Final Report Summary - EPIGENAIR (EPIGENomic markers for AIR pollution-induced health effects)
1. Final Publishable Summary Report
“This is a comprehensive summary overview of results, conclusions and the socio-economic impacts of the project. The publishable report shall be formatted to be printed as a stand alone paper document. This report should address a wide audience, including the general public. Moreover, do not include in the summary report any confidential information, whose publication might undermine the protection of commercial interests, including intellectual property, or privacy and the integrity of the individuals, in particular in accordance with Community legislation regarding the protection of personal data. Please ensure that it:
- Is of suitable quality to enable direct publication by the REA or the Commission. - Is comprehensive, and describes the work carried out to achieve the project's objectives; the main results, conclusions and their potential impact and use and any socio-economic impact of the project. Please mention any target groups such as policy makers or civil society for whom the research could be relevant. “
Ambient air pollution can originate from burning of fossil fuels (i.e. the coal and petroleum related to traffic and energy production) and consists of noxious gases (sulphur dioxide, nitrogen oxides, carbon monoxide, chemical vapours, etc.). These pollutants can form fine particles. Being exposed to polluted air is associated with cardiovascular diseases and increases the risk for lung cancer at the population level. Air pollutants can be particularly harmful to people belonging to high risks groups such as children and the elderly. How exposure is harmful for health is not fully understood but oxidative damage or effects on cellular structures are candidate mechanisms involved. Epigenetic modifications play a crucial role in gene expression and its regulation and are as well affected by external stressors. As such these constitute promising to gain knowledge on the mechanisms involved in the effect mediation of air pollution exposure. One such example is the methylation of DNA which regulates the expression of genes and can be influenced by external factors including toxic exposures. Previous epidemiological studies indicate that particulate air pollution affects global and gene-specific DNA methylation. New high-resolution technology of sensor systems and molecular analytical approaches provide opportunities to improve the understanding of how the environment influences disease risk and outcome. In this project, we analysed DNA methylation data in relation to estimates of exposure to air pollutants in order to gain a novel insight into epigenetically mediated effects of exposure in both adults and children.
We measured the methylation status in blood using the 450K human Illumina methylation array, which assesses methylation levels of more than 480,000 loci across the genome. The levels of exposure to air pollution at participants’ homes were estimated via models taking into account the land use. These land-use regression models are based on equations that describe the relationship between measured pollutant concentrations and potential predictor variables, using a geographic information system. Individual levels for 2 gases: NO2 and NOx, fine particles with a diameter of 2.5 µg/m3 (PM2.5) between 2.5 and 10 µg/m3 (PMcoarse) and 10 µg/m3 (PM10), and a measure for soot in the air (absorbance of the PM2.5 filter, PM2.5abs) were estimated. We used (generalised) linear regression models to study the association between DNA methylation and exposure and accounted for several important characteristics of the participants such as the gender, age and smoking behaviour.
In healthy adult volunteers from two cohorts in Italy and the Netherlands that are a part of the European Prospective Investigation Into Cancer and Nutrition Cohort Study (EPIC), we studied the overall methylation status across the entire genome. We observed that increased exposure to NO2 and NOx decreases global DNA methylation. We found that regions flanking portions of DNA with densely distributed places that could be methylated (CpG islands) show aberrant DNA methylation patterns in relation to higher NO2 and NOx concentrations. In the children from the Avon Longitudinal Study of Parents and Children (ALSPAC), we identified a similar pattern in cord blood of new-borns and, in blood from children of age 15 but not in 7-years old children, were the pattern seemed reversed. DNA methylation protects the genome and low methylation can cause genome instability, as such lower DNA methylation resulting from exposure to NO2 and NOx might enable the development of cancers. These findings may further explain how being exposed to air pollutants can contribute to cancer risk, and in this regard hypomethylation might be potential pathway leading to the development of cancer.
We identified several specific regions along the genome whose methylation was associated with NO2, NOx, PM2.5 and PM2.5abs exposures in EPIC-Italy and a multitude of loci associated with all components of air pollution in EPIC-NL. However, these signals appeared to be location-specific. In new-borns and children we identified various locations on the DNA with differential methylation when higher exposed to PM10. The DNA loci that were identified from these studies as being potentially involved in exposure to polluted air were more closely inspected for potential mechanisms to better understand how air pollution causes its effects. On the other hand, we could not prove that these locations on the DNA are also important in other studies. This suggests that methylation changes on specific locations following exposure to air pollution may not be extremely stable and so far not reproducible in other studies.
In this project, we showed that DNA methylation is a potential mechanistic link between exposure to polluted air and cancer, and prenatal exposure might influence the development of adult chronic diseases. New hypotheses concerning the mechanisms of exposure to air pollution were proposed, to which further research can be dedicated to.
“This is a comprehensive summary overview of results, conclusions and the socio-economic impacts of the project. The publishable report shall be formatted to be printed as a stand alone paper document. This report should address a wide audience, including the general public. Moreover, do not include in the summary report any confidential information, whose publication might undermine the protection of commercial interests, including intellectual property, or privacy and the integrity of the individuals, in particular in accordance with Community legislation regarding the protection of personal data. Please ensure that it:
- Is of suitable quality to enable direct publication by the REA or the Commission. - Is comprehensive, and describes the work carried out to achieve the project's objectives; the main results, conclusions and their potential impact and use and any socio-economic impact of the project. Please mention any target groups such as policy makers or civil society for whom the research could be relevant. “
Ambient air pollution can originate from burning of fossil fuels (i.e. the coal and petroleum related to traffic and energy production) and consists of noxious gases (sulphur dioxide, nitrogen oxides, carbon monoxide, chemical vapours, etc.). These pollutants can form fine particles. Being exposed to polluted air is associated with cardiovascular diseases and increases the risk for lung cancer at the population level. Air pollutants can be particularly harmful to people belonging to high risks groups such as children and the elderly. How exposure is harmful for health is not fully understood but oxidative damage or effects on cellular structures are candidate mechanisms involved. Epigenetic modifications play a crucial role in gene expression and its regulation and are as well affected by external stressors. As such these constitute promising to gain knowledge on the mechanisms involved in the effect mediation of air pollution exposure. One such example is the methylation of DNA which regulates the expression of genes and can be influenced by external factors including toxic exposures. Previous epidemiological studies indicate that particulate air pollution affects global and gene-specific DNA methylation. New high-resolution technology of sensor systems and molecular analytical approaches provide opportunities to improve the understanding of how the environment influences disease risk and outcome. In this project, we analysed DNA methylation data in relation to estimates of exposure to air pollutants in order to gain a novel insight into epigenetically mediated effects of exposure in both adults and children.
We measured the methylation status in blood using the 450K human Illumina methylation array, which assesses methylation levels of more than 480,000 loci across the genome. The levels of exposure to air pollution at participants’ homes were estimated via models taking into account the land use. These land-use regression models are based on equations that describe the relationship between measured pollutant concentrations and potential predictor variables, using a geographic information system. Individual levels for 2 gases: NO2 and NOx, fine particles with a diameter of 2.5 µg/m3 (PM2.5) between 2.5 and 10 µg/m3 (PMcoarse) and 10 µg/m3 (PM10), and a measure for soot in the air (absorbance of the PM2.5 filter, PM2.5abs) were estimated. We used (generalised) linear regression models to study the association between DNA methylation and exposure and accounted for several important characteristics of the participants such as the gender, age and smoking behaviour.
In healthy adult volunteers from two cohorts in Italy and the Netherlands that are a part of the European Prospective Investigation Into Cancer and Nutrition Cohort Study (EPIC), we studied the overall methylation status across the entire genome. We observed that increased exposure to NO2 and NOx decreases global DNA methylation. We found that regions flanking portions of DNA with densely distributed places that could be methylated (CpG islands) show aberrant DNA methylation patterns in relation to higher NO2 and NOx concentrations. In the children from the Avon Longitudinal Study of Parents and Children (ALSPAC), we identified a similar pattern in cord blood of new-borns and, in blood from children of age 15 but not in 7-years old children, were the pattern seemed reversed. DNA methylation protects the genome and low methylation can cause genome instability, as such lower DNA methylation resulting from exposure to NO2 and NOx might enable the development of cancers. These findings may further explain how being exposed to air pollutants can contribute to cancer risk, and in this regard hypomethylation might be potential pathway leading to the development of cancer.
We identified several specific regions along the genome whose methylation was associated with NO2, NOx, PM2.5 and PM2.5abs exposures in EPIC-Italy and a multitude of loci associated with all components of air pollution in EPIC-NL. However, these signals appeared to be location-specific. In new-borns and children we identified various locations on the DNA with differential methylation when higher exposed to PM10. The DNA loci that were identified from these studies as being potentially involved in exposure to polluted air were more closely inspected for potential mechanisms to better understand how air pollution causes its effects. On the other hand, we could not prove that these locations on the DNA are also important in other studies. This suggests that methylation changes on specific locations following exposure to air pollution may not be extremely stable and so far not reproducible in other studies.
In this project, we showed that DNA methylation is a potential mechanistic link between exposure to polluted air and cancer, and prenatal exposure might influence the development of adult chronic diseases. New hypotheses concerning the mechanisms of exposure to air pollution were proposed, to which further research can be dedicated to.