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ToxSci Advance Access published online on May 12, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh169
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received March 19, 2004
Accepted May 5, 2004

Endocrine Toxicology

Dose-Dependent Alterations in Gene Expression and Testosterone Synthesis in the Fetal Testes of Male Rats Exposed to Di (n-Butyl) Phthalate

Kim P. Lehmann 1, Suzanne Phillips 1, Madhabananda Sar 1, Paul M. D. Foster 1, Kevin W. Gaido 1*

1 CIIT Centers for Health Research, Research Triangle Park, NC 27709

* To whom correspondence should be addressed. E-mail: gaido{at}ciit.org.


  Abstract

Exposure to di (n-butyl) phthalate (DBP) in utero impairs development of the male rat reproductive tract. The adverse effects are due in part to a coordinated decrease in expression of genes involved in cholesterol transport and steroidogenesis with a resultant reduction in testosterone production in the fetal testis. To determine the dose-response relationship for the effect of DBP on steroidogenesis in fetal rat testes, pregnant Sprague-Dawley rats received corn oil (vehicle control) or DBP (0.1, 1.0, 10, 50, 100, or 500 mg/kg/day) by gavage daily from gestation day (gd) 12 to 19. Testes were isolated on gd 19, and changes in gene and protein expression were quantified by RT-PCR and Western analysis. Fetal testicular testosterone concentration was determined by radioimmunoassay. DBP exposure resulted in significant dose-dependent reductions in mRNA and protein concentration of scavenger receptor, steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage, 3{beta}-hydroxysteroid dehydrogenase, and cytochrome P450c17. Testicular testosterone was reduced at doses of 50 mg/kg/day and above. Whole-testis expression of peripheral benzodiazepine receptor (PBR) mRNA, which functions with StAR to transport cholesterol across the mitochondrial membrane, was up-regulated following exposure to DBP at 500 mg/kg/day. By immunocytochemistry however, PBR protein was reduced in interstitial cells and also expressed but not reduced in gonocytes. Our results demonstrate a coordinate, dose-dependent reduction in expression of key genes and proteins involved in cholesterol transport and steroidogenesis and a corresponding reduction in testosterone in fetal testes following maternal exposure to DBP at dose levels below which adverse effects are detected in the developing male reproductive tract. Alterations in gene and protein expression and testosterone synthesis may serve as sensitive indicators of testicular response to DBP.

Key Words: phthalate di (n-butyl), in utero exposure, male reproductive development, antiandrogen, molecular mechanisms, androgen receptor, dose response, steroidogenesis .


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