Issue Date: September 28, 2015
The Exposome Turns 10
“Omes” are all the rage these days. The genome, the proteome, the metabolome—they’ve been dominating the scientific scene.
One “ome” that hasn’t been on the tip of everyone’s tongue, though, is the exposome. Christopher P. Wild, now director of the International Agency for Research on Cancer, in Lyon, France, introduced the concept in 2005, defining it as the sum of environmental exposures a person experiences from conception until death. These exposures include chemicals in the environment as well as the body’s response to infection and psychological stress.
Measuring those exposures and their impact has been a challenge, however, keeping the exposome out of the limelight. At the American Chemical Society national meeting in Boston last month, researchers took stock of the current state of exposome research in a symposium sponsored by the Division of Chemical Toxicology.
“Ten years later, it’s a nice time to stop and see where we are in addressing this question and where we are with the quality of our tools for exposure assessment,” said Silvia Balbo, organizer of the symposium and assistant professor of public health at the University of Minnesota.
When conceived, the exposome represented a big change from conventional exposure analysis. The traditional approach examines chemical exposures one at a time, or it looks at a specific class of molecules to which a person might have been exposed. But that’s not really true to life.
We are constantly barraged by chemicals inside and out. And those exposures accumulate over time. What are those exposures and how do they affect our health? Scientists hope the answers to those questions can be found in the exposome.
When Wild proposed the exposome, he knew that it wouldn’t be feasible to measure the effects of every exposure on a person, but he wanted to draw attention to the need for better tools and a more expansive view. The concept “challenges people to think much bigger about what we should be trying to capture,” said Wild, who couldn’t attend the symposium in Boston.
Stephen M. Rappaport, an exposure biologist at the University of California, Berkeley, School of Public Health, has been a leading proponent of the exposome approach. He estimates that conventional exposure studies have focused on the same set of 300 compounds for the past five decades.
“Some of those 300 compounds have been shown to be causes of disease. That’s why we started looking at them in the first place,” Rappaport told C&EN. “But by continually studying those same 300 chemicals, we’re not going to explain any more disease incidence than we have already. It’s time to put those 300 behind us.”
Instead of targeting a prescribed list of chemicals, studying the exposome involves taking an untargeted approach of analyzing everything that can be detected. “I don’t think we’re smart enough to guess which molecules out of all the hundreds of thousands that are possible are likely to be the most important,” Rappaport said.
“The exposome has brought to our attention the fact that we need to look at multiple things at the same time,” Balbo explained. “We have to move away from the typical experiment in which you have an acute exposure and you look at what happens. That has brought some understanding, but it’s not really helped us much in terms of understanding what happens when you have complex diseases in which genetic factors and various types of exposures play a role.”
To do such untargeted analyses, scientists are relying on mass spectrometry methods that were originally developed for the various “omics,” especially metabolomics. In fact, the metabolome, which encompasses all the small molecules produced by cellular processes, could be considered a subset of the exposome. That’s because many metabolites that cells produce are directly influenced by environmental exposure.
During the symposium in Boston, researchers discussed advances in exposome research using metabolomics and “adductomics” approaches. Adductomics is the untargeted study of chemical modifications that have been made to proteins and DNA in the body as a result of environmental exposure.
Kurt Pennell, an environmental engineer at Tufts University, and Dean Jones, a biochemist at Emory University, use metabolomics methods to determine the biological response to environmental exposure. They use high-resolution mass spectrometry to do untargeted analysis of metabolites. They can detect more than 50,000 spectral features in about 10 minutes, Pennell said.
But the researchers don’t know what all those metabolites are, and they’re even further from being able to quantify all of them. It would be impossible to run calibration curves for thousands of different chemicals, Pennell said.
“The key thing is to keep expanding the number of compounds we can measure with confidence,” Pennell said. “This will come with better instruments and better methods of standardization.”
Pennell’s goal is to relate exposome information to genetic information. In one study, his group is collaborating with researchers at Children’s Hospital in Boston to relate chemical exposure and whole-genome sequencing of mothers and children with autism spectrum disorder. The researchers hope to one day understand what combinations of genetic mutations and environmental exposures contribute to autism.
Pennell’s collaborators have already done whole-genome sequencing of the parent and child pairs. They will soon share blood samples with Pennell’s and Jones’s labs to run exposure and metabolomics analyses.
Margareta Törnqvist, a researcher at Stockholm University, in Sweden, has long studied protein adducts formed as a result of environmental exposure. When she started studying such adducts, she would look for them one at a time. Over the years, she has studied such adduct-forming chemicals as ethene from tobacco smoke and acrylamide from food.
The compounds Törnqvist identifies are electrophiles that form adducts with the N-terminal valine of the red blood cell protein hemoglobin. “These electrophiles are very short-lived in the body,” Törnqvist said. But after they form covalent adducts, they are stable enough for her team to detect them.
Hemoglobin is a good choice for capturing adducts because people carry around large quantities of it, and adducts accumulate over the lifetime of red blood cells, which is about four months in humans.
Törnqvist has recently moved beyond looking at specific adducts on hemoglobin and developed a method to screen for unknown adducts. She uses a modified Edman degradation method that specifically detaches N-terminal adducts. Then she uses mass spectrometry fragmentation patterns to identify them. In a preliminary study comparing smokers with nonsmokers, her group found 19 unknown adducts related to cigarette smoking (Chem. Res. Toxicol. 2014, DOI: 10.1021/tx5002749).
Balbo is taking a similar approach to the analysis of DNA adducts. She uses high-resolution mass spectrometry to screen for chemically modified DNA bases. Eventually she hopes to determine whether adducts are being formed at specific locations on the DNA that lead to changes in transcription of the DNA to RNA.
The technology needed for many exposome measurements is now in place, said Rappaport, who was unable to attend the symposium in Boston. The thing that’s missing is good biospecimens.
“If you really want to find causes of disease, you have to remove that reactive element that’s associated with changes that happen because of the disease itself,” he told C&EN. “You need biospecimens that were collected a long time before the disease presented itself.” These specimens would come from people who were recruited and followed for the rest of their lives.
One sign that the exposome is slowly approaching the status of the other “omes” is the extent to which the National Institute of Environmental Health Sciences, part of the National Institutes of Health, is promoting the approach. It is part of NIEHS’s current strategic plan, which has a goal to “transform exposure science by enabling consideration of the totality of human exposures and links to biological pathways.” David Balshaw, head of NIEHS’s Exposure, Response & Technology Branch, has been the main champion of the approach at NIEHS. Scheduling conflicts prevented him from attending the symposium in Boston.
When Wild first coined the term exposome, Balshaw and others doubted it was feasible. “We’ll never be able to measure everything, always, in everybody,” Balshaw told C&EN. But over the past 10 years, he said, it’s become clear that “we can measure a lot of things.”
“A critical piece of the exposome is the ideal of data-driven discovery,” Balshaw continued. “We can find things that we know we’re exposed to but don’t think are a problem. We can find things that we don’t know we’re exposed to that are potential effectors of health. And we can discover interactions between environmental factors that we wouldn’t necessarily hypothesize.”
And NIEHS is ponying up money to make exposome analysis possible for researchers who might not have the necessary technology in their own labs. The institute is preparing to launch the Children’s Health Exposure Analysis Resource, which will include a network of laboratories that will provide targeted and untargeted analyses of samples from NIH-funded children’s health studies. The program will also run a data center with a public-access repository and data analysis tools and services. The services will be free to recipients of NIH grants focused on children’s health. The program is being paid for with funds redirected from the discontinued National Children’s Study.
Wild worries that people are conflating omics measurements with the exposome itself. “It’s really important not to confuse the measurement with the thing we’re trying to measure. We may need to bring together all sorts of different tools for different components of the exposome.”
What’s needed now is a concrete success in identifying an unanticipated association between an exposure marker and a disease risk, Wild told C&EN. “Over the next three to five years, we should start to see results coming out of projects that are integrating measurements of multiple exposures in relation to disease endpoints.”
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