Sex-Specific Transcriptional Responses of the Zebrafish (Danio rerio) Brain Selenoproteome to Acute Sodium Selenite Supplementation

M.BennerDr. Maia Benner is a postdoctoral researcher currently working on a Bioinformatics focused project in the lab of Dr. Robert Hancock in Microbiology and Immunology at the University of British Columbia in Vancouver, Canada. She completed her degree in Biology and Ph.D. in Bioinformatics and Computational Biology at the University of Idaho (UofI; Moscow, Idaho).

She started working with zebrafish (Danio rerio) as an undergraduate as a way of edging closer to a career in Marine Biology. Dr. Benner has published a paper titled: ‘Sex-specific transcriptional responses of the zebrafish (Danio rerio) brain selenoproteome to acute sodium selenite supplementation’ in the journal Physiological Genomics.

Background of the study

The research focus of Dr. Robison’s lab is to understand the underlying genetic component of behavioral adaptation to captivity. He had observed that zebrafish populations that were raised in captivity for several generations displayed ‘bold’ behaviors relative to their wild counterparts (recently collected from native habitat in West Bengal, India) that displayed ‘shy’ or anxious behaviors. Specifically, domesticated zebrafish spent a significantly greater proportion of time swimming toward the front and top of their tanks (close to a human observer and potential predation) and fed quickly at the surface of the water, whereas the wild fish preferred swimming locations close to the bottom and back of their tanks (as far from a human observer and potential predation as possible) and took longer to feed at the surface, if they fed at all. At the time, Dr. Robison was using zebrafish as a model for understanding the occurrence of behavioral domestication in hatchery-raised salmon that was resulting from hatchery practices which have since been reformed.

When I joined Dr. Robison’s lab, he and his (at the time) post doctorate, Dr. Rob Drew, had just completed a microarray experiment comparing the brain transcriptomes of domesticated and wild zebrafish populations. When reviewing the results of the microarray, Dr. Robison and Drew were particularly struck by one gene, selenoprotein P, which was down-regulated in the brain of wild/anxious zebrafish populations relative to domesticated/bold populations. Neither Dr. Robison, nor Dr. Drew had heard of selenoprotein P or knew its physiological functions. I was then given this project with the goal of understanding the role of selenoprotein P in the brain and its potential relationship to anxiety-related behaviors.

In my investigations of selenoprotein P, I learned that it functions in transporting the trace element, selenium, throughout the body and is essential for maintaining homeostatic levels of selenium in the brain. Selenium is an essential micronutrient for maintaining brain, immune, thyroid, and reproductive functions, and deficiencies are associated with a greater risk of some cancers and viral infections. The health implications of selenium expand beyond what I mention here, but my investigation was primarily focused on selenium’s associations with brain function. Several neurodegenerative diseases are associated with a low selenium status in humans, including Alzheimer’s disease, Parkinson’s disease, epilepsy, schizophrenia, cognitive decline, and mood disorders such as depression and anxiety. In humans, the beneficial effects of selenium supplementation on mood are controversial, with several studies observing positive effects and others showing no relationship. Available data suggests that hundreds of millions of people globally may be selenium deficient. However, this is also controversial as selenium is toxic at higher doses, and high levels of inorganic selenium (selenite) are associated with an increased risk of amyotrophic lateral sclerosis (ALS).

Based on my literature findings concerning selenoprotein P and selenium, I decided to perform several dietary manipulation experiments with zebrafish. I altered selenium levels in the diet and measured responses in anxiety-related behavior and expression of selenoprotein P in the brain (as well as several other selenoproteins) in wild and domesticated zebrafish. I expected to observe a basic linear association between increasing dietary selenium levels, increasing brain selenium status (higher expression of selenoprotein P), and in turn reducing anxiety-related behaviors – obviously expecting to observe a stronger response in wild zebrafish. However in a nutshell, the behavioral response and transcriptional response of selenoproteins in the brain depended on sex and zebrafish population, with an indication that the lower the initial selenium status, the stronger or more likely it was to observe a response to selenium.

Findings

The general conclusion of my research in zebrafish is that selenium may influence anxiety behaviors, but whether a response is observed and the type of response depends on sex and population (or genotype). Also, the behavioral response may manifest through transcriptional changes of selenoproteins in the brain, but if so, the influence is not direct.

Zebrafish (Danio rerio)
Zebrafish (Danio rerio)

Implications

These finding support the need for more research into personalized diets, or at least sex and population specific dietary recommendations. Current dietary recommendations for specific nutrients are based on lower and upper limits for the global population, but in reality factors such as sex and genotype can strongly influence nutrient requirements and responses to nutrients. In recent years, human studies have also observed genotype and sex specific responses to selenium.

Additional research

Observations from other studies led me to hypothesize that genetic polymorphisms within selenoproteins influence the response to selenium supplementation. Prior to graduating from UofI, Dr. Robison and I collaborated with the Institute of Bioinformatics and Evolutionary Studies (IBEST) Genomics Resources Core (GRC) at UofI to sequence the brain transcriptomes of four zebrafish populations known to vary in their response to selenium. GRC Director, Dr. Matt Settles, and I are currently analyzing these data to identify potential genetic polymorphisms within zebrafish selenoproteins that may be mediating sex and population specific responses to selenium. These results may provide insight into the discrepant effects of selenium supplementation on mood in human studies.

Increasing awareness

I think more research is required concerning sex and population (or genotype) specific responses to selenium before any changes can be made to current recommended intakes. As more studies are performed, I think the public will become more aware of how different factors such as sex and genotype can influence their nutrient requirements for health.

Advice from the field

My best advice for students, whether they are pursuing a degree in bioinformatics specifically, or science, business, computer science, etc. careers, is to broaden their knowledge and expertise. Make a point to learn, and develop contacts and skills across disciplines, programs, and/or degrees. Science and technology are evolving and becoming more complex and interrelated, so the new careers are for people who can easily meld knowledge from different fields together.

About the department

My affiliated department at the University of Idaho was Biological Sciences, however, the Institute of Bioinformatics and Evolutionary Studies (IBEST) at UofI supported my Bioinformatics degree program. IBEST financially supported the last two years of my PhD. IBEST is a highly interdisciplinary and interactive group devoted to the study of evolutionary processes. IBEST blends expertise from biologists, biochemists, mathematicians, statisticians, physicists, and computer scientists to examine the underpinnings of evolutionary biomedicine and to develop the analytical tools needed to do so.