The proposed pilot studies will determine if new multi-gene arrays can be used to detect and categorize changes in gene expression that may be caused by environmental neurotoxicants. How environmental contaminants affect the developing nervous system is a central concern; yet, in many cases, there is relatively little understanding of the molecular mechanisms by which xenobiotics act during development. Exposure to environmental neurotoxicants during critical developmental stages can produce behavioral changes in adult animals. Such behavioral changes could arise due to neurotoxicant interference with one or more of the large number of molecular and cellular processes required for successful development of the nervous system. Though there have been successes, it remains a daunting and expensive task to test how every xenobiotic of concern might affect each step in neural development. Many of these stages of development, however, share a requirement for highly regulated changes in gene expression. Given this central role of regulated gene expression in development, I propose that many neurotoxicants will alter patterns of gene expression in the developing nervous system. Further, I propose that DNA gene arrays and computational methods can be used to identify and categorize changes in gene expression patterns induced by neurotoxicants. The experiments are designed to produce the initial results needed to test these ideas.
The specific aims are to: (i) Use multi-gene arrays to measure levels of mRNAs encoding greater than 1000 identified genes in embryonic nervous system cells grown in the absence or presence of selected xenobiotics, and (ii) Use computational methods to identify functionally-related groups of genes with expression patterns that are altered by xenobiotic exposure. Our pilot studies will determine if such changes in expression can be detected and used to generate hypotheses about potential links between neurotoxicant-induced molecular changes and changes in later behavior.
