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ToxSci Advance Access published online on March 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi150
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received December 21, 2004
Accepted March 10, 2005

Endocrine Toxicology

Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring

Anne Marie Vinggaard 1*, Sofie Christiansen 1, Peter Laier 1, Mette Erecius Poulsen 2, Vibeke Breinholt 1, Kirsten Jarfelt 1, Helene Jacobsen 1, Majken Dalgaard 1, Christine Nellemann 1, and Ulla Hass 1

1 Danish Institute for Food and Veterinary Research, Dept. of Toxicology and Risk Assessment, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark, Tel.: +45 72347549
2 Department of Chemistry, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark

* To whom correspondence should be addressed.
Anne Marie Vinggaard, E-mail: amv{at}dfvf.dk


  Abstract

Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptor, agonizes the Ah receptor and inhibits aromatase activity. In vivo prochloraz acts antiandrogenic in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing LH levels. The purpose of this study was to investigate reproductive toxic effects after exposure during gestation and lactation to prochloraz alone and a mixture of five pesticides (deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl). Prochloraz (30mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from GD 7 until PND 16. Some dams were taken for caesarean sections at GD 21 and others were allowed to give birth. Results showed that prochloraz and the mixture significantly reduced plasma and testicular testosterone levels in GD 21 male fetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. Chemical analysis of the rat breast milk showed that prochloraz was transferred to the milk. In males a significant increase of nipple retention was found, and the bulbourethral gland weight was decreased, whereas other reproductive organs were unaffected. In addition CYP1A activities in livers were induced by prochloraz, possibly as a result of Ah receptor activation. Behavioral studies showed that the activity level and sweet preference of adult males were significantly increased. Overall these results strongly indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due at least in part to diminished fetal steroidogenesis.

Keywords: prochloraz; pesticide; antiandrogen; feminization; CYP450 activity; behavior.
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