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Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

May 2018

Atherosclerosis as a model for studying combined exposures

In the first workshop of its kind, clinicians, psychologists, and researchers gathered at NIEHS April 3-4 to explore approaches for studying interactions in the body from exposures to both chemicals and nonchemical stressors. Organizers from NIEHS and the National Heart, Lung, and Blood Institute (NHLBI) selected atherosclerosis as the model disease for the workshop because both types of exposures are known to play a role in its development.

“We know that lifestyle, nutrition, age, and gender all affect atherosclerosis, but how do other things, such as psychosocial stress, lack of sleep, or the chemicals we’re exposed to on a daily basis?” asked Danielle Carlin, Ph.D., one of the lead organizers and a scientist in the NIEHS Hazardous Substance Branch.

“There’s evidence that arsenic, lead, and cadmium, contribute,” she continued. “Can we find specific mechanisms through which these factors interact with each other?” Although the answers are far from clear, Carlin noted that inflammatory processes appear to be highly involved.

She and two scientists from NHLBI — Michelle Olive, Ph.D., and Catherine Stoney, Ph.D. — led the organizing effort. They and others will prepare a paper on outcomes from the two days of presentations, discussions, and brainstorming sessions, for publication in a peer-reviewed journal.

Carlin, right, and Olive Carlin, right, and Olive said the workshop goal was to identify key mechanisms and pathways involved in the combined role of chemical and nonchemical stressors in atherosclerosis. (Photo courtesy of Michael Garske)

Combined exposures and NIEHS mission

David Goff, M.D., Ph.D., director of the NHLBI Division of Cardiovascular Sciences, and Linda Birnbaum, Ph.D., director of NIEHS and the National Toxicology Program (NTP) welcomed attendees to the workshop.

David Goff Goff’s division co-sponsored the workshop with NIEHS. (Photo courtesy of Michael Garske)

Birnbaum charged them with determining approaches to studying biological mechanisms and interactions of both types of stressors with respect to atherosclerosis. The disease is dangerous because it results in constricted blood vessels and the potential for plaque to rupture, leading to a clot that can block blood flow.

Furthermore, scientists know that the body may respond more intensely to a combination of chemicals compared with a response to a single chemical. Birnbaum noted that Goal 4 of the 2012-2017 Strategic Plan calls for promoting research on how combined exposures contribute to disease.

“You can rest assured that combined exposures will be a part of the new strategic plan,” Birnbaum told the audience, referring to the strategic plan update that is underway.

Catherine Stoney Co-organizer Stoney moderated a session on nonchemical stressors and atherosclerosis. (Photo courtesy of Michael Garske)

Interdisciplinary, collegial

Stoney was pleased by the intense focus of meeting attendees. “It was a very collegial group,” she said. “They took their task very seriously, which gives a sense of how important the topic is.”

Participants visibly enjoyed the interdisciplinary nature of the discussions. Olive said the meeting drew a unique mix of scientists, including cardiologists, comparative medicine experts, toxicologists, psychologists, immunologists, epidemiologists, public health scientists, systems biology experts, imaging experts, geneticists, and chemists.

Complex factors and mechanisms

Not surprisingly, the exposures and mechanisms discussed were similarly broad and complex. Presenters highlighted chemical stressors such as ozone, fine particulate matter (PM2.5), nutrient deficiencies, and metals — in excess or deficiency — as well as bisphenol A and polychlorinated biphenyls. Geo-spatial data on heart disease mortality highlighted increasing geographic disparities.

Nonchemical stressors ranged from poverty, psychosocial stress, and the built environment to sleep and circadian rhythm disruptions, depression, anxiety, infection, and sedentary lifestyles.

participants broke into three work groups When participants broke into three work groups to brainstorm data needs and research approaches, the discussions were animated and fruitful. (Photo courtesy of Michael Garske)

Inflammatory pathways

“Cytokines, bone marrow, and the sympathetic nervous system are involved,” said Stoney, highlighting inflammatory pathways addressed in many of the talks. “When you’re under a lot of stress, it triggers the bones to produce more inflammatory cells, that make their way into blood vessels and cause plaque formation.”

On the chemical side, for example, inhalation of particulate matter is linked to both pulmonary oxidative stress and inflammation. Both eventually affect the heart. Olive, who summarized the first day’s presentations, pointed out that oxidative stress is associated with atherosclerosis.

“There’s definitely room for more research,” Olive said. “For the paper, we’ll invite each participant to reference the literature that supports known mechanisms.”

Webinars prepare participants

Organizers helped participants prepare for the meeting by offering two webinars on the concept of adverse outcome pathways (AOPs), which are a means of studying mechanisms involved in development of disease, especially from exposures.

The first webinar introduced the AOP framework. The second webinar addressed approaches to assembling and assessing AOP information.


Ana Navas-Acien Ana Navas-Acien, Ph.D., from Columbia University, presented epidemiological evidence and potential mechanisms for the role of metals in CVD. (Photo courtesy of Michael Garske)
Cavin Ward-Caviness Cavin Ward-Caviness, Ph.D., from the U.S. Environmental Protection Agency, discussed the importance of genetic and epigenetic factors in susceptibility to atherosclerosis. (Photo courtesy of Michael Garske)
Andy Rooney and Koren Mann From left, Andy Rooney, Ph.D., from NTP, and Koren Mann, Ph.D., from McGill University, each co-moderated a breakout session. (Photo courtesy of Michael Garske)
Steven Edwards Steven Edwards, Ph.D., from RTI International, discussed potential uses of AOP for documenting collective causes of atherosclerosis. (Photo courtesy of Michael Garske)
Karina Davidson and Sanjay Srivastava From left, Karina Davidson, Ph.D., from Columbia University, discussed nonchemical stressors. Sanjay Srivastava, Ph.D., directs the University of Louisville’s Superfund Research Center. (Photo courtesy of Michael Garske)
Jesus Araujo Jesus Araujo, M.D., Ph.D., from the University of California at Los Angeles, described studies of air pollution using animal models of atherosclerosis. (Photo courtesy of Michael Garske)
Daniel Conklin and Robert Furberg Daniel Conklin, Ph.D., left, from the University of Louisville, and Robert Furberg, Ph.D., from RTI International worked together in one of the breakout groups. (Photo courtesy of Michael Garske)
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