ToxSci Advance Access originally published online on April 13, 2005
Toxicological Sciences 2005 86(1):161-174; doi:10.1093/toxsci/kfi172
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Published by Oxford University Press 2005.
Altered Gene Expression During Rat Wolffian Duct Development following Di(n-Butyl) Phthalate Exposure
CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709
Received March 3, 2005; accepted April 8, 2005
Di(n-butyl) phthalate (DBP) is a common plasticizer and solvent that disrupts androgen-dependent male reproductive development in rats. In utero exposure to 500 mg/kg/day DBP on gestation days (GD) 12 to 21 decreases androgen biosynthetic 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.
Key Words: antiandrogen; male reproductive development; phthalate; di(n-butyl); Wolffian duct; epididymis; insulin-like growth factor.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Tomaszewski, A. Joseph, D. Archambeault, and H. H.-C. Yao Essential roles of inhibin beta A in mouse epididymal coiling PNAS, July 3, 2007; 104(27): 11322 - 11327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Welsh, P. T. K. Saunders, N. I. Marchetti, and R. M. Sharpe Androgen-Dependent Mechanisms of Wolffian Duct Development and Their Perturbation by Flutamide Endocrinology, October 1, 2006; 147(10): 4820 - 4830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. David Proposed Mode of Action for In Utero Effects of Some Phthalate Esters on the Developing Male Reproductive Tract Toxicol Pathol, April 1, 2006; 34(3): 209 - 219. [Abstract] [PDF]
|
|