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Investigation of the mechanism for phthalate-induced toxicity during male sexual differentiation in the rat
Citation:
Hannas, B. R., J. R. FURR, C. R. LAMBRIGHT, V. S. WILSON, AND L. E. GRAY. Investigation of the mechanism for phthalate-induced toxicity during male sexual differentiation in the rat. Presented at Society of Toxicology Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
The ultimate goal of this study was to identify the proximate mechanism of toxicity induced by in utero phthalate exposure by evaluating candidate signaling pathways.
Description:
Male rats exposed to phthalate esters during sexual differentiation (GDI4-GDI8) display various developmental abnormalities of the reproductive tract that are manifested later in adult life. Induction of these malformations is associated with declines in fetal testicular testosterone (T) production and insulin-like three hormone (Insl-3) gene expression levels. Beyond measurement of these indicators of hormonal disruption, little is known about the precise mechanism behind phthalate-induced testosterone and Insl-3 gene expression declines. The ultimate goal of this study was to identify the proximate mechanism of toxicity induced by in utero phthalate exposure by evaluating candidate signaling pathways. Our approach was to identify the earliest time point within the sexual differentiation period at which we could detect a significant decline in fetal testicular T production following administration of a single maternal dose of dipentyl phthalate (DPP). We performed a fetal testicular T production ontogeny study and determined that GD 16 is the earliest day that we could detect T production by radioimmunoassay. Sex differences in whole body T levels could be detected one day earlier (GD15). Next we performed dose response and time course studies and demonstrated that an oral dose of 850 mg/kg DPP results in significant T production decline on GD17 and 3 hours following maternal dosing. We will continue to evaluate this time point by assessing the dose-response of T production to DPP at early time points following dosing. Ongoing studies will interrogate toxicity pathways by analyzing response expression of target genes using RT-PCR arrays. Additionally, we assessed early postnatal effects of DPP in utero exposure during sexual differentiation. Dams were dosed with 0, 11, 33, 100, or 300 mg/kg/d DPP throughout GD8-18. Evaluation at postnatal day (PND) 2 revealed a clear dose-responsive decline in male anogenital distance (AGD) and increase in nipple retention incidence on PND 13. At 6 months of age, we will assess both female and male rats during necropsy for reproductive tissue abnormalities. Together, these studies will facilitate additional investigations related to elucidating the protein or gene-level mechanism behind the reproductive toxicity associated with phthalates and enable us to correlate fetal hormone and gene alterations with the postnatal effects. This abstract does not necessarily reflect EPA policy.