ReviewTranscriptional involvement in neurotoxicity
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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Curcumin administration suppress acetylcholinesterase gene expression in cadmium treated rats
2017, NeuroToxicologyCitation Excerpt :However, co-treatment with curcumin caused a significant decrease on AChE mRNA expression levels in Cd-treated rats when compared with Cd alone (Fig. 2). AChE promoter analysis revealed that it contains c-fos, a transcription factor known to regulate AChE gene expression under stress and transcriptional control of AChE production also depends on an internal enhancer positioned within the first intron, which contains consensus-binding sites for SP1 (Specificity Protein 1 containing a zinc finger protein motif) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells a protein complex that controls transcription of DNA) (Chan et al., 1999; Zawia, 2003). The decrease in mRNA expression levels of AChE by curcumin following Cd exposure may be due to alterations in the transcriptional factors like SP1, cfos and NF-κB which consequently deranges cell signalling and alters gene expression systems (Simeonova and Luster, 2000; Hu et al., 2002; Saritha et al., 2014).
Cadmium coordination to the zinc binding domains of the non-classical zinc finger protein Tristetraprolin affects RNA binding selectivity
2012, Journal of Inorganic BiochemistryCitation Excerpt :Zn(II) is generally thought to be the in vivo metal cofactor for ZFs; however, there is a growing body of literature that implicates these proteins as targets for toxic metal ions [9–29]. In many instances, these toxic metal ions are proposed to coordinate to the ZF in place of Zn(II) and alter the protein's structure and function [10–13,15–18,20–34]. Cadmium is a toxic metal and environmental pollutant in which humans are exposed to daily from a wide range of sources including cigarette smoke, car exhaust and waste from industrial production of plastics and batteries [35–37].
Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia
2011, Clinical BiochemistryCitation Excerpt :In the developing brain, Pb2+ causes an inappropriate release of neurotransmitters at rest and competes with Ca2+ to interfere with evoked neurotransmitter release. This increase in basal release and decrease in evoked release may interfere with selective pruning of synaptic connections in the brain during the first few years of brain development [5]. Pb also interferes with excitatory neurotransmission by glutamate, which is the transmitter at more than half the synapses in the brain and is critical for learning.
In vitro Pb exposure disturbs the balance between Aβ production and elimination: The role of AβPP and neprilysin
2011, NeuroToxicologyCitation Excerpt :The cellular effects of Pb are widespread and are elicited through a variety of different mechanisms, including altered gene transcription (Garza et al., 2006). Pb is thought to interfere with gene expression by competing for the metal binding sites of transcription factors, such as zinc finger proteins (Basha et al., 2003; Zawia, 2003). We performed quantitative real-time RT-PCR to evaluate the effects of Pb on intracellular AβPP and NEP mRNA levels, relative to GAPDH.