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ToxSci Advance Access published online on March 30, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm069
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Published by Oxford University Press 2007.

Cumulative Effects of dibutyl phthalate and diethylhexyl phthalate on Male Rat Reproductive Tract Development: Altered Fetal Steroid Hormones and Genes

Kembra L. Howdeshell*,{dagger}, Johnathan Furr{dagger}, Christy R. Lambright{dagger}, Cynthia V. Rider*, Vickie S. Wilson{dagger} and L. Earl Gray, Jr{dagger}

* North Carolina State University, Department of Molecular Biomedical Sciences, Raleigh, NC 27606 {dagger} U. S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, Endocrinology Branch, Research Triangle Park, North Carolina 27711

Correspondence and reprint requests: L. Earl Gray, Jr, US EPA, NHEERL, RTD (MD-72), Research Triangle Park, NC 27711, Phone: (919) 541-7750, Fax: (919) 541-4017, Email: gray.earl{at}epa.gov

Received February 12, 2007; revision received March 2, 2007; accepted March 12, 2007


  Abstract

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 co-administered 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 (SD) 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 qrt-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.

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.

Grant support: KLH was funded by the NCSU/US EPA Cooperative Training program in Environmental Sciences Research, Training Agreement CT826512010 with North Carolina State University during this project.


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