Page 255 - The Toxicology of Fishes

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Receptor-Mediated Mechanisms of Toxicity

Mark E. Hahn and Eli V. Hestermann

CONTENTS
Introduction............................................................................................................................................235
Fish as Targets and Models ...................................................................................................................236
Comparative Toxicology: Complications and Opportunities ......................................................237
Ligand–Receptor Interactions: General Principles................................................................................239
Affinity..........................................................................................................................................240
Measurement of Affinity.....................................................................................................241
Efficacy.........................................................................................................................................244
Ligand–Receptor Interactions and Receptor Function: Approaches and Methods .............................. 247
Ligand-Binding Assays ................................................................................................................247
Cell Culture ..................................................................................................................................249
In Vivo Assays ..............................................................................................................................249
Gene Knock-Down .............................................................................................................249
Transgenics .........................................................................................................................251
Chromatin Immunoprecipitation ........................................................................................251
Genomics and Gene Expression Profiling...................................................................................251
Structural Genomics ...........................................................................................................251
Functional Genomics and Proteomics................................................................................251
The Aryl Hydrocarbon Receptor Signaling Pathway............................................................................253
Other Receptors and Ligand-Activated Transcription Factors..............................................................256
Nuclear Receptors ........................................................................................................................256
Neurotransmitter Receptors..........................................................................................................258
Olfactory Receptors......................................................................................................................258
Other Xenobiotic-Activated Transcription Factors......................................................................258
Conclusions and Future Directions .......................................................................................................259
Acknowledgments..................................................................................................................................259
References..............................................................................................................................................259

Introduction
Chemicals cause toxicity by interfering with the structure and function of cellular macromolecules such
as proteins (e.g., enzyme inhibition and inactivation), lipids (e.g., lipid peroxidation), and nucleic acids
(e.g., formation of DNA adducts). Chemicals or their metabolites also may act through interference with
physiological signaling pathways, often by altering gene expression. In some cases, biotransformation
of the original chemical modifies toxicity, either enhancing it through bioactivation to more reactive
derivatives or reducing it through inactivation and enhanced excretion.
This general description of mechanisms of toxicity is as true for fish as it is for humans and other
animals. In fact, most mechanisms of toxicity are not specific to fish. Thus, to understand mechanisms
of toxicity in fish it is necessary first to obtain a strong foundation in mammalian toxicology, where

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