Linking Environmental Particulate Matter with Genetic Alterations
Environ Health Perspect. doi:10.1289/ehp.0900830 available via http://dx.doi.org [Online 22 July 2009]
Referencing: Effects of Particulate Matter on Genomic DNA Methylation Content and iNOS Promoter Methylation
In their article, Tarantini et al. (2009) focused on the basic question of mutual relationships between environmental and genetic factors. From a more general point of view, this also involves the question concerning the relative role of “intrinsic toxicity” of xenobiotics and individual susceptibility or host response. In particular, data from epidemiologic and in vitro studies must cope with pathologic evidence for pathologists, as well as cause-and effect-relationships for pathophysiologists. In between are inferences and extrapolations on the basis of plausibility.
Tarantini et al. (2009) showed, for the first time in humans, that reactive oxygen species (ROS)—which are considered one of the main cellular stressors generated by PM exposure—may produce genomic hypomethylation and increased expression and activity of inducible nitric oxide synthase (iNOS) not only in vitro, but in humans exposed to particulate matter (PM). Although this finding is expected, it is a step forward, based on DNA adduct generation produced by polycyclic aromatic hydrocarbons (PAHs) and other PM components, namely transition metals. Alterations of DNA methylation of the promoter is a common finding in environmental-related chronic or cancerous diseases.
Alterations in DNA methylation and iNOS methylation, as observed by Tarantini et al. (2009) in association with exposure to PM < 10 µm in aerodynamic diameter, may represent an initial step in reproducing decreases in global DNA methylation content that are eventually observed in cardiovascular diseases and cancer.
However, pathologists and pathophysiologists are required to interpret more correctly what this means. Subjects with inherited multitumoral syndromes have a germline mutation, usually a point mutation present in all cells of the body, which determines the occurrence of multiple tumors in the same individual. The occurrence of DNA adducts or mutations in some cells or tissues due to exposure to PAHs or diesel exhaust does not necessarily induce clinically evident outcomes in the future, because each individual is endowed with a wide variety of natural defenses and repair mechanisms that usually overcome every type of DNA damage. Therefore, the first inference to avoid is that DNA adduct formation or alterations in the promoter methylation of a gene causes cancer in the absence of inherited or acquired predisposition (i.e., a point germline mutation of a tumor suppressor gene or an acquired sporadic mutation). In addition, even in patients with inherited multitumoral syndromes (i.e., in subjects with germline mutations of suppressor genes), tumor occurrence (type and severity) is also greatly influenced by epigenetic factors, environmental stimuli, or even long-distance catastrophes. We previously demonstrated an increased incidence of papillary thyroid carcinoma in three members of the same familial adenomatous polyposis (FAP) family (i.e., a kindred having a 1061 APC gene mutation). This mutation is responsible for FAP, in part as a side effect (long-term–long-distance) after the Chernobyl disaster, thus suggesting a wider than expected impact of environmental disasters in predisposed subjects (Cetta et al. 1997, 2000).
Analogously, chronic exposure to toxic or carcinogenic environmental substances does not elicit the same results in all individuals. The final clinical outcome (cancer, asthma, pulmonary fibrosis, atherosclerosis, or coronary diseases) seems to be less dependent on the toxic potency of the pollutant or of the exposure dose and more on the individual susceptibility of the host (Cetta 2009a, 2009b). This approach should facilitate a better understanding of the < 5% incidence of mesotheliomas in subjects with the same chronic exposure to asbestos, or the absence of health effects in husbands with chronic occupational exposure to asbestos but the occurrence of mesotheliomas in wives with minor indirect exposure from their husbands (Cetta F, unpublished data).
However, acute and chronic inflammation is the first pathological step. The final clinical outcome (e.g. cancer) does not depend on the first DNA adduct formed or a genetic mutation produced by xenobiotics. A long, automaintaining process will start, such as in liver cirrhosis, leading to cancer or chronic alterations as the final result of the interactions between host and the pathogenic agent. This process is greatly influenced by individual susceptibility or resistance. In PM-related diseases, a major role—in addition to the intrinsic toxicity of the xenobiotic—is played by individual host susceptibility and reactivity, similar to what occurs in autoimmune or autoinflammatory diseases.
This work was supported by the Flagship Project, PROLIFE, City of Milan, Italy.
The authors declare they have no competing financial interests.
Francesco Cetta
Armand Dhamo
Giuliana Malagnino
Department of Surgery
Research Doctorate in Oncology and Genetics
University of Siena
Siena, Italy
E-mail: cetta@unisi.it
Mauro Galeazzi
Department of Clinical Medicine and Immunology,
University of Siena,
Siena, Italy
References
Cetta F, Dhamo A, Azzarà A, Moltoni L. 2009a. The role of inherited predisposition and environmental factors in the occurrence of multiple different solid tumors in the same individual. The experience of the University Hospital of Siena. In: Multiple Primary Malignancies (Renda A, ed). Milan:Springer Verlag, 157–178.
Cetta F, Dhamo A, Moltoni L, Bolzacchini E. 2009b. Adverse health effects from combustion-derived nanoparticles: the relative role of intrinsic particle toxicity and host response [Letter]. Environ Health Perspect 117:A190.
Cetta F, Montalto G, Gori M, Curia MC, Cama A, Olschwang S. 2000. Germline mutations of the APC gene in patients with familial adenomatous polyposis associated thyroid carcinoma: results from a European cooperative study. J Clin Endocrinol Metab 85:286–292.
Cetta F, Montalto G, Petracci M, Fusco A. 1997. Thyroid cancer and the Chemobyl accident: are long-term and long distance side effects of fall-out radiation greater than estimated? [Letter]. J Clin Endocrinol Metab 82:2015–2016.
Tarantini L, Bonzini M, Apostoli P, Pegoraro V, Bollati V, Marinelli B, et al. 2009. Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect 117:217–222.
Environmental Particulate Matter and Genetic Alterations: Tarantini et al. Respond
Environ Health Perspect. doi:10.1289/ehp.0900830R available via http://dx.doi.org [Online 22 July 2009]
We thank Cetta et al. for the interest they express in our recent article (Tarantini et al. 2009). The basis for our hypothesis that foundry workers exposed to air particles might have hypomethylation of DNA repetitive element was existing evidence demonstrating that inhaled airborne particles induce oxidative stress and in vitro studies indicating that oxidative stress might generate hypomethylation throughout the genome. We are glad to see that Cetta et al. also find such hypothesis well grounded in previous existing work. Our investigation showed for the first time that airborne particles induce hypomethylation in repetitive sequences that are widely represented across the human genome, and indicated that hypomethylation of the inducible nitric oxide synthase (iNOS) gene is one potential mechanism contributing to particle-induced oxidative stress and inflammation. In addition, we showed that such processes can be detected in a DNA source, such as peripheral blood leukocytes, which is easily obtainable from human subjects. Our findings might be extended to ambient air pollution exposures, as suggested by our related investigations demonstrating repetitive element hypomethylation, as well as other gene-specific modifications, in blood DNA from individuals exposed to airborne benzene (Bollati et al. 2007) or to ambient particulate matter (Baccarelli et al. 2009).
In their letter, Cetta et al. rightly emphasize the possible roles of personal genetic features in determining which individuals will develop adverse health outcomes in response to air particle exposure. This is also confirmed by several other investigations that evaluated different health-related end points, including our previous work demonstrating genetic polymorphisms in pathways related to oxidative stress responses (Chahine et al. 2007) and our results on methyl nutrient metabolism (Baccarelli et al. 2008), both of which augment the negative effects of ambient particulate matter on cardiac autonomic function. In comparison with genetic variations, DNA methylation and other epigenetic modifications are of particular interest with respect to air particle effects, because—as demonstrated by animal models of environmental epigenetic toxicity —they are reversible and may be restored to their original state by dietary or pharmacologic interventions (Baccarelli and Bollati 2009; Dolinoy and Jirtle 2008; Jirtle and Skinner 2007).
We agree that the investigation of mechanisms closer to the final health outcomes in the chain of events started and/or maintained by air pollution exposures is as important as investigating early events. Studies tackling air pollution effects from different angles are needed to link together early events with the diseases of concern. As early events may be more susceptible to interventions aimed at reversing them or slowing their progression, we hope that our contribution to identify novel modifiable mechanisms induced by air particle exposures can help reach the goal recently set forth for environmental scientists by the newly appointed director of the National Institute of Environmental Health Sciences “to prevent or stop the progression of complex health problems” (Birnbaum 2009).
The authors declare they have no competing financial interests.
Letizia Tarantini
Matteo Bonzini
Valeria Pegoraro
Valentina Bollati
Barbara Marinelli
Laura Cantone
Giovanna Rizzo
Pier Alberto Bertazzi
Andrea Baccarelli
Laboratory of Environmental Epigenetics
Department of Preventive Medicine and Department of
Environmental and Occupational Health
University of Milan and IRCCS
Maggiore Hospital
Mangiagalli and Regina Elena Foundation Milan, Italy
E-mail: letizia.tarantini@unimi.it
Pietro Apostoli
Department of Experimental and Applied Medicine
Occupational Medicine and Industrial Hygiene
University of Brescia
Brescia, Italy
Lifang Hou
Department of Preventive Medicine Feinberg School of Medicine
Northwestern University
Chicago, Illinois, USA
Joel Schwartz
Exposure, Epidemiology and Risk Program
Department of Environmental Health
Harvard School of Public Health
Boston, Massachusetts, USA
References
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Baccarelli A, Cassano PA, Litonjua A, Park SK, Suh H, Sparrow D, et al. 2008. Cardiac autonomic dysfunction: effects from particulate air pollution and protection by dietary methyl nutrients and metabolic polymorphisms. Circulation 117(14):1802–1809.
Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, Suh HH, et al. 2009. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med 179(7):572–578.
Birnbaum L. 2009. Leading the world’s premier environmental health organization: a message from Linda Birnbaum [Editorial]. Environ Health Perspect 117:A138.
Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D, et al. 2007. Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67(3):876–880.
Chahine T, Baccarelli A, Litonjua A, Wright RO, Suh H, Gold DR, et al. 2007. Particulate air pollution, oxidative stress genes, and heart rate variability in an elderly cohort. Environ Health Perspect 115:1617–1622.
Dolinoy DC, Jirtle RL. 2008. Environmental epigenomics in human health and disease. Environ Mol Mutagen 49(1):4–8.
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Tarantini L, Bonzini M, Apostoli P, Pegoraro V, Bollati V, Marinelli B, et al. 2009. Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect 117:217–222.