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ENDOTHELIN-A RECEPTOR ANTAGONISM IN EMBRYO CULTURE: WINDOW OF SENSITIVITY AND TIMING OF DEFECT
Citation:
Brannen, K. C., J M. Rogers, AND E S. Hunter. ENDOTHELIN-A RECEPTOR ANTAGONISM IN EMBRYO CULTURE: WINDOW OF SENSITIVITY AND TIMING OF DEFECT. Presented at Teratology Society Meeting, Palm Beach, FL, June 23-28, 2000.
Description:
BRANNEN, K.C., J.M. ROGERS, and E.S. HUNTER, Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina, and Reproductive Toxicology Division, NHEERL, U.S. EPA, Research Triangle Park, North Carolina. Endothelin-A receptor antagonism in embryo culture: window of sensitivity and timing of defect.
Signaling between the endogenous vasoactive peptide endothelin-1 (ET-1) and the endothelin-A receptor (ET-AR) is important to normal development of a number of pharyngeal arch derivatives of neural crest origin. We have previously shown that pharmacological antagonism of ET-AR in two-day whole embryo cultures of CD-1 mouse embryos results in defects of the pharyngeal arches. In order to determine when during this culture period embryos are most sensitive to ET- AR antagonism, cultured embryos were treated with 100 :M BQ-123, an ET-AR selective antagonist, for either the first or second day in culture (gestation day 8 or 9, respectively). While the percent of embryos affected was not strikingly different (100% gd 8; 83% gd 9), the severity of the defects was much worse in embryos treated on gd 8 than on gd 9. The severity of the arch defects was scored from 0 (normal) to 3 (severe). The mean scores were 0 for controls, 3 for gd 8 treated embryos, and 1.6 for gd 9 treated embryos. In addition to this greater sensitivity on the first day of culture, we have found that BQ-123 exposure for only the first 4 hr in vitro was sufficient to cause the same effect. However, the effect on arch morphology is not evident until more than 24 hr later. Further, preliminary results of Lysotracker staining for apoptosis suggest a slight increase in apoptosis after 24 hr, but not 12 hr, of BQ-123 exposure. The discrepancy between the time of sensitivity to exposure and development of dysmorphology suggests a latent effect of receptor antagonism on neural crest development. [Supported by EPA/UNC agreement CT902908. This abstract does not reflect EPA policy.]