Page 279 - The Toxicology of Fishes

Receptor-Mediated Mechanisms of Toxicity 259

Conclusions and Future Directions
Our current understanding of receptor-mediated mechanisms of toxicity in fishes is only modest, but
recent technical developments and the availability of genome-scale information have greatly accelerated
the rate at which progress is being made. During the next 10 years, we anticipate substantial advances
in our understanding of the impact of chemicals on fishes (fish as targets) as well as new mechanistic
insights of more fundamental significance (fish as models). These advances are most likely to occur in
the area of developmental toxicology, especially neurotoxicology, and will be facilitated by a more
complete understanding of differences between mammals and fishes in the number and diversity of
receptors that are targets for chemicals.
In the next few years, genome-scale profiling (functional genomics, proteomics, metabolomics) will
contribute to the description of complex regulatory networks and an understanding of how they are
perturbed by chemicals. These networks will include not only receptor-dependent signaling pathways,
which we currently depict essentially as linear sequences of events, but also the various cross-talk and
positive/negative feedback loops that are associated with them. Understanding such interactions will be
essential to assessing risks to populations exposed to multiple toxicants and other environmental stressors.
With regard to receptor-dependent mechanisms of toxicity in fishes, many important questions remain;
for example, what is the role of receptors in determining sensitivity to chemicals and in explaining species-
and population-specific differences in susceptibility? What is the relative importance of differences in
receptor diversity (number of paralogs), protein sequence, or receptor expression? What is the role of
receptor polymorphisms in differential susceptibility observed among individuals and populations (Greytak
and Callard, 2007; Hahn et al., 2004; Roy and Wirgin, 1997)? What are the target genes that are regulated
by receptors, and which ones are directly involved in mechanisms of toxicity? These and many other
questions will continue to provide interesting challenges and opportunities to researchers interested in
understanding the impact of chemicals on fishes, whether for their own sake or as models for humans.

Acknowledgments

Preparation of this chapter was supported in part by National Institutes of Health grants R01ES006272,
P42ES007381 (Superfund Basic Research Program at Boston University), R15CA115405, and
P20RR016461 (South Carolina INBRE). We thank Dr. Susan Bello (Jackson Laboratories) and Dr.
Michael Carvan (University of Wisconsin–Milwaukee) for permission to use unpublished data, and two
anonymous reviewers for helpful suggestions.

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