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MAP KINASE ERK 1/2 INHIBITORS INDUCE DYSMORPHOLOGY IN MOUSE WHOLE EMBRYO CULTURE
Citation:
Rosen, M B. AND E I. Hunter. MAP KINASE ERK 1/2 INHIBITORS INDUCE DYSMORPHOLOGY IN MOUSE WHOLE EMBRYO CULTURE. Presented at Teratology Society Meeting, Vancouver, British Columbia, Canada, June 26 - July 1, 2004.
Description:
ROSEN, M.B. and E. S. HUNTER. Reproductive Toxicology Division, NHEERL, ORD, U.S. EPA, Research Triangle Park, North Carolina. MAP kinase Erk1/2 inhibitors induce dysmorphology in mouse whole embryo culture.
MAP Kinase signal transduction is associated with a variety of cellular functions including programmed cell death, proliferation/differentiation, and response to stress. It is likely, therefore, that MAP Kinase signalling pathways play an important role during development. Here we utilize whole embryo culture to evaluate the concentration dependent effects of two specific Erk1/2 pathway inhibitors, U0125 and U0126, on the development of GD8 (3-6 somite stage) CD-1 mouse conceptuses. Both chemicals inhibit MEK1 and MEK2, however, U0126 has been shown in cell culture to be a more potent compound. An inactive congener, U0124 was included as a control. U0126 (1-150uM) produced 81% dysmorphic embryos (n=21) at a concentration of 100uM following a 26 hr exposure. At this concentration, dysmorphogenesis of the eye and heart were observed as well as neural tube closure defects, prosencephalic hypoplasia, and first pharyngeal arch hypoplasia. As predicted based on it's published activity, U0125 (50-200uM) induced a similar spectrum of defects but at a concentration of 200uM (79% dysmorphic embryos, n=14). In contrast, 200uM U0124 induced only a low percentage of heart dysmorphology (24%, n=17). The background incidence of abnormal control embryos was small (9% dysmorphic, n=64). These data indicate that chemical inhibition of Erk1/2 signalling disrupts craniofacial development. Future studies will correlate changes in Erk1/2 signalling and gene expression during early craniofacial development.
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