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Effects of 5HPP-33,an antiangiogenic thalidomide analog, in mouse whole embryo culture
Citation:
Hoopes, M., N. Klleinstreuer, K. Chandler, T. Knudsen, AND E. S. HUNTER. Effects of 5HPP-33,an antiangiogenic thalidomide analog, in mouse whole embryo culture. Presented at Teratology Society Meeting, San Diego, CA, June 23 - 29, 2011.
Impact/Purpose:
These findings support the hypothesis that chemicals that induce alterations in angiogenesis/vasculogenesis are a class of active developmental toxicants.
Description:
Thalidomide is a well-known example of a teratogen which has been shown to have an inhibitory effect on angiogenesis. As a result of its targeted effect on immature blood vessels, anti-angiogenic specific chemical analogs were developed to maximize this mechanism of thalidomide effect. One such antiangiogenic analogue, 5-Hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1 ,3-dione (5HPP-33), has been shown to disrupt vessel development in the Human Umbilical Vein Endothelial Cell (HUVEC) assay. When assessing antiangiogenic potencies, 5HPP-33 produced more than twice the inhibitory effects as the same concentration of thalidomide. We hypothesized that 5HPP-33 would be developmentally toxic and result in effects related to disruption of vascular developmental processes. We evaluated the morphological effects of 5HPP-33 in mouse whole embryo culture. 3-6 somite staged CD-1 mouse conceptuses (GD8) were exposed to 0.1 -500 uM concentrations of 5HPP-33 for 24-or 48-hrs of culture. Conceptuses were also exposed to the DMSO vehicle as control. 5HPP-33 exposure for 24 hours had no demonstrable effect on embryo morphology below 100 uM, but, induced deficient growth of the forebrain, 1st pharyngeal arch, and heart in all embryos exposed at 200 uM. This concentration did not, however, decrease the number of somite pairs. Higher concentrations of 5HPP33 blunted yolk sac vascularization and arrested development at the 8-10 somite stage (300 uM), or produced early embryolethality (400 uM). Extending 5HPP33 exposure to 48 hr resulted in insufficient forebrain expansion and limb-bud abnormalities observed at 100 uM. These findings support the hypothesis that chemicals that induce alterations in angiogenesis/vasculogenesis are a class of active developmental toxicants. This abstract does not necessarily reflect EPA Policy.