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Di(n)butyl phthalate reduces testicular weight, testosterone and associated gene expression in fetal Harlan Sprague Dawley rats.
Citation:
HOWDESHELL, K., J. Furr, C. R. Lambright, V. S. WILSON, AND L. E. GRAY. Di(n)butyl phthalate reduces testicular weight, testosterone and associated gene expression in fetal Harlan Sprague Dawley rats. Presented at Society of Toxicology 49th Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
We evaluated the effects of di(n)butyl phthalate (DBP) on testosterone, and genes associated with androgen-signaling and insulin-like peptide hormone 3 (ins13) in the Harlan SD rat.
Description:
Certain phthalate esters (PE) cause reproductive malformations in male rats when exposure occurs during sexual differentiation in utero. Reductions in fetal testosterone levels are causally linked to the induction of these malformations. While reproductive development studies on PEs have been conducted in a variety ofrat strains, the sensitivity ofthe Harlan Sprague Dawley (SD) rat to PEs is not known. We evaluated the effects of di(n)butyl phthalate (DBP) on testosterone, and genes associated with androgen-signaling and insulin-like peptide hormone 3 (ins13) in the Harlan SD rat. Pregnant rats were dosed orally on gestation days (GD) 8-18 with 0,33,50, 100,300,600 or 900 mg DBP/kg/day, and fetuses were collected on GD18. In the first experiment, one testis from three males per litter was incubated for testosterone production, while the remaining testes were analyzed for gene expression by qrt-PCR. Inthe second experiment, we recorded fetal body weights, testis weights, and maternal and fetal liver weights. Testes were etherextracted and testosterone was measured. Fetal testosterone production, extracted testosterone, and paired testes weights were reduced in a dose-dependent manner with a significant reduction by lOOmg DBP/kg/d (for testosterone production). Testicular expression of StAR, cyp 11a and ins13 mRNA were significantly reduced by 300-600 mg DBP/kg/d relative to controls. Preliminary results from a qrt-PCR array also confirmed a significant reduction in testicular cypll(al) and cyp17al mRNA by 600 mg DBPlkg/d. In contrast, there were no effects oftreatment on maternal or fetal body or liver weights up to 600 mg/kg/d. Fetal endpoints were not assessed at 900 mg DBPlkg/d due to high fetal mortality. These data demonstrate that the DBP is a specific developmental reproductive toxicant that reduces testosterone levels in the Harlan SD rat similar to other rat strains. Study funded by EPA lAG # RW-75-9228550l-0, NTP # Yl-ES-80124-01. This abstract does not necessarily reflect USEPA policy.