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EARLY CRANIOFACIAL DEVELOPMENT: LIFE AMONG THE SIGNALS
Citation:
Hunter III, E S. AND K. Ward. EARLY CRANIOFACIAL DEVELOPMENT: LIFE AMONG THE SIGNALS. Presented at Triangle Consortium for Reproductive Biology, (NIEHS)RTP, NC, January 27, 2001.
Description:
Early Craniofacial Development: Life Among the Signals. Sid Hunter and Keith Ward. Reproductive Toxicology Division, NHEERL, US EPA, RTP, NC, 27711
Haloacetic acids (HAA) are chemicals formed during drinking water disinfection and present in finished tap water. Exposure of rodent conceptuses to HAAs produced a variety of defects and induced cell death. The types of malformations and locality of cell death produced by HAAs suggest that neural crest cells (NCC) are a target cell population. The NCCs are formed from neuroepithelium by an epithelio-mesenchymal transformation and contribute to a large number of craniofacial structures such as the facial skeleton. The mechanisms by which the HAAs perturb NCC morphogenesis are unknown, however, HAAs perturb MAP kinase and PKA signal transduction pathways in adult tissues. We wanted to determine if exposure to specific kinase inhibitors (MAP Kinase, PKA, PKC, or PKG) would disrupt embryogenesis and produce effects on NCCs. Neurulation staged mouse conceptuses in whole embryo culture exhibit dysmorphogenesis following exposure to staurosporine (broad spectrum inhibitor), bisindolmaleimide 1 (Bis 1, classic PKC inhibitor) and PD 98059 (MAP kinase inhibitor). Staurosporine produced high levels of cell death, while exposure to Bis 1 did not. NCCs will form and migrate from neural fold explants in vitro. Using this culture system, Staurosporine induced massive cell death and PD 98059 and Bis1 inhibited NCC migration. Thus, inhibitors of signal transduction pathways disrupt craniofacial development in NCC and in the whole embryo. Perturbation of signal transduction pathways by the HAAs may be responsible for their induction of birth defects. This abstract does not present EPA policy.