A principal goal in neurotoxicology research is to identify and characterize discrete mechanisms by which a given chemical or mixture induces detrimental effects on formation and/or function of the nervous system. Advancing this goal is integral to risk assessment for toxicants to which people are exposed. There are more than 80,000 chemicals in commercial use today, and the approximately 2,000 new chemicals introduced each year for which there is little to no toxicological data (http://ntp.niehs.nih.gov/
). Furthermore, we continue to come in contact with persistent environmental toxicants, such as mercury, lead and arsenic, with insufficient knowledge of their mechanism of action, particularly in the context of the developing fetus. Understanding toxic mechanisms relies on identifying genes and gene products (e.g. genomic DNA, mRNA transcripts and/or proteins) that are targeted for disruption by the xenobiotics we are likely to encounter in our world. Equally important is characterization of genes, and their products, that act in defense toward individual or classes of toxic compounds. Developing informative, sensitive and rapid assays to screen for neurotoxicity has therefore become a priority.
Fortunately, our understanding of nervous system development and physiology is highly advanced, thanks in large part to decades of genetic, molecular and behavioral studies conducted in simple non-mammalian models. The roundworm (Caenorhabditis elegans), the fruit fly (Drosophila melanogaster) and the zebrafish (Danio rerio) are the predominant alternative models that have been perpetuated through the genomic and post-genomic revolution of the last decade. Each of these models has its distinct advantages with respect to generation time, laboratory expenses, genetic manipulability, efficiency of screening methods and conservation with higher organisms. In this article I advocate the use of Drosophila in the modern regimen of toxicological testing, emphasizing its unique attributes for assaying neurodevelopment and behavior. Genetic manipulability and ease of detecting phenotypes made Drosophila the model of choice for mutagenesis screens of the 1980’s and 90’s. These same features make Drosophila ideal for toxicological screens. Indeed, flies have been, and continue to be, used routinely in mutagenicity tests. Recent investigations have propagated a number of powerful assay methods with Drosophila in developmental and behavioral toxicology.
In this article I present a brief summary of the features of the Drosophila model and a generalized overall scheme for its use in toxicology studies. As well, I allude to examples from the literature where the fly has proven fruitful in evaluating common toxicants in our environment. Finally, I summarize three areas where development and application of the fly model might most benefit toxicology. This review does not attempt to be a comprehensive survey of Drosophila in toxicology. For instance, Drosophila have proven highly effective in modeling a number human neurodegenerative diseases and have found a niche in drug discovery, which is reviewed in depth elsewhere [11
]. Yet, the rationale for using flies in these other arenas holds true for its application to conventional toxicology. Furthermore, incorporating fly-based assays into toxicological testing is a direct answer to the call for a paradigm shift in testing proposed jointly by the EPA, National Toxicology Program (NTP) and National Institute of Health Chemical Genomics Center (NCGC) [23
]. Moreover, recommendations put forth by the National Research Council Committee on Toxicology proclaim Drosophila, along with C. elegans and zebrafish, as models of choice to advance the science behind risk assessment of developmental toxicants [75
The relatively unique life cycle, form, function and experimental manipulations of the fly, with respect to worms and fish, encompass an area of research for which I suggest the name “Drosophotoxicology”.