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ToxSci Advance Access first published online on April 13, 2005
This version published online on May 27, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi172
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Published by Oxford University Press 2005.
Received March 3, 2005
Accepted April 8, 2005

Reproductive and Developmental Toxicology

Altered gene expression during rat Wolffian duct development following di(n-butyl) phthalate exposure

Christopher J. Bowman 1*, Katie J. Turner 2, Madhabananda Sar 3, Norman J. Barlow 4, Kevin W. Gaido 3, and Paul M. D. Foster 5

1 CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA, 27709; Current address: WIL Research Laboratories, Ashland, Ohio, USA, 44805
2 CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA, 27709; Current address: Merck Research Laboratories, West Point, Pennsylvania, USA, 19486
3 CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA, 27709
4 CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA, 27709; Current address: Sanofi-Aventis, Bridgewater, New Jersey, USA, 08807
5 CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA, 27709; Current address: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA, 27709

* To whom correspondence should be addressed.
Christopher J. Bowman, E-mail: cbowman{at}wilresearch.com


  Abstract

Di(n-butyl) phthalate (DBP) is a common plasticizer and solvent that disrupts androgendependent male reproductive development in rats. In utero exposure to 500 mg/kg/day DBP on gestation days (GD) 12 to 21 decreases androgen biosythetic enzymes, resulting in decreased fetal testicular testosterone levels. One consequence of prenatal DBP exposure is malformed epididymides in adult rats. Reduced fetal testosterone levels may be responsible for the malformation since testosterone is required for Wolffian duct stabilization and their development into epididymides. Currently, little is understood about the molecular mechanisms of Wolffian duct differentiation. The objective of this study was to identify changes in gene expression associated with altered morphology of the proximal Wolffian duct following in utero exposure to DBP. Pregnant Crl:CD®(SD) rats were gavaged with corn oil vehicle or 500 mg/kg/day DBP from GD 12 to GD 19 or 21. There were only small morphological differences between control and DBP-exposed Wolffian ducts on GD 19. On GD 21, 89% of male fetuses in the DBP dose group showed marked underdevelopment of Wolffian ducts, characterized by decreased coiling. RNA was isolated from Wolffian ducts on GD 19 and 21. Together with empirical information, cDNA microarrays were used to help identify candidate genes that could be associated with the morphological changes observed on GD 21. These candidate genes were analyzed by real-time RT-PCR. Changes in mRNA expression were observed in genes within the insulin-like growth factor (IGF) pathway, the matrix metalloproteinase (MMP) family, the extracellular matrix, and in other developmentally conserved signaling pathways. On GD 19, immunolocalization of IGF-1 receptor protein demonstrated an increase in cytoplasmic expression in the mesenchymal and epithelial cells. There was also a variable decrease in androgen receptor protein in ductal epithelial cells on GD 19. This study provides insight into the effects of antiandrogens on the molecular mechanisms involved in Wolffian duct development. The altered morphology and changes in gene expression following DBP exposure are suggestive of altered paracrine interactions between ductal epithelial cells and the surrounding mesenchyme during Wolffian duct differentiation due to lowered testosterone production.

Keywords: antiandrogen; male reproductive development; phthalate; di(n-butyl); Wolffian duct; epididymis; insulin-like growth factor.
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