ToxSci Advance Access originally published online on March 30, 2007
Toxicological Sciences 2007 99(1):190-202; doi:10.1093/toxsci/kfm069
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Published by Oxford University Press 2007.
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Cumulative Effects of Dibutyl Phthalate and Diethylhexyl Phthalate on Male Rat Reproductive Tract Development: Altered Fetal Steroid Hormones and Genes
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* North Carolina State University, Department of Molecular Biomedical Sciences, Raleigh, North Carolina 27606
U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division (MD-72), Endocrinology Branch, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed. Fax: (919) 541-4017. E-mail: gray.earl{at}epa.gov.
Received February 12, 2007; accepted March 12, 2007
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Abstract |
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Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that coadministered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production, and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague Dawley rats were gavaged on gestation days (GD) 14–18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP + DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production and processed for gene expression by quantitative real-time PCR . The DBP + DEHP dose increased the incidence of many reproductive malformations by 
50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and cyp11a were cumulatively decreased by the DBP + DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose-additive effects when administered as a mixture.
Key Words: endocrine disruptors; developmental toxicity; postnatal; epididymis; RT-PCR; reproductive tract; male; phthalates.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and has been approved for publication. Approval does not necessarily reflect the views and policies of the agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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