Superfund Research Program
NIEHS Distinguished Lecture Series Features SRP Grantee
During an NIEHS Distinguished Lecture on February 7, Ronald Evans, Ph.D., discussed how a large family of molecules discovered in his lab, called nuclear hormone receptors, respond to hormones, lipids, vitamins, and xenobiotics, and how they can be used as targets to treat disease.
Evans, Director of the Gene Expression Laboratory at the Salk Institute for Biological Sciences and a University of California, San Diego Superfund Research Program (UCSD SRP) Center project leader, highlighted a variety of the innovative findings about these receptors from his lab over the years. As part of the UCSD SRP Center, Evans and his team are focusing on nuclear hormone receptors to investigate molecular mechanisms of toxicity from exposure to hazardous chemicals.
Among the receptors discussed was the vitamin D receptor. Although it is widely studied for its role in calcium balance and bone health, Evans discovered and probed its unique role in repairing damaged cells, particularly in the liver.
When the liver is damaged – which can happen via hepatitis virus infection, excessive alcohol consumption, and nonalcoholic steatohepatitis – specialized liver cells called hepatic stellate cells are signaled to create fibrous scar tissue around the damaged site. As fibrosis progresses, healthy liver cells are replaced by scar tissue until eventually the liver can no longer function.
Vitamin D receptors are uncommon in liver tissues, but Evans and his team discovered they are expressed at very high levels in hepatic stellate cells. They found that a synthetic form of vitamin D, called calcipotriol, activates the vitamin D receptor and turns off the fibrotic response in the livers of mice by blocking activation of the hepatic stellate cells. Unlike natural vitamin D, the synthetic ligand is less susceptible to breakdown and is therefore not depleted quickly in the body. His team also recently identified another therapeutic target for liver fibrosis called BRD4.
In addition to identifying potential therapies for liver fibrosis, Evans and his team are advancing the field of molecular genetics by identifying novel targets of pharmacological treatment for a wide range of diseases, including pancreatic cancer, diabetes, breast cancer, atherosclerosis, prostate cancer, obesity, leukemia, asthma, osteoporosis, and hypertension.
UNC Team Meets with WIC Program to Enhance Communication of Fish Advisories to Vulnerable Populations
On January 18, members of the University of North Carolina at Chapel Hill (UNC) Superfund Research Program (SRP) Center presented information on contaminants in fish in local waterways to a group of 22 nutritionists and case managers with the Lincoln Community Health Center WIC Program in Durham, North Carolina. UNC SRP Research Translation Core (RTC) leader Kathleen Gray described local fish consumption advisories (FCAs) and effective ways to communicate them to the general public, focusing on key messaging and how communication can be improved.
The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is funded by the U.S. Department of Agriculture. WIC nutritionists and case managers are responsible for providing nutrition information to clients in the program. Since about half of the meeting participants share information about fish consumption with WIC recipients at least weekly, the group was interested in obtaining more information and resources for communicating the risks of fish consumption while balancing and highlighting the health benefits of eating fish.
Residents of North Carolina who receive benefits from federal assistance programs like WIC are eligible to receive subsistence fishing waivers. In recent years, more than 79,000 North Carolina residents obtained such waivers, according to the North Carolina Wildlife Resources Commission. Since fish make up a larger portion of the diets of these individuals, they are at higher risk of exposure to contaminants compared to typical fish consumers. Previous research by the UNC RTC near a local Superfund site points to the need to communicate FCAs and associated health information in culturally sensitive, low-literacy, and bilingual formats.
At the meeting with WIC staff, Gray piloted new outreach materials developed for low-literacy and non-English speaking audiences and received feedback and input from the participants. WIC staff expressed interest in working with the RTC to collaboratively develop materials that could be shared with their clients. WIC classes offering information on nutrition and health, such as FCAs, have shown successful retention rates compared to written materials alone. This partnership also offers an evidence-based path to reach women of childbearing age who may not be aware of relevant FCAs.
Moving forward, Gray and the UNC RTC team are pursuing similar training opportunities with nurses, nutritionists, and case managers in other local WIC programs. Fish are an important part of a healthy diet, and partnerships with WIC staff will help inform families about local FCAs and educate them on making the best choices among locally available fish. For more information about the possible contaminants in fish and their health effects, as well as local FCAs, visit the UNC SRP Eat Fish, Choose Wisely website and see a recent NIEHS Environmental Factor article highlighting this work.
Using Zebrafish for Chemical Screening and Sustainable Chemical Design
A recent review out of the Oregon State University Superfund Research Program (OSU SRP) describes how zebrafish have become an important model to screen for chemical toxicity. The article, published in the journal Green Chemistry, points to major advances in testing methods that have positioned zebrafish as an applicable model for chemical safety evaluations and efforts to develop more sustainable chemicals.
According to the authors, led by OSU SRP Center investigator Robert Tanguay, Ph.D., there is a growing recognition that the use of traditional test models and empirical approaches is impractical to screen the toxicity of thousands of chemicals in the environment and hundreds of new chemicals introduced each year. This has prompted efforts to implement more predictive approaches to evaluate chemical toxicity early in product development.
The use of zebrafish has accelerated recently in genetic toxicology, high throughput screening (HTS), and behavioral testing. HTS technologies with zebrafish enable the screening of large chemical libraries for bioactivity early in the development of new chemicals. Previous research has shown that many toxic responses are shared among fish and mammals owing to their generally well-conserved development, cellular networks, and organ systems. These shared responses have been observed for chemicals that impair endocrine functioning, development, and reproduction, as well as those that elicit cardiotoxicity and carcinogenicity, among other diseases.
With zebrafish, researchers are able to characterize toxic effects of chemicals in a variety of cellular processes and compare those processes to changes in the fish, such as developmental malformations. Zebrafish also can be used to assess the toxicity of real-world multi-chemical exposures.
Tanguay leads an OSU SRP Center project that uses systems approaches in zebrafish to understand the mechanisms of toxicity of complex mixtures of polycyclic aromatic hydrocarbons (PAHs), which are routinely found at Superfund sites. Several studies have shown increased incidence of lung, skin, and urinary cancer in humans exposed to PAH mixtures. Many individual PAH compounds also have been classified as probable or possible carcinogens. Because PAHs are widespread in the environment as mixtures, it is difficult to tease out exposure and toxic effects. Researchers led by Tanguay are using zebrafish to identify environmentally relevant PAH mixtures that pose a hazard and to identify the gene responses that drive the toxic endpoints.