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ALTERED RA SIGNALING IN THE GENESIS OF ETHANOL-INDUCED LIMB DEFECTS
Citation:
JOHNSON, C., K. K. SULIK, AND E. S. HUNTER. ALTERED RA SIGNALING IN THE GENESIS OF ETHANOL-INDUCED LIMB DEFECTS. Presented at Teratology Society Meeting, Vancouver, British Columbia, Canada, June 26 - July 1, 2004.
Description:
Altered RA Signaling in the Genesis of Ethanol-Induced Limb Defects
Johnson CS(1), Sulik KK(1,2) Hunter, ES III(3)
(1) Dept of Cell and Developmental Biology, UNC-Chapel Hill (2) Bowles Center for Alcohol Studies, UNC-CH (3) NHEERL, ORD, US EPA, RTP, NC
Administration of ethanol to pregnant C57BL/6J mice on embryonic day 9.25 causes distal forelimb reduction defects. The mechanism(s) of these and other ethanol-induced defects remains unclear. Several lines of evidence have linked ethanol's teratogenicity to hypovitaminosis A. Ethanol exposure decreases RA concentrations in mouse embryos and targeted double mutations of RA receptor (RAR) - and - or of RALDH2 cause limb dysmorphogenesis. We demonstrate in vivo that disulfiram, a known RA synthesis inhibitor, BMS-189453, a pan-RAR antagonist (RAR-A), and ethanol produce a comparable spectrum of limb malformations. Postaxial forelimb ectrodactyly in which 1 to 4 digits were absent was commonly observed in all three treatment groups. Within 8 hours of maternal ethanol treatment, cell death was observed in the distal ectoderm of limb buds. RAR-A also produced cell death in the distal limb ectoderm. Importantly, ethanol-induced cell death is ameliorated by the co-administration of RA. These results demonstrate morphological and pathological consistency among ethanol, disulfiram, and RAR-A treatment groups, supporting the hypothesis that reduction in RA levels underlies ethanol-induced limb defects. Microarray experiments are currently under way to examine the extent to which RA signaling is involved in the response of the developing limb to ethanol exposure.
Supported by grants from NIAAA. Disclaimer: This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.