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Dose addition predicts the effects of a mixture of five phthalate esters to inhibit fetal testosterone production and gene expression, and postnatal reproductive development in the Sprague Dawley rat
Citation:
HOWDESHELL, K., V. S. WILSON, J. R. FURR, C. R. LAMBRIGHT, C. V. RIDER, D. Bermudez, AND L. E. GRAY. Dose addition predicts the effects of a mixture of five phthalate esters to inhibit fetal testosterone production and gene expression, and postnatal reproductive development in the Sprague Dawley rat . Presented at Triangle Consortium of Reproductive Toxicology, NIEHS, RTP, NC, January 31, 2009.
Impact/Purpose:
Presented to the Triangle Consortium of Reproductive Biology Meeting.
Description:
Exposure to some phthalate esters (PE) during sexual differentiation induces reproductive malformations in male and female rats. In the fetal male, these lesions result from phthalate-induced reductions in testicular testosterone (T) production and insulin-like hormone 3 (insl3) levels. We hypothesized that dose addition modelling would predict the effects of co-administration of five PEs [benzyl butyl (BBP), di(n)butyl (DBP), diethylhexyl (DEHP), diisobutyl (DiBP) and dipentyl (DPP)] on fetal testicular T production and gene expression since they act via a common mode of toxicity. First, we characterized the dose response effects of six individual PEs on gestation day (GD) 18 testicular T production following exposure to rats on GD8-18. BBP, DBP, DEHP, and DiBP were equipotent (ED50=441 mg/kg), and DPP was about 3-fold more potent (ED50=130.9 mg/kg); diethyl phthalate (DEP) had no effect. Next, dams were dosed at 100, 80, 60, 40, 20, 10, 5 or 0% of a mixture of BBP, DBP, DEHP, DiBP (300 mg/kg per chemical) and 100 mg DPP/kg; this ratio was selected so that each phthalate would contribute equally to the reduction in T. As predicted, the PE mixture dose-additively inhibited fetal T production [ED50, observed (obs)=480 vs predicted (pre)=360 mg/kg] and mRNA expression of insl3 (ED50, obs=388 vs pre=288 mg/kg) and steroidogenic genes [cyp11a (ED50, obs=345 vs pre=533 mg/kg) and StAR (ED50, obs=297 vs pre=724 mg/kg)]. In a postnatal study, dose additive effects were observed for the PE mixture on anogenital distance (ED50, obs=743 vs pre=724 mg/kg) as well as other reproductive tract endpoints. The ED50 for female malformations was 450 mg PE mixture/kg. The data demonstrate that individual PEs with a similar mechanism of action elicit dose additive effects on rat reproductive development. This abstract does not necessarily reflect USEPA policy.