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Transcriptomics within the Exposome Paradigm

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Unraveling the Exposome

Abstract

The advent of omics technologies has enhanced significantly our capacity to interpret mechanistically the association between environmental exposure and disease. Although understanding these interactions requires capturing perturbations at different levels of biological organization, transcriptomics holds a key role. Modulation of gene expression represents the initial biological perturbations due to environmental exposure. This is of particular importance when assessing real-life exposure that involves multiple stressors in highly variable time regimes. This chapter aims at (a) demonstrating the place of transcriptomics in modern risk assessment and environmental health associations, highlighting the respective bioinformatics tools that are necessary for the interpretation and (b) demonstrating the feasibility of transcriptomics of understanding environmental risk associated to real-life ubiquitous mixtures. Although environmental exposures occur to mixtures of chemicals rather than to individual agents, most of the toxic effects of air pollutants are ascribed to single chemicals. There is a growing feeling in both the scientific and regulatory communities, however, that there is a need for more comprehensive approaches toward managing the potential impact of complex environmental chemical mixtures on human health. In this perspective, it is expected that toxicogenomics would be the appropriate screening method for assessing biological effects of complex chemical mixtures, allowing us to review the whole spectrum of potential biological response rather than focusing on a predefined number of endpoints as in classical toxicological analysis. In this chapter, beyond the overview of the analytical and computational aspects necessary for implementing toxicogenomics in the context of the exposome, a concrete example of such an application on a typical indoor air mixture as defined in the EU-wide review study INDEX and on a mixture of polyaromatic hydrocarbons (PAHs) isolated from urban air in the city of Milan is given with the aim to identify specific sets of biomarkers for each of the two types of exposure (indoor or outdoor). A human cell line derived from a bronco-pulmonary system (A549) was used as the appropriate in vitro model to support the investigation of the molecular basis for adverse outcomes that are attributed to indoor and/or outdoor air pollution based on epidemiological evidence. Applying a Total Gene Expression assay by Applied Biosystems Microarrays, large sets of genes modulated by single mixtures exposure were profiled. This process led us to identify common biochemical pathways and specific molecular responses. Indoor air mixtures induced a higher level of gene modulation than ambient air PAHs. A closer look at the differences in biological response confirmed major discrepancies in the mode of action of the two mixtures. Indoor air induced primarily modulation of genes associated to protein targeting and localization including in particular cytoskeletal organization; PAHs modulated mostly the expression of genes related to cell motility and gene networks regulating cell–cell signaling, as well as cell proliferation and differentiation. These results provide biological information useful for articulating mechanistic hypotheses linking exposure to xenobiotic mixtures and physiological responses. The evidence on the latter is supported by a large amount of epidemiological evidence, associating exposure to urban air pollution with respiratory allergies, chronic obstructive pulmonary disease, cardiovascular disease, and cancer. Lately, such evidence has been extended to include associations of exposure to polluted ambient and indoor air with kidney disease and even neurodegenerative disorders, and in particular dementia.

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Acknowledgments

The author gratefully acknowledges the support of the European Commission through the grant No. 603946 (HEALS—Health and Environment-wide Associations via Large Population Studies) funded through the 7th Framework Program for Research and Technological Development of the EU.

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Authors and Affiliations

  1. HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Thessaloniki, Greece

    D. A. Sarigiannis

  2. Environmental Engineering Laboratory, School of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece

    D. A. Sarigiannis

  3. University School for Advanced Study (IUSS), Pavia, Italy

    D. A. Sarigiannis

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  1. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK

    Sonia Dagnino

  2. The Johns Hopkins School of Medicine, Agilent Technologies, Baltimore, MD, USA

    Anthony Macherone

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Sarigiannis, D.A. (2019). Transcriptomics within the Exposome Paradigm. In: Dagnino, S., Macherone, A. (eds) Unraveling the Exposome. Springer, Cham. https://doi.org/10.1007/978-3-319-89321-1_7

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