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ToxSci Advance Access originally published online on March 23, 2005
Toxicological Sciences 2005 85(2):886-897; doi:10.1093/toxsci/kfi150
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Toxicological Sciences vol. 85 no. 2 © 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

Perinatal Exposure to the Fungicide Prochloraz Feminizes the Male Rat Offspring

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

* Department of Toxicology and Risk Assessment, Danish Institute for Food and Veterinary Research, DK-2860 Søborg, Denmark; {dagger} Department of Chemistry, Danish Institute for Food and Veterinary Research, DK-2860 Søborg, Denmark

Received December 21, 2004; accepted March 10, 2005

Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptors, agonizes the Ah receptor, and inhibits aromatase activity. In vivo prochloraz acts antiandrogenically in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing luteinizing hormone (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 (30 mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from gestational day (GD) 7 until postnatal day (PND) 16. Some dams were taken for cesarean section 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 cytochrome P450 (CYP)1A 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.

Key Words: prochloraz; pesticide; antiandrogen; feminization; cytochrome P450 activity; behavior.


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