Review
Transcriptional involvement in neurotoxicity

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Abstract

Exposure to various chemicals and environmental hazards elicits changes in the expression of a variety of genes. The study of gene expression and transcriptional regulation is an important aspect of understanding the mechanisms associated with neurotoxicity. The availability of whole genome sequences and the development of new tools to identify and monitor transcriptional activity have accelerated the rate of discovery. This review surveys the historical steps taken to study gene expression in the brain and deals with recent advances in our understanding and classification of the roles of transcription factors. Disturbances in the regulation of gene expression associated with the neurotoxic response are also presented. Specific focus and detail is presented on the effects of heavy metals on the integrity and function of zinc finger proteins.

Introduction

The nervous system is an organ whose primary function is to process, store, and transmit information. As the central computing facility of the body, the nervous system is organized in such a manner as to handle the enormous volumes of information it receives from numerous sites within the body. The complex and hierarchical cytoarchitecture of the brain facilitates vital communication among cells, which ultimately determines the behavioral response of an organism. Although the final output of brain function is behavior, such an output is a culmination of a series of biochemical and molecular events, including the expression of genes and their translation into products. These molecular events are all potential targets for modulation by environmental agents. While the number of target genes and products studied following neurotoxicant exposure are numerous, it is important to focus attention on the effects of neurotoxic agents on transcriptional regulation. Understanding the relationship between toxicant exposure and perturbations in gene transcription provides an in-depth mechanistic examination on how neurotoxicants may result in long-term perturbations of the nervous system. In this review, we will focus on transcriptional events that are involved in neurotoxicity.

Section snippets

Gene expression in the brain: then and now

The informational platform of the nervous system resides mainly in the connections between individual neurons and the pathways they represent (circuitry). The assembly of these neural networks and their long-term sustenance, however, is dependent on data mining from another information storage site within the cell, namely the genome. Neuroscientists long recognized that maintenance of the highly specialized functions of brain cells, their unique metabolic needs, and their structural properties

Regulation of gene expression

The number of genes encoded in the human genome is substantially large. However, only subsets of these genes are expressed at any given time in any particular cell. The regulation of the expression of these genes in a coordinated manner and in response to various stimuli requires elaborate and highly sophisticated machinery. Differential gene expression is the hallmark of development and the essence of a living dynamic cell. The main players of this gene regulatory system are positive-acting

Transcriptional targets in neurotoxicity

It has become more apparent that exposure to various chemicals and environmental hazards elicits changes in the expression of a variety of genes. The study of gene expression and transcriptional regulation is an important aspect of understanding the mechanisms associated with neurotoxicity. In the 1990s, molecular neurotoxicologists began studying the steady-state levels of a variety of brain-specific mRNAs in response to various chemical exposures. Some of these genes included mylein genes

Interactions of heavy metals with ZFP

The regulation of gene expression plays a central role in the long-term adaptation of cells to external stimuli and their ability to respond to signals that regulate their growth and development. Environmental metals are neurotoxic and can interfere with transcriptional events. The zinc finger is a major structural motif required for sequence-specific DNA binding of the largest known super family of transcription factors. DNA binding is a prerequisite for transcription factors to modulate gene

Direct interactions by heavy metals at the zinc finger domain

The addition of metals in vitro to nuclear extracts containing ZFP transcription factors is another way to assess whether divalent metal cations can alter the DNA binding of transcription factors. The above studies demonstrated that specific metals such as Pb and zinc had the ability to selectively alter Sp1 DNA binding in vivo. However, the mechanism by which this occurred was not clear. One possible direct way through which the activity of ZFP may be modulated is by the interactions with the

Indirect perturbations of Sp1 by metals via cell signaling pathways

We have reported that Pb and Hg directly interfered with the DNA binding of rhSp1 and Pb has been shown by others to alter the DNA binding of TFIIIA, implicating in both cases the zinc finger domain. Sp1 DNA binding is also developmentally regulated and is elevated in response to growth factors in vitro. The very strong association between high Sp1 expression and onset of differentiation is supported by a coincidence of high levels of Sp1 in newly differentiating cells and relatively low

Metal-induced disturbances in an Sp1-driven promoter

The promoter regions of genes contain the consensus elements that are recognized by transcription factors. One way to study the properties of these promoters and the requirements for their activation is to utilize constructs of such promoters linked to a reporter gene and to monitor reporter activity as an indirect measure of promoter function. The SV40 promoter contains six consensus elements for Sp1 and is linked to a luciferase reporter gene in a plasmid form (pGL3). This vector was

Conclusion

Gene transcription mediates the long-term adaptation of cells to aversive stimuli. Therefore, examining the involvement of transcriptional events as an endpoint of neurotoxicity is crucial to understanding lasting effects that may be a product of exposure to neurotoxic agents. It is also essential to know the unique aspects of transcription in the brain and the specific steps that may be targeted by a neurotoxicant following an exposure. Such an in-depth and molecular examination will bring

Acknowledgements

The author is grateful to the assistance of Drs. W. Wei and M.R. Basha, and S. Bakheet in the preparation of this manuscript.

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