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Long-Range Research Initiative (LRI) Project Abstract
Project ID: END0035-10 (NIEHS grant # R21ES11750)
Microarray Analysis of Limb Bud Reaction to Teratogen Exposure
William Scott. Children’s Hospital Medical Center, Cincinnati.
Eludication of the immediate response of embryos to xenobiotic exposure is an aspect of research
that could yield significant benefit to the estimation of teratogenic risk. We contend that some
part of this stress/adaptive response which is presumable similar across species can negatively
impact developmental signaling mechanisms some of which are known to be the same across
species. We were led to this hypothesis by the fact that many chemical and physical agents with
diverse pharmacodynamic activities induce the same, very localized limb malformation, absence
of posterior digits from the forelimb, predominantly on the right side i.e., postaxial right forelimb
ectrodactyly. Moreover, a number of these agents are well documented human teratogens such as
valproic acid, retinoic acid, and ethanol. This putative cause/effect relationship between an
adaptive response and a localized limb malformation is very attractive for exploration because we
know a developmental signaling mechanism that is altered in the limb as it develops without
posterior digits. Polarizing activity, the ability of posterior limb bud mesoderm to induce a limb
duplication when grafted to the anterior margin of a host chick wing, is widely accepted as the
basis of anterior/posterior (A/P) patterning of the limb across many species including humans.
We have shown that this activity is lost from acetazolamide exposed muring limbs. In Specific
Aim 1, we will test the hypothesis that cadmium exposure similarly reduces polarizing activity of
the murine limb bud and will examine the consequenes on gene expression patterns in the limb.
In Specific Aim 2, we propose to elucidate the adaptive response pathway of limb bud cells after
exposure to acetazolamide or cadmium, both of which induce postaxial right forelimb
extrodactyly. We will utilize microarray analysis to examine the stress response to teratogen
exposures. We hypothesize that a common adaptive response to acetazolamide and cadmium will
be induced. Future studies will examine the capability of such an adaptive response to interfere
with polarazing activity, thereby leading to congenital malformation. A very exciting additional
benefit will be the discovery and identification of new genes important in limb morphogenesis or
xenobiotic response or both.
Project Start and End Date: March 15, 2002 - January 31, 2005
Presentation(s): None to date.
Peer-reviewed publication(s): None to date.
Other publication(s): None to date.
Additional sponsors: National Institute of Environmental Health Sciences
Revision date: January 2005
______________________________________________________________________________________This abstract was prepared by the principal investigator for the project. Please see www.USLRI.org for more information about the LRI.
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