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Defining the Borders of Dose Addition: Mixture Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dibutyl phthalate on Male Rat Reproductive Tract Development
Citation:
RIDER, C. V., J. R. FURR, AND L. E. GRAY. Defining the Borders of Dose Addition: Mixture Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dibutyl phthalate on Male Rat Reproductive Tract Development. Presented at 2009 SOT Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This abstract represent a summary of data that will be presented at the SOT annual meeting.
Description:
In utero exposure to either dibutyl phthalate (DBP) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disrupts male rat reproductive tract differentiation. However, they act via different modes of toxicity and induce distinct postnatal phenotypes. DBP exposure decreases anogenital distance (AGD), and induces nipple retention and undescended testes by reducing fetal hormone levels. TCDD delays the onset of puberty, but does not reduce fetal androgen levels. Both DBP and TCDD induce epididymal agenesis and decrease sperm counts. Our hypothesis is that observed responses for endpoints targeted by only one of the chemicals would be response additive: driven by the active chemical, while those targeted by both chemicals would be dose additive: both chemicals would contribute predictably to the observed effects. Pregnant Sprague-Dawley rats were dosed with either vehicle, DBP (500 mg/kg/d on gestational days (GD) 14-18), TCDD (2 μg/kg on GD 16), or both DBP and TCDD (High Mixture Dose (HMD) = 500 mg/kg/d DBP + 2 μg/kg TCDD or Low Mixture Dose (LMD) = 320 mg/kg/d DBP + 1.3 μg/kg TCDD). Male offspring are being assessed for reproductive development. The data generally support our hypothesis, reflecting a dose-dependent TCDD-driven delay in puberty (4d delay in LMD and a 6-8d delay with TCDD or HMD) and presence of a temporary thread along the frenulum of the penis prepuce (10% in LMD and 20-40% with TCDD or HMD) and a dose-dependent DBP-driven increase in areolae retention (2 areolae/male in LMD and 3-5 with DBP or HMD). No clear trends among the treatments were evident with AGD, pup loss, or maternal weight gain. Additional endpoints include reproductive organ weights and malformations. The results from this study will contribute to determining the limits of dose additivity among reproductive toxicants. Funding provided by NCSU/EPA Cooperative Training Program CT833235-01-0. This abstract does not necessarily reflect EPA policy.