EXPOSING THE EXPOSOME

Genomics in recent decades has yielded revolutionary insights about the relationship between genes and health, yet despite the many benefits of mapping the human genome, research also suggests genetic factors are not major causes of chronic disease overall.

That finding points to environmental exposures, influences from outside the genome. It includes a dizzying range of substances and forces that might affect our health, from pathogens, chemicals, and radiation to socioeconomic factors like poverty or racism.

There is already abundant research on the health risks of some specific toxicants and other hazards. But given the scale and scope of different exposures across a human lifetime, and the potential for cumulative or compounding effects, experts say we still have a lot to learn. 

"One piece that has been missing, as we move more toward this idea of the exposome, is that it isn’t any one specific chemical, exposure or social factor that leads to disease in individuals. It's really a combination of them," says Carmen Marsit, PhD, executive associate dean for faculty affairs and research strategy.

Marsit is also director of the HERCULES Exposome Research Center, a collaboration between Rollins and Georgia Institute of Technology focused on high-impact environmental health research. Now in its 10th year, HERCULES is one of about 20 such centers across the country, part of a broad shift in exposure science to a more holistic approach.

This shift evokes the evolution of genetics research in the last century, when the focus on individual genes gave way to a more comprehensive view of the genome, says Douglas Walker, PhD, associate professor of environmental health. 

“The exposomics field is kind of where genomics was 30 or 40 years ago,” Walker notes. “A lot of the original genetic studies were focused on candidate gene studies.” In those earlier studies, researchers would often hypothesize that a certain gene predisposes people for a certain disease, then find people with the disease and test for that gene only.

“Most of the candidate gene findings have not been replicated in larger, genome-wide studies,” Walker adds. “Now we're measuring all mutations within the genome. Similarly, with exposures, rather than just focusing on known pollutants, we're focusing on as many as possible.”

Hence the “exposome” — like the genome, but for exposures.

Coined in a 2005 paper by molecular epidemiologist Christopher P. Wild, the word “exposome” refers to a person’s complete history of exposures “from the prenatal period onwards.” If that sounds like too much to measure, you’re not alone.

Wild acknowledged this conundrum in his paper. “Developing reliable measurement tools for such a complete exposure history is extremely challenging,” he wrote. “Unlike the genome, the exposome is a highly variable and dynamic entity that evolves throughout the lifetime of the individual. It is not without good cause that progress has been limited in meeting this goal.”

The exposome still poses an extreme challenge nearly 20 years later, but the concept and its importance have caught on, while new technology offers potentially game-changing ways to measure previous exposures and anticipate new ones.

“We can measure things to smaller concentrations, and we can measure a lot of different types of chemicals, which allows us to try to capture that piece of it,” Marsit says. “Similarly, on the more geographic-based exposures, we're getting better at modeling what air pollution or other types of climate effects might be. We can bring all that data in as well as capture a lot of the social factors that might exist because of where a person lives.”

Air pollution is a pervasive threat to public health, with 99% of all humans exposed to levels exceeding World Health Organization (WHO) standards. The combined effects of indoor and outdoor air pollution are associated with 6.7 million premature deaths globally per year, according to the WHO, which estimates outdoor air pollution alone causes 4.2 million. Traffic exhaust is a major factor, as are sources ranging from wildfires to power plants.

Exposomics would be daunting under any circumstances, but it’s especially difficult given the volume and diversity of ongoing human-caused environmental problems. Along with timeless, relentless hazards like soot or heavy metals, there are newer plastics, pesticides, and “forever chemicals,” plus thousands of emerging industrial chemicals with unknown effects on human health.

Still, while the exposome may be expanding, so is our capacity to explore it, thanks to researchers like Walker. Using high-resolution mass spectrometry, Walker has found a high-throughput and cost-effective method for measuring up to 100,000 chemical signals from a biological sample, hinting at the potential exposomics may hold for precision medicine.

“It's a powerful approach because it not only lets us detect very low levels of chemicals in a biological sample, but it also gives us information that lets us predict the identity of the chemicals we're measuring,” he says. “We can detect tens of thousands of chemical signals without necessarily knowing what they are ahead of time.”

Data science can then help suss out the most important signals linked to health outcomes. Walker’s lab focuses on developing analytical methods that are both powerful and practical for large-scale population screening. “We can use these methods to measure about 20,000 blood samples per year,” he says. “We can do very large exposome screening.”

Truly capturing every exposure across a person’s lifespan is unrealistic, but if tools like these can reveal enough about the most relevant exposures, it may also be unnecessary.   

“The traditional definition was focused on all exposures across the lifespan, but that's sort of a pie-in-the-sky definition,” Walker says. “It will never be possible to measure every exposure from birth to when we die. What we really focus on are the key measurements we can use to better understand and evaluate the history of exposure and how the biochemical changes that occur might predispose us to illnesses like cancer and heart disease.”

The exposome begins before birth and grows rapidly with each day’s exposures. If unexplained health problems emerge later in life, clues about their origins may be hidden somewhere in that massive, murky history.

Research has found clear health risks from traffic-related air pollution, especially components like fine particulate matter (PM 2.5) and nitrogen dioxide (NO2). Similarly, there’s ample evidence of the dangers of radiation, or metals like lead and mercury. We also have a decent understanding of how some pesticides and industrial compounds might affect us. But that knowledge is still dwarfed by how much we don’t know about countless other chemicals.

“When we think about all the exposures that you could be exposed to, it's kind of scary,” says Donghai Liang, PhD, assistant professor of environmental health. “Just think about air pollutants. It's not just PM 2.5. In fact, there are hundreds to thousands of different air pollutants out there. But the EPA (Environmental Protection Agency) only monitors six of them.”

Most people are exposed to a diverse blend of pollutants during their lives, including some known and suspected carcinogens. There is clear evidence of cancer risk for certain exposures like cigarette smoke, Marsit notes, but despite compelling hints that air pollution and other contaminants may also lead to cancer, certainty remains elusive overall.

“There's actually an increase in lung cancers among people who are nonsmokers,” Marsit says. “So what role are other air constituents playing in that? There's a thought it could be related to some of these exposures, but we lack clear evidence like we have with cigarette smoking. And the same is true for chemicals related to other types of cancers.”

Since many cancers develop slowly, any precipitating exposures could have occurred decades earlier. “It's really hard to understand what those exposures were at the time when those initial cancer cells developed, that then had to grow for 20, 30, 40 years to be diagnosed as a cancer,” Marsit says. “So that's the real challenge with cancer — that you have these long latencies and it's hard to make some of those connections because of that time period.”

In addition to the possible cancer risk from some pollutants, an array of other health concerns is also associated with chemicals we frequently encounter. They include endocrine disruptors — chemicals that can mimic or interfere with hormones.

“We can see that exposure to these endocrine disruptors during pregnancy may lead to developmental impacts in children,” Marsit says. “Attention deficit disorder or autism spectrum disorders can be linked to a lot of endocrine-disrupting exposures during pregnancy because they are relatively common outcomes. And it's a pretty short window. You can go from pregnancy to kids who by age 5 or 6 start showing these outcomes. There are a lot of studies following children like that, so you're able to make those connections.”

Such studies are a focus at Rollins, where environmental health research often concentrates on prenatal exposures, healthy pregnancies, and children’s health outcomes.

Liang, for one, studies how prenatal exposure to some chemicals affects child and maternal health. His research covers air pollution and persistent organic pollutants, including a notorious group of chemicals called per- and polyfluoroalkyl substances (PFAS).

“The problem with PFAS is that, unlike many other organic or nonorganic pollutants like pesticides or insecticides, PFAS persist in the environment because they break down very slowly, both in the environment and the human body,” Liang says.

That fact earned them the nickname “forever chemicals,” and while their persistence is useful for some industrial purposes, it’s bad news in a biological context. Extreme durability and bioaccumulation are two red flags for PFAS, according to the National Institute of Environmental Health Sciences. Their prevalence in common products — from food takeout containers to flame-retardant materials — offer more exposure opportunities. Animal studies have linked PFAS to health risks including liver damage, but effects in humans remain unclear.

Liang is trying to identify health effects from exposure to PFAS and other chemicals as well as unmask the molecular pathways enabling those effects. “For example, how can we explain why, when you are exposed to a high level of PFAS, you have a higher risk of preterm birth or restrictive fetal growth?” he says.

Micro- and nanoplastics are another ubiquitous form of pollution, commonly appearing in human blood, lungs, and other organs. Research suggests they might harm us, maybe acting as endocrine disruptors, but their health effects remain largely unknown, Walker says.

That’s true for many industrial chemicals, which Marsit attributes to a U.S. regulatory approach that allows new compounds to be approved without evidence of their safety. “All of our bans or controls of any kind on chemical exposures only occur after toxicity is demonstrated,” he says. “Companies are not upfront having to demonstrate that a product is safe.”

If a chemical is proven harmful and eventually banned, industries are free to turn to other chemicals with similar properties to take its place, adds Amina Salamova, PhD, assistant professor of environmental health. Another pesticide that kills a specific pest or another nonstick or flame-retardant material are easy possibilities.

“Often, if one chemical is banned, industry will replace it with a different one, which is usually not very different in terms of chemical structure,” she says. Thus, the new chemical poses similar risks to those of its predecessor. Even if the replacement hails from a different class of chemicals, its effects on human health may simply be unknown.

Amid this chaos, there are few clear links from specific pollutants to specific effects, Liang points out. “It's very challenging to isolate an individual pollutant effect, especially in a population health study,” he says. “On the epidemiological side, you always assume people are only exposed to one pollutant, but in the real world, they're exposed to multiple ones.”

None of these exposures occur in a vacuum, points out Lauren McCullough, PhD, associate professor of epidemiology. While obesity alone is a risk factor for cancer, the danger varies significantly depending on other exposures, beyond those contributing to the obesity itself.

“If you pair obesity with living in a high-pollutant area with endocrine-disruptive chemicals, that combination can be synergistic for the initiation of cancer,” she says. “So we try to think about how these multiple exposures interact in a way that puts someone at heightened or reduced risk.”