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COMBINATION DOSE OF TWO PHTHALATES ADDITIVELY DEPRESSES TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RAT FETUSES
Citation:
HOWDESHELL, K., J. FURR, C. R. LAMBRIGHT, V. S. WILSON, AND L. E. GRAY. COMBINATION DOSE OF TWO PHTHALATES ADDITIVELY DEPRESSES TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RAT FETUSES. Presented at Triangle Consortium for Reproductive Biology, Durham, NC, February 12, 2005.
Description:
Diethylhexyl phthalate (DEHP) and di(n-butyl) phthalate (DBP) are phthalate esters used to modify plastic and polymer textures. Individually,DEHP and DBP reduce testosterone production, inhibit reproductive tract development, andinduce reproductive organ malformationsin male rats, thusindicating an anti-androgenic mode of action.In addition,DEHP exposure decreases expression of insulin-like factor 3 (insl3), a gene responsible for gubernacular ligament development.In the current study, we tested whether co-administered DEHP and DBP act in a dose-additive fashion to inhibit testosterone production and suppress gene expression in the steroidogenic pathway, specifically steroidogenic acute regulatory protein (StAR) and cyp11a. We also examined insl3 expression. Pregnant rats were gavaged on gestation days (GD) 14-18 with 500 mg/kg DEHP, DBP or a combination of both chemicals (500 mg/kg each).On GD18, three pairs of fetal testes per litter wereexplanted and incubated in media for testosterone production. The remaining fetal testes were used to measure gene expression by real time rt-PCR. As hypothesized, the combination dose resulted in an additive inhibition oftestosterone production relative to the single dose of DEHP or DBP. Althougheach single chemicalsignificantly decreased testosterone production relative to control, the DEHPdose resulted in lower testosterone production levels than the DBP dose.The expression of insl3 was also additively decreased by the combination dose, while it was significantly decreased by DEHP and tended to be lower with DBP exposure. Preliminary results show comparable, significant decreases in StAR and cyp11a expression with DEHP and the combination dose, but not the DBP dose. These results support the hypothesis that DEHP and DBP act in an additive fashion to decrease testosterone production and insl3 expression, and suggest that DEHP is more potent than DBP for the endpoints tested in this study. Disclaimer: Abstract of a proposed presentation and does not necessarily reflect EPA policy