Research Highlight: Using Zebrafish As Models for Toxicology Investigations

The genome is an organism's hereditary information, encoded in DNA. Genomics is the study of the structure, function, evolution, and mapping of genomes. A xenobiotic (in Greek, xenos means “stranger” and biotic means “related to living beings”) is any substance that is foreign to the body. Drugs, pesticides, and carcinogens are examples of xenobiotics. Xenobiotic disposition, or drug metabolism, refers to the biochemical changes (biotransformation) made by enzymes in the body that break down and eliminate drugs and other foreign substances from the body.

Our Genomics of Xenobiotic Disposition Area of Research Emphasis (ARE) focuses on understanding why individuals metabolize drugs differently. Why do some people break down and eliminate a drug or toxin relatively quickly compared to others who retain it longer? People who retain a xenobiotic are exposed to it for a longer time and are thus potentially more vulnerable for harmful health effects.

Factors that influence individual differences in xenobiotic disposition include genetics, previous exposure to the xenobiotic (or other xenobiotics), nutritional status, and the individual’s stage of development.

It is known that xenobiotics such as cadmium, copper, and certain pesticides interfere with the sense of smell in fish. Fish depend on their sense of smell to find prey, sense predators, and find their way to natal streams. Salmon are particularly at risk because they rely so much on their sense of smell.

Genomics of Xenobiotic Disposition ARE core leader Evan Gallagher is working to understand what happens at the cellular, molecular, and biochemical levels to the olfactory system of fish when they are exposed to copper.

In a recent study, his team exposed adult zebrafish for 24 hours to 3 concentrations of copper, concentrations within the range of copper concentrations from urban runoff. The olfactory systems of the fish were then harvested and analyzed to discover whether genes involved in pathways in the sense of smell, the olfactory system, behaved differently when the fish were exposed to copper.

Current research suggests that copper exposure causes epigenetic changes in the genes in the olfactory pathway. Epigenetic changes are changes in the activity of genes not caused by changes in the DNA sequence. Epigenetic changes regulate whether the genes are turned on or off.

In this study, the researchers looked at epigenetic changes caused by microRNAs, or miRNAs, small molecules found in plants and animals that regulate genes. The research team identified changes in the concentrations of several miRNAs that regulate various genes in the olfactory system. Some of the dysregulated genes are involved in neurogenesis, the creation of new nerve cells needed to heal after an injury to the nervous system. The change in miRNA levels was greater as the concentration of copper increased.

These results suggest that changes in the concentration of miRNA molecules are a possible mechanism by which copper damages the olfactory system. The next step is to focus on the target genes identified in this study and explore their specific roles in the olfactory system in fish.

This study appears to be the first to look at miRNA regulation as the mechanism by which copper damages the olfactory system in fish. The results provide new information about the potential role of miRNA molecules in gene regulation when fish are exposed to copper.

Gallagher’s work on metal exposure in fish doesn’t discourage him from eating fish. An avid fly fisherman, he says, “It's my opinion that our salmon are overwhelmingly beneficial for us, especially in the Puget Sound region. They have all the things you find in over-the-counter vitamins and supplements – Vitamin E, antioxidants, omega-3 fatty acids – that protect against heart disease and age-related disorders.”

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