You are here:
A mixture of five phthalate diesters cummulatively inhibit fetal testicular testoserone production in a manner consisent with their predicted reporduction toxicity in the Sprague Dawley rat.
HOWDESHELL, K. L., V. S. WILSON, J. R. FURR, C. R. LAMBRIGHT, C. V. RIDER, C. R. BLYSTONE, A. K. HOTCHKISS, AND L. E. GRAY. A mixture of five phthalate diesters cummulatively inhibit fetal testicular testoserone production in a manner consisent with their predicted reporduction toxicity in the Sprague Dawley rat. Presented at Triangle Consortium of Reproductive Biology, Durham, NC, February 23, 2008.
Abstract of a presention for the TCRB Conference
Phthalate diesters are commonly-used plasticizers in intravenous bags, plastic food wrap and children’s toys, and the metabolites of multiple phthalates are detected in humans. In utero exposure to certain phthalates during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal rat, gestational exposure to the phthalates di(n)butyl (DBP), diethylhexyl (DEHP), and benzylbutyl (BBP) decreases testicular testosterone (T) production and insulin-like hormone 3 levels. We characterized the sigmoidal dose response effects of six individual phthalates [BBP, DBP, DEHP, diethyl phthalate (DEP), diisobutyl phthalate (DiBP), and dipentyl phthalate (DPeP)], administered orally to Sprague-Dawley rat dams from gestational day (GD) 8-18, on fetal testicular T production measured on GD18. DEHP, DBP, DiBP and BBP were equipotent (ED50 = 1.41 0.19 M), DPeP was about 3-fold more potent (ED50 = 0.43 M) and DEP had no effect on fetal T production. Since these phthalates disrupt reproductive tract differentiation via a common mechanism of toxicity, we hypothesized that co-administration of anti-androgenic phthalates would reduce fetal T production in a cumulative, dose-additive fashion. In a second study, SD rat dams were administered oral doses on GD8-18 of a phthalate mixture at 100, 80, 60, 40, 20, 10, 5 or 0% of the top dose of the five anti-androgenic phthalates. The top dose contained DBP, DiBP, BBP, DEHP at 300 mg/kg/d per chemical and 100 mg/kg/d DPeP, such that each phthalate would contribute equally to the reduction in fetal T. Dose-addition predictions for the phthalate mixture were calculated based upon the individual chemical dose response data. The reduction in fetal T production on GD18 was accurately predicted by the dose-additive model (ED50 expressed as DEHP equivalence: observed = 1.47 M versus predicted = 1.10 M). Several of the individual phthalates (DPeP, BBP and DiBP) as well as the phthalate mixture induced fetal mortality, due to partial or complete pregnancy loss, in a manner predicted by dose addition modelling. These data demonstrate that individual phthalates with a similar mechanism of action can elicit dose additive effects on fetal T production and pregnancy maintenance when administered as a mixture.