The exposome concept encourages holistic consideration of the non-genetic factors (environmental exposures including lifestyle) that influence an individual's health over their life course. However, disconnect between the concept and practical application has promoted divergent interpretations of the exposome across disciplines and reinforced separation of the environmental (emphasizing exposures) and biological (emphasizing responses) research communities. In particular, while knowledge of biological responses can help to distinguish actual (i.e. experienced) from potential exposures, the inclusion of endogenous processes has generated confusion about the position of the exposome in a multi-omics systems biology context. We propose a reattribution of "exposome" to exclusively represent the totality of contact with external factors that a biological entity experiences, and introduce the term "functional exposomics" to denote the systematic study of exposure-phenotype interaction. This reoriented definition of the exposome allows a more readily integrable dataset for multi-omics and systems biology research.

Department of Environmental Health Sciences Mailman School of Public Health Columbia University New York NY USA

Department of Environmental Medicine and Public Health Icahn School of Medicine at Mount Sinai New York NY USA

Faculty of Sports Studies Masaryk University Kamenice 753 5 Brno 62500 Czech Republic

Oniris INRAE LABERCA Nantes France

RECETOX Faculty of Science Masaryk University Kotlarska 2 Brno 60200 Czech Republic

Service de Biochimie Métabolomique et Protéomique Hôpital Necker Enfants Malades AP HP Paris France

Silent Spring Institute Newton MA USA

Univ Rennes EHESP Inserm Irset UMR_S 1085 Rennes 35000 France

Université de Paris T3S Inserm UMR S 1124 Paris 75006 France

Zobrazit více v PubMed

Anthony J.C., Eaton W.W., Henderson A.S. Looking to the future in psychiatric epidemiology. Epidemiol. Rev. 1995;17:240–242. doi: 10.1093/oxfordjournals.epirev.a036182. PubMed DOI

Arah O.A. On the relationship between individual and population health. Med. Heal. Care Philos. 2009;12:235–244. doi: 10.1007/s11019-008-9173-8. PubMed DOI PMC

Arora M., Giuliani A., Curtin P. Biodynamic interfaces are essential for human–environment interactions. Bioessays. 2020;42:2000017. doi: 10.1002/bies.202000017. PubMed DOI

Ashauer R., O’Connor I., Escher B.I. Toxic mixtures in time - the sequence makes the poison. Environ. Sci. Technol. 2017;51:3084–3092. doi: 10.1021/acs.est.6b06163. PubMed DOI

Assmus H.E., Herwig R., Cho K.H., Wolkenhauer O. Dynamics of biological systems: role of systems biology in medical research. Expert Rev. Mol. Diagn. 2006;6:891–902. doi: 10.1586/14737159.6.6.891. PubMed DOI

Athersuch T.J., Keun H.C. Metabolic profiling in human exposome studies. Mutagenesis. 2015;30:755–762. doi: 10.1093/mutage/gev060. PubMed DOI

Balbus J.M., Barouki R., Birnbaum L.S., Etzel R.A., Gluckman S.P.D., Grandjean P., Hancock C., Hanson M.A., Heindel J.J., Hoffman K., et al. Early-life prevention of non-communicable diseases. Lancet. 2013;381:3–4. doi: 10.1016/S0140-6736(12)61609-2. PubMed DOI PMC

Barouki R., Audouze K., Becker C., Blaha L., Coumoul X., Karakitsios S., Klanova J., Miller G.W., Price E.J., Sarigiannis D. The exposome and toxicology: a win–win collaboration. Toxicol. Sci. 2021:kfab149. doi: 10.1093/toxsci/kfab149. PubMed DOI PMC

Beauchaine T.P. Physiological markers of emotion and behavior dysregulation in externalizing psychopathology. Monogr. Soc. Res. Child Dev. 2012;77:79–86. doi: 10.1111/j.1540-5834.2011.00665.x. PubMed DOI PMC

Behnke M., Buchwald M., Bykowski A., Kupiński S., Kaczmarek L.D. Psychophysiology of positive and negative emotions, dataset of 1157 cases and 8 biosignals. Sci. Data. 2022;9:1–15. doi: 10.1038/s41597-021-01117-0. PubMed DOI PMC

Bergelson J., Kreitman M., Petrov D.A., Sanchez A., Tikhonov M. Functional biology in its natural context: a search for emergent simplicity. Elife. 2021;10:1–12. doi: 10.7554/eLife.67646. PubMed DOI PMC

Bodein A., Scott-Boyer M.-P., Perin O., Lê Cao K.-A., Droit A. Interpretation of network-based integration from multi-omics longitudinal data. Nucleic Acids Res. 2021:gkab1200. doi: 10.1093/nar/gkab1200. PubMed DOI PMC

Boyce W.T., Sokolowski M.B., Robinson G.E. Genes and environments, development and time. Proc. Natl. Acad. Sci. U S A. 2020;117:23235–23241. doi: 10.1073/pnas.2016710117. PubMed DOI PMC

Braun J.M., Kalloo G., Kingsley S.L., Li N. Using phenome-wide association studies to examine the effect of environmental exposures on human health. Environ. Int. 2019;130:104877. doi: 10.1016/j.envint.2019.05.071. PubMed DOI PMC

Braveman P., Gottlieb L. The social determinants of health: it’s time to consider the causes of the causes. Public Health Rep. 2014;129:19–31. doi: 10.1177/00333549141291s206. PubMed DOI PMC

Broadrup R.L., Mayack C., Schick S.J., Eppley E.J., White H.K., Macherone A. Honey bee (apis mellifera) exposomes and dysregulated metabolic pathways associated with nosema ceranae infection. PLoS One. 2019;14:1–18. doi: 10.1371/journal.pone.0213249. PubMed DOI PMC

Brunekreef B. Exposure science, the exposome, and public health. Environ. Mol. Mutagen. 2013;54:596–598. doi: 10.1002/em.21767. PubMed DOI

Canali S. What is new about the exposome? Exploring scientific change in contemporary epidemiology. Int. J. Environ. Res. Public Health. 2020;17:2879. doi: 10.3390/ijerph17082879. PubMed DOI PMC

Canzler S., Schor J., Busch W., Schubert K., Rolle-Kampczyk U.E., Seitz H., Kamp H., von Bergen M., Buesen R., Hackermüller J. Prospects and challenges of multi-omics data integration in toxicology. Arch. Toxicol. 2020;94:371–388. doi: 10.1007/s00204-020-02656-y. PubMed DOI

Chung M.K., Rappaport S.M., Wheelock C.E., Nguyen V.K., van der Meer T.P., Miller G.W., Vermeulen R., Patel C.J. Utilizing a biology-driven approach to map the exposome in health and disease: an essential investment to drive the next generation of environmental discovery. Environ. Health Perspect. 2021;129:085001. doi: 10.1289/EHP8327. PubMed DOI PMC

Committee on Human and Environmental Exposure Science in the 21st Century; Board on Environmental Studies and Toxicology; Division on Earth and Life Studies; National Research Council . National Academies Press; 2012. Exposure Science in the 21st Century: A Vision and a Strategy. PubMed DOI

Comunidad Los Horcones Types of relationships between events: their implication in the stimulus-response relationship. Behav. Dev. Bull. 2005;12:55–61. doi: 10.1037/h0100561. DOI

David A., Chaker J., Price E.J., Bessonneau V., Chetwynd A.J., Vitale C.M., Klánová J., Walker D.I., Antignac J., Barouki R., Miller G.W. Towards a comprehensive characterisation of the human internal chemical exposome: challenges and perspectives. Environ. Int. 2021;156:106630. doi: 10.1016/j.envint.2021.106630. PubMed DOI

David A., Lange A., Abdul-Sada A., Tyler C.R., Hill E.M. Disruption of the prostaglandin metabolome and characterization of the pharmaceutical exposome in fish exposed to wastewater treatment works effluent as revealed by nanoflow-nanospray mass spectrometry-based metabolomics. Environ. Sci. Technol. 2017;51:616–624. doi: 10.1021/acs.est.6b04365. PubMed DOI

Dennis K.K., Auerbach S.S., Balshaw D.M., Cui Y., Fallin M.D., Smith M.T., Spira A., Sumner S., Miller G.W. The importance of the biological impact of exposure to the concept of the exposome. Environ. Health Perspect. 2016;124:1504–1510. doi: 10.1289/EHP140. PubMed DOI PMC

Escher B.I., Hackermüller J., Polte T., Scholz S., Aigner A., Altenburger R., Böhme A., Bopp S.K., Brack W., Busch W., et al. From the exposome to mechanistic understanding of chemical-induced adverse effects. Environ. Int. 2017;99:97–106. doi: 10.1016/j.envint.2016.11.029. PubMed DOI PMC

Everett J.R., Holmes E., Veselkov K.A., Lindon J.C., Nicholson J.K. A unified conceptual framework for metabolic phenotyping in diagnosis and prognosis. Trends Pharmacol. Sci. 2019;40:763–773. doi: 10.1016/j.tips.2019.08.004. PubMed DOI

Fang M., Hu L., Chen D., Guo Y., Liu J., Lan C., Gong J., Wang B. Exposome in human health: utopia or wonderland? Innovation (N Y) 2021;2:100172. doi: 10.1016/j.xinn.2021.100172. PubMed DOI PMC

Fava G.A., McEwen B.S., Guidi J., Gostoli S., Offidani E., Sonino N. Clinical characterization of allostatic overload. Psychoneuroendocrinology. 2019;108:94–101. doi: 10.1016/j.psyneuen.2019.05.028. PubMed DOI

Fink G. Stress: concepts, definition and history. Neurosci. Biobehav. Psychol. 2016:549–555. doi: 10.1016/B978-0-12-809324-5.02208-2. DOI

Gao P. The exposome in the era of one health. Environ. Sci. Technol. 2021;55:2790–2799. doi: 10.1021/acs.est.0c07033. PubMed DOI

Gao P., Shen X., Zhang X., Jiang C., Zhang S., Zhou X., Miryam S. Precision environmental health monitoring by longitudinal exposome and multi-omics profiling. bioRxiv. 2021 doi: 10.1101/2021.05.05.442855. PubMed DOI PMC

Ghosh C. Relative matrix effects: a step forward using standard line slopes and ANOVA analysis. Arab. J. Chem. 2019;12:1378–1386. doi: 10.1016/j.arabjc.2014.11.019. DOI

Gillman M.W. Developmental origins of health and disease. N. Engl. J. Med. 2005;353:1848–1850. doi: 10.1056/NEJMe058187. PubMed DOI PMC

Haddad N., Andrianou X.D., Makris K.C. A scoping review on the characteristics of human exposome studies. Curr. Pollut. Rep. 2019;5:378–393. doi: 10.1007/s40726-019-00130-7. DOI

International Programme on Chemical Safety & Organisation for Economic Co-operation and Development . WHO; 2004. IPCS Risk Assessment Terminology.https://apps.who.int/iris/handle/10665/42908

Ioannidis J.P.A. Exposure-wide epidemiology: revisiting Bradford Hill. Stat. Med. 2016;35:1749–1762. doi: 10.1002/sim.6825. PubMed DOI

Jackson M.C., Pawar S., Woodward G. The temporal dynamics of multiple stressor effects: from individuals to ecosystems. Trends Ecol. Evol. 2021;36:402–410. doi: 10.1016/j.tree.2021.01.005. PubMed DOI

Juarez P.D., Matthews-Juarez P., Hood D.B., Im W., Levine R.S., Kilbourne B.J., Langston M.A., Al-Hamdan M.Z., Crosson W.L., Estes M.G., et al. The public health exposome: a population-based, exposure science approach to health disparities research. Int. J. Environ. Res. Public Health. 2014;11:12866–12895. doi: 10.3390/ijerph111212866. PubMed DOI PMC

Kaur S., Peters T.J., Yang P., Luu L.D.W., Vuong J., Krycer J.R., O’Donoghue S.I. Temporal ordering of omics and multiomic events inferred from time-series data. NPJ Syst. Biol. Appl. 2020;6:1–7. doi: 10.1038/s41540-020-0141-0. PubMed DOI PMC

Kohane I.S., Masys D.R., Altman R.B. The incidentalome. JAMA. 2006;296:212. doi: 10.1001/jama.296.2.212. PubMed DOI

Lenart P., Kuruczova D., Kukla L., Scheringer M., Vasku J.B. Putting the dynamic pathosome in practice: a novel way of analyzing longitudinal data. arXiv. 2021 doi: 10.48550/arXiv.2103.12822. DOI

Lenart P., Scheringer M., Bienertova-Vasku J. The pathosome: a dynamic three-dimensional view of disease–environment interaction. Bioessays. 2019;41:1–6. doi: 10.1002/bies.201900014. PubMed DOI

Li J., Li X., Zhang S., Snyder M. Gene-environment interaction in the era of precision medicine. Cell. 2019;177:38–44. doi: 10.1016/j.cell.2019.03.004. PubMed DOI PMC

Li J., Lu Q., Wen Y. Multi-kernel linear mixed model with adaptive lasso for prediction analysis on high-dimensional multi-omics data. Bioinformatics. 2020;36:1785–1794. doi: 10.1093/bioinformatics/btz822. PubMed DOI PMC

Li S., Cirillo P., Hu X., Tran V., Krigbaum N., Yu S., Jones D.P., Cohn B. Understanding mixed environmental exposures using metabolomics via a hierarchical community network model in a cohort of California women in 1960’s. Reprod. Toxicol. 2019;92:57–65. doi: 10.1016/j.reprotox.2019.06.013. PubMed DOI PMC

Logan A.C., Prescott S.L., Haahtela T., Katz D.L. The importance of the exposome and allostatic load in the planetary health paradigm. J. Physiol. Anthropol. 2018;37:15. doi: 10.1186/s40101-018-0176-8. PubMed DOI PMC

Mahner M., Kary M. What exactly are genomes, genotypes and phenotypes? and what about phenomes? J. Theor. Biol. 1997;186:55–63. doi: 10.1006/jtbi.1996.0335. PubMed DOI

Maitre L., Bustamante M., Hernandez-Ferrer C., Thiel D., Lau C.-H.E., Siskos A.P., Vives-Usano M., Robinson O., Wright J., Cadiou S., et al. Multi-omics signatures of the human early life exposome. medRxiv. 2021 doi: 10.1101/2021.05.04.21256605. PubMed DOI PMC

Mason J.W. A historical view of the stress field. J. Hum. Stress. 1975;1:6–12. doi: 10.1080/0097840X.1975.9940399. PubMed DOI

Mayeux R. Biomarkers: potential uses and limitations. NeuroRx. 2004;1:182–188. doi: 10.1602/neurorx.1.2.182. PubMed DOI PMC

McEwen B.S., Wingfield J.C. The concept of allostasis in biology and biomedicine. Horm. Behav. 2003;43:2–15. doi: 10.1016/S0018-506X(02)00024-7. PubMed DOI

Miller G.W. Integrating the exposome into a multi-omic research framework. Exposome. 2021;1:2–4. doi: 10.1093/exposome/osab002. PubMed DOI PMC

Miller G.W., Jones D.P. The nature of nurture: refining the definition of the exposome. Toxicol. Sci. 2014;137:1–2. doi: 10.1093/toxsci/kft251. PubMed DOI PMC

Myers S.S., Gaffikin L., Golden C.D., Ostfeld R.S., Redford K.H., Ricketts T.H., Turner W.R., Osofsky S.A. Human health impacts of ecosystem alteration. Proc. Natl. Acad. Sci. U S A. 2013;110:18753–18760. doi: 10.1073/pnas.1218656110. PubMed DOI PMC

Nakamura J., Mutlu E., Sharma V., Collins L., Bodnar W., Yu R., Lai Y., Moeller B., Lu K., Swenberg J. The endogenous exposome. DNA Repair (Amst.) 2014;19:3–13. doi: 10.1016/j.dnarep.2014.03.031. PubMed DOI PMC

Nicholson J.K., Wilson I.D. Understanding “global” systems biology: metabonomics and the continuum of metabolism. Nat. Rev. Drug Discov. 2003;2:668–676. doi: 10.1038/nrd1157. PubMed DOI

Niedzwiecki M.M., Walker D.I., Vermeulen R., Chadeau-Hyam M., Jones D.P., Miller G.W. The exposome: molecules to populations. Annu. Rev. Pharmacol. Toxicol. 2019;59:107–127. doi: 10.1146/annurev-pharmtox-010818-021315. PubMed DOI

Pan Y., Lei X., Zhang Y. Association predictions of genomics, proteinomics, transcriptomics, microbiome, metabolomics, pathomics, radiomics, drug, symptoms, environment factor, and disease networks: a comprehensive approach. Med. Res. Rev. 2022;42:441–461. doi: 10.1002/med.21847. PubMed DOI

Peters A., Hoek G., Katsouyanni K. Understanding the link between environmental exposures and health : does the exposome promise too much? J. Epidemiol. Community Health. 2012;66:103–105. doi: 10.1136/jech-2011-200643. PubMed DOI

Peters A., Nawrot T.S., Baccarelli A.A. ll Hallmarks of environmental insults. Cell. 2021;184:1455–1468. doi: 10.1016/j.cell.2021.01.043. PubMed DOI PMC

Prior L. Allostatic load and exposure histories of disadvantage. Int. J. Environ. Res. Public Health. 2021;18:7222. doi: 10.3390/ijerph18147222. PubMed DOI PMC

Prohaska S.J., Stadler P.F. The use and abuse of -omes. Methods Mol. Biol. 2011;719:173–196. doi: 10.1007/978-1-61779-027-0_8. PubMed DOI

Purdy K.J., Hurd P.J., Moya-Laraño J., Trimmer M., Oakley B.B., Woodward G. Systems biology for ecology. From molecules to ecosystems. Adv. Ecol. Res. 2010;43:87–149. doi: 10.1016/B978-0-12-385005-8.00003-4. DOI

Rappaport S.M. Implications of the exposome for exposure science. J. Expo. Sci. Environ. Epidemiol. 2011;21:5–9. doi: 10.1038/jes.2010.50. PubMed DOI

Rappaport S.M., Smith M.T. Environment and disease risks. Science. 2010;330:460–461. doi: 10.1126/science.1192603. PubMed DOI PMC

Sabbioni G., Berset J.D., Day B.W. Is it realistic to propose determination of a lifetime internal exposome? Chem. Res. Toxicol. 2020;33:2010–2021. doi: 10.1021/acs.chemrestox.0c00092. PubMed DOI

Scholz S., Nichols J.W., Escher B.I., Ankley G.T., Altenburger R., Blackwell B., Brack W., Burkhard L., Collette T.W., Doering J.A., et al. The eco-exposome concept: supporting an integrated assessment of mixtures of environmental chemicals. Environ. Toxicol. Chem. 2022;41:30–45. doi: 10.1002/etc.5242. PubMed DOI PMC

Schumacher B., Pothof J., Vijg J., Hoeijmakers J.H.J. The central role of DNA damage in the ageing process. Nature. 2021;592:695–703. doi: 10.1038/s41586-021-03307-7. PubMed DOI PMC

Selye H. Psychopathology of Human Adaptation. Springer US; 1976. Stress without distress; pp. 137–146. DOI

Selye H. Confusion and controversy in the stress field. J. Hum. Stress. 1975;1:37–44. doi: 10.1080/0097840X.1975.9940406. PubMed DOI

Senier L., Brown P., Shostak S., Hanna B. The socio-exposome: advancing exposure science and environmental justice in a postgenomic era. Environ. Sociol. 2017;3:107–121. doi: 10.1080/23251042.2016.1220848. PubMed DOI PMC

Sher K.J., Dick D.M., Crabbe J.C., Hutchison K.E., O’Malley S.S., Heath A.C. Consilient research approaches in studying gene × environment interactions in alcohol research. Addict. Biol. 2010;15:200–216. doi: 10.1111/j.1369-1600.2009.00189.x. PubMed DOI PMC

Sillé F. The exposome – a new approach for risk assessment. ALTEX. 2020;37:3–23. doi: 10.14573/altex.2001051. PubMed DOI

Stringhini S., Carmeli C., Jokela M., Avendaño M., Muennig P., Guida F., Ricceri F., D’Errico A., Barros H., Bochud M., et al. Socioeconomic status and the 25 × 25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1·7 million men and women. Lancet. 2017;389:1229–1237. doi: 10.1016/S0140-6736(16)32380-7. PubMed DOI PMC

Teixeira A.P., Dias J.M.L., Carinhas N., Sousa M., Clemente J.J., Cunha A.E., von Stosch M., Alves P.M., Carrondo M.J.T., Oliveira R. Cell functional enviromics: unravelling the function of environmental factors. BMC Syst. Biol. 2011;5:92. doi: 10.1186/1752-0509-5-92. PubMed DOI PMC

Tipton M. A case for combined environmental stressor studies. Extrem. Physiol. Med. 2012;1:1–2. doi: 10.1186/2046-7648-1-7. PubMed DOI PMC

Toscano W.A., Oehlke K.P. Systems biology: new approaches to old environmental health problems. Int. J. Environ. Res. Public Health. 2005;2:4–9. doi: 10.3390/ijerph2005010004. PubMed DOI PMC

U.S. Food and Drug Administration (FDA) - National Institutes of Health (NIH), Biomarker Working Group BEST (biomarkers, EndpointS, and other tools) resource. 2016. https://www.ncbi.nlm.nih.gov/books/NBK326791/pdf/Bookshelf_NBK326791.pdf PubMed

United States Environmental Protection Agency Terminology servies glossary. 2009. https://sor.epa.gov/sor_internet/registry/termreg/searchandretrieve/glossariesandkeywordlists/

VanderWeele T.J. Outcome-wide epidemiology. Epidemiology. 2017;28:399–402. doi: 10.1097/EDE.0000000000000641. PubMed DOI PMC

VanderWeele T.J., Mathur M.B., Chen Y. Outcome-wide longitudinal designs for causal inference: a new template for empirical studies. Stat. Sci. 2020;35:437–466. doi: 10.1214/19-sts728. DOI

Vermeulen R., Schymanski E.L., Barabási A.L., Miller G.W. The exposome and health: where chemistry meets biology. Science. 2020;367:392–396. doi: 10.1126/science.aay3164. PubMed DOI PMC

Vijg J., Montagna C. Genome instability and aging: cause or effect? Transl. Med. Aging. 2017;1:5–11. doi: 10.1016/j.tma.2017.09.003. DOI

Wagner M., Grodstein F., Leffondre K., Samieri C., Proust-Lima C. Time-varying associations between an exposure history and a subsequent health outcome: a landmark approach to identify critical windows. BMC Med. Res. Methodol. 2021;21:1–15. doi: 10.1186/s12874-021-01403-w. PubMed DOI PMC

Wild C.P. The exposome: from concept to utility. Int. J. Epidemiol. 2012;41:24–32. doi: 10.1093/ije/dyr236. PubMed DOI

Wild C.P. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol. Biomarkers Prev. 2005;14:1847–1850. doi: 10.1158/1055-9965.EPI-05-0456. PubMed DOI

World Health Organization & International Programme on Chemical Safety Assessing human health risks of chemicals: derivation of guidance values for health-based exposure limits. 1994. https://apps.who.int/iris/handle/10665/40675 Environ. Heal. Criteria 170.

World Health Organization & International Programme on Chemical Safety Biomarkers and risk assessment: concepts and principles. 1993. https://apps.who.int/iris/handle/10665/39037 Environ. Heal. Criteria 155.

Xu Y. Envirotyping for deciphering environmental impacts on crop plants. Theor. Appl. Genet. 2016;129:653–673. doi: 10.1007/s00122-016-2691-5. PubMed DOI PMC

Xue B.K., Sartori P., Leibler S. Environment-to-phenotype mapping and adaptation strategies in varying environments. Proc. Natl. Acad. Sci. U S A. 2019;116:13847–13855. doi: 10.1073/pnas.1903232116. PubMed DOI PMC

Zaehringer J., Jennen-Steinmetz C., Schmahl C., Ende G., Paret C. Psychophysiological effects of downregulating negative emotions: insights from a meta-analysis of healthy adults. Front. Psychol. 2020;11 doi: 10.3389/fpsyg.2020.00470. PubMed DOI PMC

Zartarian V., Bahadori T., McKone T. Adoption of an official ISEA glossary. J. Expo. Anal. Environ. Epidemiol. 2005;15:1–5. doi: 10.1038/sj.jea.7500411. PubMed DOI

High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage

Adopting Mechanistic Molecular Biology Approaches in Exposome Research for Causal Understanding

The Exposome and Toxicology: A Win-Win Collaboration