SCOTT R. DIEHL, PHD, PROFESSOR, DEPARTMENT OF ORAL BIOLOGY, AND DIRECTOR, CENTER FOR
PHARMACOGENOMICS AND COMPLEX DISEASE RESEARCH, UMDNJ-NEW JERSEY DENTAL SCHOOL
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he adverse effects of air pollution on health are well-established. However, the actual biological mechanisms that underlie our bodies’ responses to different types of gases and particles in the air are only partially understood. Very recently, scientists have begun to recognize that all people are not the same in terms of how air pollution affects their health. A new focus is beginning to emerge on individual differences in responses to these toxic substances. This strategy is based on studying inherited variation in genes that metabolize the toxic substances or are involved in cardiovascular or pulmonary pathways that are most severely affected by air pollution exposure.With the great expansion of industrial activity in recent years, much of China has seen decreases in air quality. In Beijing, air pollution levels are usually much higher than even in the most severely polluted places in the U.S. During last summer’s (2008) Olympics, unprecedented measures were implemented by the government with the goal of reducing air pollution during the Games so that athletes’ performances would not be adversely affected. A collaborative team of UMDNJ and Chinese scientists and clinicians worked together to take advantage of this unique opportunity to learn more about the “how and why” of air pollution’s effects on human health.
Great improvements have been made in the air quality in this country and in much of the developed world during the past 50 years. Nevertheless, even the reduced levels of pollution in the air here still cause serious health problems, especially for those who are at increased risk due to other health conditions such as asthma, emphysema, COPD and cardiovascular diseases. Unfortunately, the air quality in much of the developing world has declined dramatically, coincident with the rapid economic growth accompanied with increased industrial activities and motor vehicles. China has been one of the primary locations where this rapid industrialization has taken place, and a major increase in levels of air pollution has occurred throughout much of the country. In Beijing, air pollution levels are usually much higher than even in the most severely polluted places in the U.S. Efforts by the government are beginning to address this very serious problem, and these were given a major jump start and test run last August when the Olympic Games were held in Beijing. As a condition of being awarded the opportunity to host the Games, the Chinese authorities committed to taking truly unprecedented measures to improve the air quality in Beijing. Although some of these measures could only be implemented for a few weeks around the games themselves, others were designed to improve air quality over the longer term. These measures were mostly successful, and the Games were generally considered a great success.
Performing research on health effects of exposure to toxic substances requires us to address important ethical and logistical challenges and limitations. We obviously cannot expose subjects to very high levels of pollutants for long periods of time in the laboratory, then take away the pollutants and see how this change affects measures of health. Research conducted in cities under naturally-occurring circumstances has shown that very large increases in air pollution for a period of days or weeks leads to substantially increased rates of sickness and death due to heart attacks and pulmonary crises. However, few studies have been conducted to examine health effects of air pollution reduction. The problem was that it is difficult if not impossible under normal circumstances to predict when a prolonged reduction in pollution across a large area would occur. The situation scheduled to take place in Beijing during the Olympics thus presented us with a unique opportunity to study the effects of air pollution reduction on human health. Our research team capitalized on this by developing a study plan and obtaining grants from both the Health Effects Institute and the NIH to support the research. We recruited experts from the broad array of disciplines needed for this research including our colleagues Drs. Howard Kipen, Pamela Ohman-Strickland, David Rich and Shou-En Lu from UMDNJ and Drs. Tong Zhu, Wei Huang, Min Hu, GuangFa Wang, Ping Zhu and Yuedan Wang in Beijing.
JUNFENG (JIM) ZHANG, PHD, PROFESSOR AND CHAIR, DEPARTMENT OF ENVIRONMENTAL AND OCCUPATIONAL HEALTH; ASSOCIATE DEAN, PISCATAWAY/NEW BRUNSWICK CAMPUS; ASSOCIATE DEAN FOR GLOBAL
PUBLIC HEALTH, UMDNJ-SCHOOL OF PUBLIC HEALTH
Subjects participating in our study were evaluated for “biomarkers” of inflammation, body burden of oxidative stress, autonomic tone, and cardiovascular function (thought to be responsible for many of the negative health effects) in their blood, urine and exhaled breath. In addition, subjects provided saliva samples that we used to extract DNA. Each participant was assessed six times, twice before the Olympics began and before the air pollution reduction measures were put in place, twice during the Olympics when air quality was supposed to be improved, and two more times after the Games were over when some of the air pollution control measures were relaxed and air pollution was expected to increase. We are currently analyzing these data by running assays in our labs here in the U.S. and in China and have already seen dramatic changes in some of the inflammatory and oxidative stress biomarkers that correlate nicely with these different time points.
Although the very negative effects of air pollution on health are well-established, the actual biological mechanisms that underlie our bodies’ responses to different types of gases and particles in the air are only partially understood. A new focus is beginning to emerge on individual differences in response to these toxic substances. We are employing this strategy of “individualized medicine” in our study of the health effects of air pollution in Beijing. We are measuring inherited variation in genes that metabolize the toxic substances in the air or genes that are involved in the cardiovascular or pulmonary pathways most severely affected by air pollution exposure. Most of the DNA variants that we will study are Single Nucleotide Polymorphisms (abbreviated as “SNPs” and pronounced “snips”). These are places in the genome where a single DNA base has been changed, for example, from a “C” nucleotide to a “T” base. When these changes occur in the portion of a gene that codes for a protein’s amino acids, a different amino acid may be inserted into the protein, changing the protein’s function in a subtle or a dramatic way. Other SNPs may cause the protein’s synthesis to be terminated prematurely and be totally non-functional. Still other inherited variants may affect the level of expression of mRNA and protein and thereby influence the person’s response to toxic substances in the air. Our laboratory uses several different assay methods to determine the DNA sequence at positions of interest in the genome. One of these methods is called the TaqMan assay and this is illustrated in Figure 1.
FIGURE 1. MOLECULAR ASSAY OF A POLYMORPHISM IN THE VITAMIN K EPOXIDE REDUCTASE COMPLEX GENE. EACH DOT REPRESENTS THE GENOTYPE OF INDIVIDUAL SUBJECTS. GREEN IS THE COMMON A/A GENOTYPE, ORANGE A/G AND BLUE G/G. LIGHT BLUE DOTS ARE NEGATIVE CONTROLS AND BLACK DOTS REPRESENT OCCASIONAL
FAILURES OF THE ASSAY. VITAMIN K IS ESSENTIAL FOR BLOOD CLOTTING BUT MUST BE ENZYMATICALLY ACTIVATED FOR THE CARBOXYLATION OF GLUTAMIC ACID RESIDUES IN SOME BLOOD-CLOTTING PROTEINS. THIS GENE ENCODES THE ENZYME RESPONSIBLE FOR REDUCING VITAMIN K 2,3-EPOXIDE TO THE ENZYMATICALLY ACTIVATED FORM. FATAL BLEEDING CAN BE CAUSED BY VITAMIN K DEFICIENCY AND MUTATIONS ARE ASSOCIATED WITH DEFICIENCIES IN VITAMIN-K-DEPENDENT CLOTTING FACTORS AND RESISTANCE TO THE DRUG WARFARIN. AIR POLLUTION EXPOSURE IS THOUGHT TO DISTURB THE NORMAL BALANCE OF CLOTTING FACTORS AND THIS MAY BE ONE MECHANISM BY WHICH IT INCREASES RISK OF HEART ATTACKS AND STROKE.
In the coming months, it will be exciting to see whether any of the candidate gene polymorphisms we are testing have a major impact as to how different people respond to changes in air pollution exposure. In the future, we hope to build on this experience to recruit a much larger number of subjects so that we’re able to perform studies looking at the entire genome. If successful, our strategy of focusing on individuals’ inherited differences offers great potential for advancing our understanding of the “how and why” of the biological mechanisms that underlie air pollution’s effects on human health.
Scott Diehl is the director of the Center for Pharmacogenomics and Complex Disease and a professor in the Department of Oral Biology at UMDNJ- New Jersey Dental School. He earned his PhD from the University of Texas at Austin and conducted research at the University of Michigan, the Medical College of Virginia and the National Institutes of Health before moving to UMDNJ in 2002. His other research involves genetic studies of susceptibility to pain and side effects of pain medications, periodontal disease, dental caries, dental fluorosis, head and neck cancer, and the birth defect, cleft lip and palate.
Junfeng (Jim) Zhang is a professor of Environmental and Occupational Health at UMDNJ-School of Public Health (SPH) and a member of the Environmental and Occupational Health Sciences Institute (EOHSI), jointly sponsored by UMDNJ-Robert Wood Johnson Medical School and Rutgers University. He received a PhD degree in Environmental Sciences and Public Health jointly from UMDNJ and Rutgers University and an MS degree in Atmospheric Chemistry from Peking University. His research interests include assessing human exposures to environmental contaminants and resulting health effects, both on a global scale and within a local context. Dr. Zhang’s laboratories at SPH and EOHSI develop novel methods for biomarkers of human exposure and health effects.
