Revealing the link
Genomics
Revealing the link

“Arsenic is everywhere,” says Dr. Donna Zhang, a professor in the Department of Pharmacology and Toxicology at the University of Arizona. “It’s a big environmental contaminant that causes many diseases.” Dr. Zhang is one of the leading experts on the subject. Her lab studies the mechanism by which arsenic promotes disease. “We know there is a link between exposure to arsenic and diseases such as cancer and type II diabetes, but the mechanism is not well understood,” she says. “Our work focuses on revealing that mechanism. If we can do that, then we can find a way to prevent or slow down the disease.”

Dr. Donna Zhang is a professor in the department of pharmacology and toxicology at the University of Arizona College of Pharmacy in the US. QIAGEN Genomic Services is working with her laboratory to help the team understand Nrf2 regulation and the role of Nrf2 in diabetic disease.

Arsenic occurs naturally in many areas of the world, often in the water supply. Very low levels are not a risk, but concentrations above 10 micrograms per liter are unsafe for humans, according to the World Health Organization. Chronic exposure to arsenic at these levels increases the likelihood of a person developing numerous serious diseases, including cancer and type II diabetes.

An estimated 200 million people are exposed to unsafe levels of arsenic in the environment. Dangerous levels have been detected in regions across the world, including in Bangladesh, Taiwan, China, Thailand, Brazil, and parts of the United States.

Dr. Matthew Dodson, a post-doctoral research associate, has been working in Dr. Zhang’s lab for four years, leading experiments using mouse models to examine how chronic exposure to arsenic causes genetic changes and how those changes are linked to disease development. “It’s my goal to find ways to treat or help people that get diseases,” he says.

Arsenic contamination is documented worldwide. Exposure is associated with an increased risk of developing Type II diabetes and it significantly increases the expression of genes involved in lipid metabolism, glutathione metabolism, and membrane transport. This environmental chemical can contaminate food and water and the World Health Organization estimates that 200 million people are exposed to unsafe levels of arsenic concentrations globally.

The unseen danger

Type II diabetes is the most common form of diabetes. It is a metabolic disease-causing elevation of blood sugar and leading to serious health problems. It affects many organs in the body, potentially leading to heart or kidney problems, nerve damage, or vision loss. “Often people who have been exposed to arsenic in the environment are unaware of the fact and they may also be unaware that they are already in the early stages of developing a disease,” says Dr. Dodson. “That’s one reason why it is so important to determine the mechanism by which arsenic exposure leads to the development of the disease.”

Dr. Dodson already knew that autophagy plays an important role. Autophagy is the process by which cells recycle their old parts to rebuild themselves. Damaged and long-lived proteins that aren’t needed are degraded to make new ones. Dr. Dodson set out to look at how arsenic blocks this process.

“Often people who have been exposed to arsenic in the environment are unaware of the fact and they may also be unaware that they are already in the early stages of developing a disease.”
Dr. Matthew Dodson, Department of Pharmacology and Toxicology, University of Arizona

The team looked at the role of prolonged changes in a set of RNA molecules called the Nrf2 transcriptome. Nrf2 is a master regulator of redox, protein, and metabolic homeostasis. In a normal cell, it is activated intermittently. In a cancer cell or a cell where autophagy is not working properly, Nrf2 is activated for extended periods or continuously. The latter is what happens when a person is exposed to arsenic over a long period of time. When autophagy stops working, Nrf2 is not activated in the normal way, and this, in turn, promotes disease.

As the effects that arsenic has on cells are comparable to the effects of high-fat diets, the experimental model examined not only the role of Nrf2 in promoting arsenic-linked diabetes but also the role of diet. Dr. Dodson compared high-fat diets and exposure to high levels of arsenic in four groups of mice: one group was given a normal diet with no exposure to arsenic, the second received a normal diet with high exposure to arsenic, the third received a high-fat diet with no exposure to arsenic, and the fourth received a high-fat diet with high exposure to arsenic. In half the mice in each group, Nrf2 had been inactivated. “We wanted to get an initial assessment of overall transcriptomic changes across these different groups,” says Dr. Dodson.

Dr. Matthew Dodson is a post-doctoral research associate working in Dr. Zhang’s laboratory. He was recently awarded the first prize by the Mechanisms Specialty Section of the Society of Toxicology in the US.

A massive data set

This is where  QIAGEN Genomic Services came in. “Dr. Zhang’s team had a vision for the project. Our experts talked it through with them and suggested using our new UPX transcriptome service because it is a great tool for screening a lot of samples and our Unique Molecular Identifiers allow us to assess gene expression with a high level of accuracy,” says Jon Olson, QIAGEN’s sales manager.” The team at QIAGEN extracted, purified and stabilized the RNA from the biological samples using the new UPX transcriptome service, and analyzed the data.

“They had precious samples and had not worked with us before, so it was a bit of a leap of faith,” says Olson. “But we have a good group of Field Application Specialists at QIAGEN. They spoke to Dr. Zhang and her team to identify the best approach and our team turned around the sample in six weeks.”

“It was a complex model and there was a lot of data to tease out. We required significant bioinformatics capabilities and QIAGEN was able to provide this.”
Dr. Donna Zhang, Department of Pharmacology and Toxicology at the University of Arizona

The leap of faith paid off. Dr. Zhang, Dr. Dodson and the team were delighted with the results and the preliminary data. “QIAGEN was also happy to accommodate their request to analyze a higher number of samples than was originally planned so that they could gather the data needed for publication.”

“The process of working with QIAGEN and submitting samples was very easy,” says Dr. Zhang. “That’s in contrast to the analysis we needed, which was very complicated as we included the influence of diet on arsenic poisoning. It was a complex model and there was a lot of data to tease out. We required significant bioinformatics capabilities and QIAGEN was able to provide this.”

Results that point toward treatment

From the analysis, Dr. Dodson and the team found that arsenic and high-fat diets induce similar transcriptomic changes. They also found that in mice in which Nrf2 had been inactivated, there were fewer arsenic-induced changes.

“The insights we gained through QIAGEN’s analysis point the way to a possible therapeutic target for disease intervention,” says Dr. Dodson. “We could look for a way to activate autophagy so that it works normally, or ways to inhibit Nrf2.”

The findings were presented by Dr. Dodson at the Society of Toxicology annual meeting in March this year and received a great deal of interest from the toxicology community. The quality of support offered by QIAGEN’s experts played a key role. “We wanted to represent the data properly, set proper cut-offs. We wanted to know that what we are doing is right,” says Dr. Dodson.

“The insights we gained through QIAGEN’s analysis point the way to a possible therapeutic target for disease intervention.”
Dr. Matthew Dodson, Department of Pharmacology and Toxicology, University of Arizona.

He believes the subject merits further research. “You see a lot of epidemiological studies in this area. It would be good to have more mechanistic studies of arsenic and diabetes to support why the enhanced risk exists,” he says. “My hope is to find one of the gene changes that fit our arsenic model so we can tailor therapy specifically to arsenic linked diseases as opposed to therapies that exist for that disease as a whole.”

The next stage would be to move from animal models to human models. “This is the very beginning of a giant project. We have so much data. We need to dig deeper to understand the mechanism,” says Dr. Zhang. “People don’t realize how widespread arsenic is. That’s a real danger. If we can figure out the pathways that lead to diabetes, we can develop treatment and even prevent it from causing the disease.”

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