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HALOACETIC ACIDS AND KINASE INHIBITORS PERTURB MOUSE NEURAL CREST CELLS IN VITRO
Citation:
Hunter III, E S., J. Smith, AND J E. Andrews. HALOACETIC ACIDS AND KINASE INHIBITORS PERTURB MOUSE NEURAL CREST CELLS IN VITRO. Presented at Teratology Society Meeting, Montreal, Quebec, Canada, June 23-28, 2001.
Description:
HUNTER, E.S.1, J. SMITH2, J. ANDREWS1. 1 Reproductive Toxicology Division, NHEERL, US EPA, Research Triangle Park and 2 Department of Cell and Developmental Biology, UNC-CH, Chapel Hill, North Carolina. Haloacetic acids and kinase inhibitors perturb mouse neural crest cells in vitro.
Haloacetic acids (HAA) are disinfection byproducts found in drinking water. Craniofacial and heart dysmorphogenesis are produced by embryonic exposure to HAAs in whole embryo culture indicating that neural crest cells (NCCs) are a critical target cell population for HAAs. To evaluate the effects of HAAs on NCCs, primary cultures of NCCs were established by explanting cranial neural folds from 5-8 somite staged CD 1 mouse embryos. Cells were exposed to toxicants at dysmorphogenic concentrations from 1-48 hours of culture and then assessed for cell death (Live/Dead Kit, Molecular Probes) and migration from the explant. Exposure to 300 ?M dibromoacetate (DBA) induced cell death. Migration appeared to be reduced by exposure to 300 ?M bromochloroacetate or DBA. Dichloroacetate (11mM) did not alter NCC development. To determine if altered signal transduction perturbs NCC development, cultures were exposed to dysmorphogenic concentrations of bisindolylmaleimide I (BIS), a protein kinase C inhibitor, or PD98059, a mitogen activated protein kinase inhibitor. Both inhibitors produced concentration dependent cell death. At a high concentration, 100?M PD98059 or 10?M BIS decreased epithelio-mesenchymal transformation and/or emigration from the neural tube and/or reduced cell migration. A lower BIS (1?M) concentration appeared to alter NCC differentiation. These studies showed that exposure to dysmorphogenic concentrations of some HAAs altered NCC development. Since cell death and reduced NCC migration were induced by both HAAs and kinase inhibitors, HAA-induce perturbation of kinase activity may contribute to HAA-induced effects. This abstract does not reflect EPA policy.