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LIMB DEFECTS INDUCED BY RETINOIC ACID SIGNALING ANTAGONISM AND SYNTHESIS INHIBITION ARE CONSISTENT WITH ETHANOL-INDUCED LIMB DEFECTS
JOHNSON, C., K. K. SULIK, AND E. S. HUNTER III. LIMB DEFECTS INDUCED BY RETINOIC ACID SIGNALING ANTAGONISM AND SYNTHESIS INHIBITION ARE CONSISTENT WITH ETHANOL-INDUCED LIMB DEFECTS. Presented at Society for Developmental Biology, Boston, MA, July 30 - August 3, 2003.
Limb defects induced by retinoic acid signaling antagonism and synthesis inhibition are consistent with ethanol-induced limb defects
Johnson CS1, Sulik KK1,2, Hunter, ES III3
1Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, NC. 2Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, NC. 3National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Administration of ethanol to pregnant C57BL/6J mice on embryonic day 9.25 causes distal forelimb malformations. The mechanism(s) of these and other ethanol-induced defects remains unclear. Several lines of evidence have linked ethanol teratogenicity with hypovitaminosis A. Ethanol exposure decreases retinoic acid (RA) concentrations in mouse embryos and targeted double mutations of both RAR-a and RAR-g or of retinaldehyde dehydrogenase 2 (RALDH2/Aldh1a2) cause limb dysmorphogenesis. Here we demonstrate in vivo that disulfiram, a known RA synthesis inhibitor, BMS-189453, a pan-RAR antagonist, and ethanol all result in the same spectrum of limb malformations. Postaxial ectrodactyly in which 1 to 3 digits were absent was observed in all three treatment groups. In the disulfiram treatment group one fetus exhibited loss of 4 digits. Intermediate digit reductions were commonly observed in all groups. Additionally, cell death was observed in the distal ectoderm of limb buds following either ethanol or disulfiram exposure. BMS-189453 treated embryos exhibited the same pattern of cell death although less frequently and at a lower intensity than ethanol or disulfiram. These results demonstrate morphological and pathological consistency among ethanol, disulfiram, and BMS-189453 treatments, indicating that RA depletion may account for the mechanism of ethanol-induced limb defects.
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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