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Phthalate-induced toxicity: Identifying the vulnerable pathways during sexual differentiation in the male rat
Citation:
Hannas, B., V. S. WILSON, AND L. E. GRAY. Phthalate-induced toxicity: Identifying the vulnerable pathways during sexual differentiation in the male rat. Presented at Society of Toxicology (SOT), Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
Therefore, the goal of the current study was to determine the earliest point following in utero phthalate exposure at which testosterone (T) production declines to facilitate further investigations of the proximate mechanism of toxicity.
Description:
Human exposures to phthalate ester plasticizer compounds are widespread. Studies in rodents have demonstrated that in utero exposure to various phthalates throughout sexual differentiation (GD14-18) results in decreased fetal testicular androgen production, and ultimately leads to postnatal malformations in male reproductive tissues. The precise mechanism by which this hormonal disruption occurs remains unknown. Therefore, the goal of the current study was to determine the earliest point following in utero phthalate exposure at which testosterone (T) production declines to facilitate further investigations of the proximate mechanism of toxicity. We hypothesized that a single dose of dipentyl phthalate (DPP) administered early in sexual differentiation would decrease fetal testicular T production following an exposure length of 6 hours or less. To test this hypothesis, we initially determined the fetal ontogeny of ex vivo testicular T production throughout GD 14-18. We detected significant T production starting on GD 16.5. Next, we characterized the dose-response relationship between increasing maternal doses of DPP (0, 300, 600, 900, 1200 mg/kg/d) and ex vivo fetal testicular T production 5 hours after dosing. Finally, we administered a single oral dose of 850 mg/kg/d DPP to pregnant dams on GD16 and then excised fetal testes at 0.5,1.5,3,5 and 24 hours following exposure. Ex vivo T production was significantly reduced by 3 hours post-exposure. Though not significant, we detected a trend of declining T production at the 0.5 and 1.5 hour time points. Ongoing studies will investigate T production within the early period «3 hours) following DPP maternal exposure to pinpoint the exact timing of androgen disruption. We will interrogate different toxicity pathways by analyzing response expression of target genes by RT-PCR arrays.