Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes. This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available. Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation. Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10⁻⁷), which annotated to theAHRR,F2RL3,FLJ43663,HDAC4,GFI1andPHGDHgenes. Among them, cg14476101 is significantly associated with expression of thePHGDHand risk of fatty liver disease. Knockdown ofPHGDHexpression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role ofPHGDHin hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated toCACNA1AandPRDM16genes show suggestive association (P-value <5.0×10⁻⁶). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.

Chronic inflammation is an established risk factor for colorectal cancer. To study reactive products of gut inflammation and redox signaling on colorectal cancer development, we used untargeted adductomics to detect adduct features in prediagnostic serum from the EPIC Italy cohort. We focused on modifications to Cys34 in human serum albumin, which is responsible for scavenging small reactive electrophiles that might initiate cancers. Employing a combination of statistical methods, we selected seven Cys34 adducts associated with colorectal cancer, as well as body mass index (BMI; a well-known risk factor). Five adducts were more abundant in colorectal cancer cases than controls and clustered with each other, suggesting a common pathway. Because two of these adducts were Cys34 modifications by methanethiol, a microbial–human cometabolite, and crotonaldehyde, a product of lipid peroxidation, these findings further implicate infiltration of gut microbes into the intestinal mucosa and the corresponding inflammatory response as causes of colorectal cancer. The other two associated adducts were Cys34 disulfides of homocysteine that were less abundant in colorectal cancer cases than controls and may implicate homocysteine metabolism as another causal pathway. The selected adducts and BMI ranked higher as potentially causal factors than variables previously associated with colorectal cancer (smoking, alcohol consumption, physical activity, and total meat consumption). Regressions of case–control differences in adduct levels on days to diagnosis showed no statistical evidence that disease progression, rather than causal factors at recruitment, contributed to the observed differences. These findings support the hypothesis that infiltration of gut microbes into the intestinal mucosa and the resulting inflammation are causal factors for colorectal cancer.Significance: Infiltration of gut microbes into the intestinal mucosa and the resulting inflammation are causal factors for colorectal cancer.

It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin‐like growth factor 1 (IGF‐1). Several single nucleotide polymorphisms (SNPs) have been weakly associated with circulating concentrations of IGF‐1 and IGF binding protein 3 (IGFBP‐3), but none of these SNPs was associated with risk of prostate cancer. We examined whether an association between 16 SNPs associated with circulating IGF‐1 or IGFBP‐3 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5,253 cases and 4,963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes nested case–control studies within large North‐American and European cohorts. Per‐allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake, which was expressed as the percentage of energy derived from total, animal, dairy or plant protein sources, using conditional logistic regression models. Total, animal, dairy and plant protein intakes were significantly positively associated with blood IGF‐1 (p < 0.01), but not with IGFBP‐3 concentrations (p > 0.10) or with risk of prostate cancer (p > 0.20). After adjusting for multiple testing, the SNP‐prostate cancer associations did not differ by intakes of protein, although two interactions by intake of plant protein were of marginal statistical significance [SSTR5 (somatostatin receptor 5)‐rs197056 (uncorrected p for interaction, 0.001); SSTR5‐rs197057 (uncorrected p for interaction, 0.002)]. We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein.

This study aimed to estimate household pesticide exposure in adult individuals in the Metropolitan Region of Rio de Janeiro, Brazil, and to verify the accessibility of these products in local and online businesses. The data were collected by an online questionnaire (1,015 responses) and a shelf survey in physical and online stores. Among the responses analyzed, 87.5% used pesticides in the previous year, most of which against mosquitoes (64.7%). The most common application method was aerosol spray (38.1%), and the most frequent places of use were bedrooms (29.7%) and living rooms (22.1%). About 30% of respondents reported invasion of pests, and the most common pests were ants (79.1%) and cockroaches (40.4%). Service area (71.6%) and kitchen (17.5%) were the most common storage locations. Approximately 91% of those who lived with children aged under 18 used pesticides. The use of chemical group of pyrethroids prevailed (81.6%), and 90.8% of the reportedly used products are class II [55.7% (highly toxic)] or class III [35.1% (medium toxic)]. The most significant amount of purchased products was in the pest category, followed by mosquitoes. More variety of products were available in online stores than in physical stores. The high exposure of the population to pesticides at household is a public health issue and confirms the need for studies that better assess the risks and consequences of chronic and low-dose exposure to these substances. It is essential to inform the population about the uncertainties and potential risks of indiscriminate use so that they can choose whether to use pesticides in their households.

Background: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated. Methods: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case–control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions. Results: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11–1.41 for breast cancer, and 1.23; 95% CI, 1.07–1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25–1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P < 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome. Conclusions: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples. Impact: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.