations, as well as gonadal histopathology, were consistent with inhibition of steroidogenesis. Fenarimol also affected several aspects of endocrine function in vivo; however, the suite of observed effects did not reflect either aromatase inhibition or androgen receptor antagonism. These studies contribute to a better mechanistic understanding of the extrapolation of effects of endocrine-disrupting chemicals across vertebrate classes.

Keywords: Fathead minnow; prochloraz; fenarimol; reproductive toxicity.
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