ToxSci Advance Access originally published online on April 14, 2008
Toxicological Sciences 2008 105(1):153-165; doi:10.1093/toxsci/kfn077
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Published by Oxford University Press 2008.
A Mixture of Five Phthalate Esters Inhibits Fetal Testicular Testosterone Production in the Sprague-Dawley Rat in a Cumulative, Dose-Additive Manner
* Reproductive Toxicology Division, NHEERL, ORD, United States Environmental Protection Agency (USEPA), Research Triangle Park, North Carolina, 27711
Department of Molecular Biosciences, North Carolina State University/US EPA Cooperative Training Program (Grant CT82651210), Raleigh, North Carolina, 27606
1 To whom correspondence should be addressed at US EPA, NHEERL, RTD (MD-72), Research Triangle Park, NC 27711. Fax: (919) 541-4017. E-mail: Gray.earl{at}epa.gov.
Received February 14, 2008; accepted April 8, 2008
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Abstract |
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Phthalate diesters are chemicals to which humans are ubiquitously exposed. Exposure to certain phthalates during sexual differentiation causes reproductive tract malformations in male rats. In the fetal rat, exposure to the phthalates benzylbutyl phthalate (BBP), di(n)butyl phthalate (DBP), and diethylhexyl phthalate (DEHP) decreases testicular testosterone production and insulin-like 3 hormone mRNA levels. We characterized the dose-response effects of six individual phthalates (BBP, DBP, DEHP, diethyl phthalate [DEP], diisobutyl phthalate [DiBP], and dipentyl phthalate [DPP]) on gestation day (GD) 18 testicular testosterone production following exposure of Sprague-Dawley rats on GD 8–18. BBP, DBP, DEHP, and DiBP were equipotent (ED50 of 440 ± 16 mg/kg/day), DPP was about threefold more potent (ED50 = 130 mg/kg/day) and DEP had no effect on fetal testosterone production. We hypothesized that coadministration of these five antiandrogenic phthalates would reduce testosterone production in a dose-additive fashion because they act via a common mode of toxicity. In a second study, dams were dosed at 100, 80, 60, 40, 20, 10, 5, or 0% of the mixture. The top dose contained 1300 mg of total phthalates/kg/day including BBP, DBP, DEHP, DiBP (300 mg/kg/day per chemical), and DPP (100 mg DPP/kg/day). This mixture ratio was selected such that each phthalate would contribute equally to the reduction in testosterone. As hypothesized, testosterone production was reduced in a dose-additive manner. Several of the individual phthalates and the mixture also induced fetal mortality, due to pregnancy loss. These data demonstrate that individual phthalates with a similar mechanism of action can elicit cumulative, dose additive effects on fetal testosterone production and pregnancy when administered as a mixture.
Key Words: androgens; prenatal; reproductive tract; phthalates; cumulative risk; structure activity relationship.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, United States 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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