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UNDERSTANDING PATHWAYS OF TOXICITY: MAKING SENSE OF CHANGING SIGNALS
Hunter III, E S., M R. Blanton, E H. Rogers, M L. Mole, P C. Hartig, AND J E. Andrews. UNDERSTANDING PATHWAYS OF TOXICITY: MAKING SENSE OF CHANGING SIGNALS. Presented at Teratology Society Meeting, Vancouver, British Columbia, Canada, June 26 - July 1, 2004.
Understanding Pathways of Toxicity: Making sense of changing signals
Authors & affiliations:
Sid Hunter, Maria Blanton, Edward Karoly, Ellen Rogers, Leonard Mole, Phillip Hartig, James Andrews. Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US EPA, Research Triangle Park, North Carolina, USA
(Your abstract must use Normal style and must fit in this space)
Haloacetic acids (HAAs) are developmental toxicants in vivo and disrupt morphogenesis in rodent whole embryo culture. This project focused on understanding the mechanisms responsible for induction of malformations by bromochloroacetic acid (BCA) as a model for this family. BCA induced dysmorphogenesis in mouse whole embryo culture. 50?M did not induce defects and 300?M produced an approximately 100% incidence. The benchmark concentration for a 5% increase (ED05) in neural tube dysmorphogenesis is 63?M. Compared to the other HAAs, BCA is among the most potent. Exposure of conceptuses to BCA for as short as 3H induced dysmorphogenesis and a 6H exposure produced a 42% incidence of defects. BCA is more potent than its major metabolites (glycolate, glyoxylate, oxylate, formate) in embryo culture. Embryonic concentrations of 2.6pmole BCA/?g protein were found 1 hour after starting culture and remained steady for at least 6 hours. Biochemically, HAAs disrupt protein kinase activity and signal transduction in adult tissues, but there is no specific information regarding BCA. We have used Western analysis to show that BCA and two additional HAAs produce time-dependent changes in protein phosphorylation. Several phosphorylation changes are produced by all three chemicals whereas others changes are unique to each acid. We have used spotted oligonucleotide microarrays to evaluate the time and concentration-dependent changes in gene expression produced by BCA at 1, 3 and 6 H of exposure. Of the 17,800 genes evaluated on each array, 1176 show significant time- or treatment-related changes. We hypothesize that BCA-induced changes in signal transduction alter gene expression resulting in dysmorphogenesis. By correlating time-dependent induction of dysmorphogenesis with changes in protein phosphorylation and gene expression we will begin to better understand the pathways involved in BCA-induced defects.
This abstract does not represent EPA policy.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
REPRODUCTIVE TOXICOLOGY DIVISION
DEVELOPMENTAL BIOLOGY BRANCH