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May 1, 2013 (Vol. 33, No. 9)

Exposing the Exposome

  • Click Image To Enlarge +
    Scientists believe that a better understanding of the exposome will not only lead to new insights on the molecular pathways involving cancer, but may also translate those findings into the clinic more effectively. [iStockphoto/Raycat]

    Understanding the interplay between genetic and environmental factors that shape phenotypes has represented, historically, a thought-provoking area for biomedical, medical, and social sciences.

    While the biology of the genome has witnessed unprecedented advances in the past three decades, identifying and studying the impact of environmental factors on live organisms remains a challenging endeavor. To address this unmet need, a new concept was defined to include all the environmental exposures that act during an individual’s lifetime, starting with the prenatal period.

    “The principle behind the concept of the exposome was to be able to characterize a person’s complete exposure history throughout life, and this includes factors shaped by environment, lifestyle, occupation, socio-economic, and demographic conditions in order to better understand the causes of the diseases they experience,” says Christopher P. Wild, Ph.D., director of the International Agency for Research on Cancer (IARC), and author of the landmark 2005 article that first introduced the concept of the exposome.

    Exposome research capitalizes on technological advances that previously provided unprecedented opportunities to mine the human genome and compare genomic regions across individuals and populations. “At this time, we do not have an equivalent set of tools to capture an individual’s exposure history to environmental or lifestyle factors,” says Dr. Wild.

    This gap promises to be at least partially addressed by applying genomics and other related technologies such as metabolomics to reveal details about exposures. A key development is in epigenetics, a field that assumes a central position in the study of the exposome.

    In addition to the DNA damage model for carcinogenesis, recent years revealed that gene expression and function may also be modulated by mechanisms that do not involve mutagenesis, and several environmental and lifestyle factors were shown to act by these pathways, which became known as epigenetic pathways.

    Of these, DNA methylation is at the most advanced stage of understanding. “With methods that can comprehensively measure the DNA methylation status, for example, it has now become possible to explore the correlation between a particular exposure, the underlying mechanism of action, and disease risk,” explains Dr. Wild.

  • Cancer Research

    One of the areas where the exposome promises a paradigm shift is cancer research. While significant advances over the past few decades helped understand the molecular pathways of carcinogenesis, translating the findings into the clinic has been more challenging. “This has to do mostly with the fact that cancer is so heterogeneous at the molecular level, that finding treatments for any single malignant tumor will be a very complex task,” explains Dr. Wild.

    Additionally, as it is anticipated that the incidence of cancer will increase in the coming decades, particularly in the poorest countries, as a result of population expansion, an increasing life expectancy, and increased exposure to some cancer risk factors, the development of preventive interventions emerges as a priority in medicine and public health.

    “Reducing the cancer burden will not be possible solely through treatment, and this was part of the motivation behind the exposome idea, to better understand the causes of disease and implement preventive strategies,” says Dr. Wild. The focus on the exposome provides the unique opportunity to use emerging knowledge about mechanisms to identify and characterize risk factors that drive molecular changes involved in carcinogenesis.

    “I refer to this approach as two-way translational research because in addition to applying concepts from the bench to the bedside, there is also an opportunity to extend information from the bench to the population, and this is the strategy that will help understand mechanisms and lead to disease prevention,” adds Dr. Wild.

  • Estrogens

    Click Image To Enlarge +
    Exposome research, which integrates data from many areas, has the potential to shed light on how environmental factors shape gene expression and function. [Agilent Technologies]

    “Interest in the study of the exposome is growing,” says Anthony Macherone, Ph.D., senior applications chemist at Agilent Technologies, and visiting scientist at the Johns Hopkins School of Medicine. Studies on the exposome allow data from multiple layers of experimental inquiry to be integrated. Since most complex diseases are determined by genetic and environmental factors, this approach promises to help better understand environmental contributions that shape gene expression and function. Of these two groups of factors, our knowledge about genetic contributions to disease is currently at the most advanced level of understanding.

    “The environmental components will need to be further analyzed, and hopefully more long-term studies will be conducted to monitor exposure,” says Dr. Macherone. To provide a framework that illustrates the powerful applications of the emerging field of exposomics, Dr. Macherone and colleagues will present, at the upcoming American Society for Mass Spectrometry meeting, an integrated analysis of the clinical and environmental monitoring of the exposure to estrogens, hormones that are instrumental during reproductive development, participate in the morphogenesis of multiple organs and tissues, and are involved in the pathology of several conditions.

    Relying on microarray studies, endogenous measurements of estrogens, and environmental groundwater and wastewater surveys, this approach unveils the multidisciplinarity and interdisciplinarity that define this emerging field.

    “Exposomics will require a more open milieu, in which scientists across disciplines will be engaged and integrate their findings in a way that is very different from what many scientists are doing right now,” explains Dr. Macherone.

    “In terms of exploring the exposome, our tools are still limited and need to be improved, but several groups are working toward trying to better assess exposures during an individual’s lifespan,” says Francine Einstein, M.D., associate professor of obstetrics and gynecology and Women’s Health at Albert Einstein College of Medicine.

    Researchers in Dr. Einstein’s lab recently revealed that methylation changes during development occur in a sex-specific manner, with the most accentuated modification being visualized in growth-restricted male babies and overgrown female babies, indicating that sexual differences play an important and previously unsuspected role in shaping the link between epigenetic changes and phenotypes.

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