Body’s Reaction to Smog May Be Tied to Genes

It’s a quintessential smoggy afternoon in Los Angeles, one that makes you feel as if your lungs have shut down. You can’t take a deep breath without your chest hurting. Walking up a hill leaves you panting. Your eyes tear, you cough. You might even come down with a cold or the flu.

Your neighbor, on the other hand, is oblivious to the foul air. She heads out for a hearty jog, her breathing effortless, as if the skies over Southern California were cleansed by fresh country breezes.

But don’t admire her athletic prowess or her strong lungs--the difference could lie in her genes.

Scientists at the Johns Hopkins Schools of Public Health and Medicine have discovered inherited traits that might explain why some people are resistant to the effects of pollution while others are vulnerable, even if they are breathing the same air.

Fixed at birth, your genetic makeup--more than your physical fitness or your overall health--could dictate whether you are likely to suffer during smog bouts.

A genetic link has long been suspected, but the recent discovery of the specific chromosomal pattern in mice offers the first scientific evidence.

When mice bred to be genetically similar are exposed to ozone--the potent gas that is the predominant ingredient of smog--a set of three genes orders a large volume of immune cells to move into the airways, triggering inflammation, said Steven Kleeberger, an environmental health scientist who led the Johns Hopkins research.

But when these susceptible mice were treated with antibodies that turn off the proteins dispatched by the genes, the inflammation--an injury that can hamper breathing and lead to premature aging of the lungs--was prevented. The mice became virtually invulnerable to smog.

While environmental factors such as diet, vitamins and lifelong exposure to air pollution are also likely to influence who winds up sensitive, Kleeberger believes genetics plays a key--and often overlooked--role.

“What we have found with ozone is that with an appropriate exposure--closely resembling what we would find in Los Angeles--there are two or perhaps three genes that control the inflammatory response that results in injury,” Kleeberger said. Most of the findings have not yet been published, but they have been discussed at recent scientific conferences.

Although researchers have not yet looked in the human body for these same “smog genes,” found on Chromosome 17 in mice, they probably exist, because there usually is a human counterpart for genes found in mice.

“It is very, very likely,” Kleeberger said, “that whatever we found in the mouse will be found in humans as well.”

Under the Clean Air Act, air throughout the United States must be safe to breathe for even the most vulnerable people. Confirmation of a genetic link might some day redefine whom the U.S. Environmental Protection Agency considers sensitive, a critical factor in determining how stringent pollution standards need to be to protect public health.

If humans do share the smog susceptibility genes with mice, a genetic test could identify people who might choose to alter how they live and breathe, avoiding smoggy cities or spending afternoons indoors. Eventually, Kleeberger hopes the findings might even lead doctors to develop treatments to prevent the health damage, as he did with mice.

Still, the link in humans remains questionable. No one knows how many people might fit the genetic background, how strong the tie runs in families, or how big an influence the gene-caused inflammation has on symptoms.

“Almost certainly we think there is a genetic component to people’s response to ozone,” said Dr. Robert Devlin, EPA’s chief of clinical research. “There is good reason to think that’s true, but there is not what I would call compelling evidence yet.”

In fact, the only major human experiment--using 19 pairs of identical twins, who share identical genes--has found no clear pattern of sensitivity or tolerance to smog.

“I was disappointed, because I thought surely there was going to be a very striking twin effect,” said Dr. Phil Bromberg, director of the Center for Environmental Medicine and Lung Biology at the University of North Carolina, which conducted the experiments.

“There was a hereditary influence, but not to the point where scientists would care to go out on a limb and say we have the evidence that there definitely is a hereditary factor,” he said. “The fact that we’re not seeing a statistically significant result implies that the trend is weaker than one might have thought.”

In specially sealed chambers, the twins were exposed for two hours to fairly high amounts of ozone--65% greater than the Los Angeles region’s worst day last year but similar to Mexico City’s. After moderate exercise, their lung function was compared with their twin’s. In more than half of the pairs, each twin had a lung response that matched the other’s. But it wasn’t a strong enough trend to suggest that genetics played a dominant role.

“The implication is that there are environmental factors working as well,” Bromberg said, “things like diet, the amount of antioxidants you consume or other exposures, such as going to a smoky bar and breathing passive smoke.”

Bromberg, though, said the findings are “by no means definitive” in ruling out a genetic link. He is doubling the number of twins before publishing the results.

One explanation for the different results between the mice--which were bred to be genetic replicas--and the human twins is that the mice were tested for inflamed airways--the first sign of chronic lung damage caused by ozone. The twins instead were tested for reduced ability to inhale and exhale, a more immediate, acute effect caused by higher doses.

In some humans, lungs become inflamed at fairly low levels of ozone: 0.08 parts per million, which the Los Angeles region exceeds on 35% of all days. But inflammation does not always hamper breathing rapidly, so even if genes control the inflammatory damage, it might have a long-term health effect on people but not immediately change how well their lungs function.

The Los Angeles Basin--with its tons of emissions baked by sunlight, blocked by mountains and trapped near ground by stagnant weather conditions--has the nation’s worst concentrations of ozone. Formed when hydrocarbons and nitrogen oxides react with the sun’s rays, the colorless ozone often mixes with particles and other gases to form the region’s notorious whiskey-brown haze.

Reduced lung function--which means people have trouble inhaling deeply--is the most common symptom during exertion on smoggy days. In the long term, ozone exposure seems to age the lungs prematurely. Ozone also might weaken natural defenses against bacteria and viruses, bringing on colds and flu. Breathing it aggravates respiratory diseases such as asthma, but whether long-term exposure causes lung cancer and other chronic disorders is unknown.

Since the early 1980s, medical experts have found enormous differences in how individuals respond to air pollution, and it often has nothing to do with how healthy or fit they are. Some people, even some asthmatics, seem resistant even at high concentrations, while it takes a much smaller and shorter dose to trigger breathing problems in others.

“There is a tremendous amount of variability in how individual humans respond when they are exposed to the same amounts of ozone in the same way,” Bromberg said. “Some people are unable to take a deep breath, they can lose a quarter of their vital [lung] capacity. Others are totally nonreactive--nothing happens.”

Some Olympic cyclists suffered chest pain, shortness of breath and reduced exercise performance when cycling while breathing small amounts of ozone in smog chamber experiments at Rancho Los Amigos Medical Center in Downey. Others had no symptoms at all.

“It was very clear that some of these people, even though they are very fit athletes, were very susceptible to a low concentration of ozone, and they stayed very sensitive,” said Dr. Henry Gong, the medical center’s chief of environmental health, who heads one of the most experienced teams testing people in smog chambers.

“But others were probably genetically gifted,” Gong said, “with genes that either protected them from ozone somehow, or the susceptibility genes were gone.”

However, as with the twins in North Carolina, Gong said the differences in the Olympians might not have been genetic, but instead due to antioxidants in their diet such as beta carotene and vitamins C and E, or some other factor.

Isolating the smog-sensitive genes is part of a fledgling field called eco-genetics, which seeks to discover how inherited traits influence people’s response to pollution. Genes are believed to influence who gets cancer, asthma and many other diseases, so it is reasonable to assume that they play a role in injuries and illnesses linked to the environment.

Perhaps some day a genetic test can identify who is vulnerable to smog. But even if gene therapy works in the future, it doesn’t mean that the EPA and local officials will abandon their decades-long, costly efforts to clean the air. In most urban areas, air quality is improving due to regulations targeting cars, factories, consumer products and other sources.

Yet the EPA this year is expected to set a tighter health standard for ozone, which could add billions of dollars to the cost of smog cleanup. The EPA says the current limit, set 20 years ago, fails to safeguard all sensitive people. The agency deems asthmatics and others with respiratory diseases the most susceptible group, and sets its smog standard to protect them.

If smog genes do exist, Gong said, it would “open up a Pandora’s box” for the EPA, raising tough questions about who is at risk and how to protect them. The EPA, for example, would need to know if everyone with the genes is susceptible, and how much so, before basing its public health decisions on such factors.

Yet as Kleeberger strives to refine his research, and the tools of eco-genetics are improved, science may be able to help officials understand more fully who is at risk among the 70 million Americans who are breathing levels of ozone considered unhealthful.

“Extrapolation from mouse to man is always fraught with difficulties,” Bromberg said.

But as the map to human genes becomes more precise, perhaps it will provide answers to the long-standing mystery of why some people fall victim to smog.

“We don’t really know how ozone works, and if we can isolate the genes, it could provide answers,” Devlin said. “When you think how many millions of people are living in areas that [exceed] the health standard, we want to know, are there ways to protect these people?”

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Smog Sickness

Reactions to ozone in smog can be vastly different, and evidence is emerging that genetic factors may play a key role. Here are some research results related to breathing various amounts of ozone. For comparison, the Los Angeles Basin surpassed the current health standard of 0.12 parts per million on 87 days last year.

Ozone Exposure: 0.12 parts per million for 1-3 hours or 0.08 for 6 hours

Health Effect: In heavily exercising adults: Reduced lung function, cough, shortness of breath, chest pain, airway inflammation

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Ozone Exposure: 0.18 parts per million for 1-3 hours

Health Effect: In adults: Reduced exercise performance.

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Ozone Exposure: Chronic, repeated exposure to 0.12 parts per million

Health Effect: In lab animals: Changes in lung structure, function and biochemistry that could be signs of chronic lung disease.

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Ozone Exposure: 0.08 parts per million for 3 hours

Health Effect: In lab animals: Increased susceptibility to bacterial respiratory infections.

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Ozone Exposure: 0.01 to 0.15 parts per million for several days

Health Effect: In children and adolescents playing outdoors: Reduced lung function, Aggravation of asthma, increased hospital visits.

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The Research

* When mice breathe ozone, a set of genes orders immune cells to accumulate in airways, causing inflammation. In humans as well as mice, this inflammation can hamper breathing, causing premature aging of the lungs.

* When the mice with genes sensitive to smog are treated with certain antibodies, the inflammation is prevented, making them resistant to smog.

* Humans probably have the same “smog genes” as mice, but scientists have not yet looked for them.

Source: U.S. Environmental Protection Agency, Johns Hopkins University