Haem in red meat (RM) stimulates the endogenous production of mutagenic nitroso compounds (NOC). Processed (nitrite-preserved red) meat additionally contains high concentrations of preformed NOC. In two studies, of a fresh RM versus a vegetarian (VEG) diet (six males and six females) and of a nitrite-preserved red meat (PM) versus a VEG diet (5 males and 11 females), we investigated whether processing of meat might increase colorectal cancer risk by stimulating nitrosation and DNA damage. Meat diets contained 420 g (males) or 366 g (females) meat/per day. Faecal homogenates from day 10 onwards were analysed for haem and NOC and associated supernatants for genotoxicity. Means are adjusted for differences in male to female ratios between studies. Faecal NOC concentrations on VEG diets were low (2.6 and 3.5 mmol/g) but significantly higher on meat diets (PM 175 ± 19 nmol/g versus RM 185 ± 22 nmol/g; P = 0.75). The RM diet resulted in a larger proportion of nitrosyl iron (RM 78% versus PM 54%; P < 0.0001) and less nitrosothiols (RM 12% versus PM 19%; P < 0.01) and other NOC (RM 10% versus PM 27%; P < 0.0001). There was no statistically significant difference in DNA breaks induced by faecal water (FW) following PM and RM diets (P = 0.80). However, PM resulted in higher levels of oxidized pyrimidines (P < 0.05). Surprisingly, VEG diets resulted in significantly more FW-induced DNA strand breaks than the meat diets (P < 0.05), which needs to be clarified in further studies. Meats cured with nitrite have the same effect as fresh RM on endogenous nitrosation but show increased FW-induced oxidative DNA damage.

Scope Alterations in DNA methylation patterns are correlated with aging, environmental exposures, and disease pathophysiology; the possibility of reverting or preventing these processes through dietary intervention is gaining momentum. In particular, methyl donors that provide S‐adenosyl‐methionine for one‐carbon metabolism and polyphenols such as flavanols that inhibit the activity of DNA methyltransferases (DNMTs) can be key modifiers of epigenetic patterns. Methods and results DNA methylation patterns are assessed in publicly available Illumina Infinium 450K methylation datasets from intervention studies with either folic acid + vitamin B12 (GSE74548) or monomeric and oligomeric flavanols (MOF) (GSE54690) in 44 and 13 participants, respectively. Global DNA methylation levels are increased in unmethylated regions such as CpG islands and shores following folic acid + vitamin B12 supplementation and decreased in highly methylated regions, including shelves and open‐seas, following intervention with MOF. After supplementation with folic acid + vitamin B12, epigenetic age, estimated by the Horvath “epigenetic clock” model, is reduced in women with the MTHFR 677CC genotype. Conclusions The effects of supplementation with folic acid + vitamin B12 and MOF on DNA methylation age are dependent upon gender and MTHFR genotype. Additionally, the findings demonstrate the potential for these dietary factors to modulate global DNA methylation profiles.

Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.

The epitranscriptome comprises more than 100 forms of RNA modifications. Of these, N6methyladenosine (m 6 A) is the most abundantform of RNA methylation, with roles in modulating mRNA transcript processing and regulation. The aims of the study weretoexamine changes inm 6 A RNA methylation in A549 lung epithelial cells in response to environmental toxicants, anddifferential gene expression of m 6 A modulator genes ('readers', 'writers' and 'erasers') in human subjects exposed toparticulate matter (PM) and in lung cancer tissueusing publicly-available microarray datasets.Global m 6 A methylation levelsweremeasured in total RNA after exposuretotwo carcinogens (PM and sodium arsenite) for 24-and 48-hours, and totwo endocrine disruptors (bisphenol A and vinclozolin)for 24-hours.Global m 6 A methylation level significantly decreased with exposure to >62 µg/mlPM, >1 µM sodium arsenite, >1µM bisphenol A (BPA), and0.1µM vinclozolin.In an analysis of a published dataset derived from a population study, we observed that m 6 A writers (METTL3 and WTAP), erasers (FTO and ALKBH5) and readers (HNRPC) showed significantly higher expression among participants in the high-PM 2.5 exposure group compared to those in the low-exposure control group(all p<0.05).Further, the m 6 A writer METTL3shows reduced expression in lung tumors in comparison to normal lung epithelia (p<0.0001).Our findings reveal that m 6 A RNA methylation can be modified by exposure to environmental toxicants, and exposure to particulate matter is associated with differential expression level of m 6 A RNA methylation modification machinery.

Smoking tobacco is a known risk factor for the development of colorectal cancer, and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never smokers, 47 former smokers and 13 active smokers, and adjacent mucosa from 49 never smokers, 64 former smokers and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS<1×10−5) in tumours of active smokers. The APC 1A promoter was hypermethylated in 7 of 36 tumours from never smokers (19%), 12 of 47 tumours from former smokers (26%), and 8 of 13 tumours from active smokers (62%). Promoter hypermethylation was positively associated with duration of smoking (Spearman rank correlation, ρ=0.26, p=0.03) and was confined to tumours, with hypermethylation never being observed in adjacent mucosa. Further analysis of adjacent mucosa revealed significant hypomethylation of four loci associated with the TNXB gene in tissue from active smokers. Our findings provide exploratory evidence for hypermethylation of the key tumour suppressor gene APC being implicated in smoking-associated colorectal carcinogenesis. Further work is required to establish the validity of our observations in independent cohorts.

Epigenetic regulation of imprinted genes enables monoallelic expression according to parental origin, and its disruption is implicated in many cancers and developmental disorders. The expression of hormone receptors is significant in breast cancer as they are indicators of cancer cell growth rate and determine response to endocrine therapies. We investigated the frequency of aberrant events and variation in DNA methylation at nine imprinted sites in invasive breast cancer and examined the association with estrogen and progesterone receptor status. Breast tissue and blood from patients with invasive breast cancer (n=38) and benign breast disease (n=30) were compared to those from healthy individuals (n=36), matched to the cancer patients by age at diagnosis, ethnicity, BMI, menopausal status, and familial history of cancer. DNA methylation and allele-specific expression were analyzed by pyrosequencing. Tumor-specific methylation changes at IGF2 DMR2 were observed in 59% of cancer patients, IGF2 DMR0 in 38%, DIRAS3 DMR in 36%, GRB10 ICR in 23%, PEG3 DMR in 21%, MEST ICR in 19%, H19 ICR in 18%, KvDMR in 8%, and SNRPN/SNURF ICR in 4%. Variation of methylation was significantly greater in breast tissue from cancer patients than healthy individuals and benign breast disease. Aberrant methylation of three or more sites was significantly associated with negative estrogen-alpha (Fisher’s Exact Test, p=0.02) and progesterone-A (p=0.02) receptor status. Aberrant events and increased variation of imprinted gene DNA methylation therefore appear to be frequent in invasive breast cancer and are associated with negative estrogen and progesterone receptor status, without loss of monoallelic expression.

A and Guo, L (2017) The effect of morphine upon DNA methylation in ten regions of the rat brain. Epigenetics, 12 (12 AbstractMorphine is one of the most effective analgesics in medicine. However, its use is associated with the development of tolerance and dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided insight into mechanisms possibly underlying addiction. In this study, we sought to identify epigenetic changes in ten regions of the rat brain following acute and chronic morphine exposure. We analyzed DNA methylation of six nuclear-encoded genes implicated in brain function (Bdnf, Comt, Il1b, Il6, Nr3c1 and Tnf) and three mitochondrially-encoded genes (Mtco1, Mtco2 and Mtco3), and measured global 5-methylcytosine (5-mc) and 5-hydroxymethylcytosine (5-hmc) levels. We observed differential methylation of Bdnf and Il6 in the pons, Nr3c1 in the cerebellum, and Il1b in the hippocampus in response to acute morphine exposure (all p<0.05). Chronic exposure was associated with differential methylation of Bdnf and Comt in the pons, Nr3c1 in the hippocampus and Il1b in the medulla oblongata (all p<0.05). Global 5-mc levels significantly decreased in the superior colliculus following both acute and chronic morphine exposure, and increased in the hypothalamus following chronic exposure. Chronic exposure was also associated with significantly increased global 5-hmc levels in the cerebral cortex, hippocampus and hypothalamus, but significantly decreased in the midbrain. Our results demonstrate, for the first time, highly localized epigenetic changes in the rat brain following acute and chronic morphine exposure. Further work is required to elucidate the potential role of these changes in the formation of tolerance and dependence.

BackgroundThe menstrual cycle is regulated by reproductive hormones such as estrogen which has been implicated in the pathogenesis of hypertension and is associated with obesity. However, to date there has scant study of hypertension in relation to menstrual characteristics and abnormalities. We hypothesize that adverse menstrual characteristics are associated with an increase the prevalence of hypertension and that this relationship is exacerbated by obesity.MethodsOur study leverages 178,205 healthy female participants (mean age = 29) in a population-based cross-sectional study in Tianjin, China. Menstrual characteristics including menstrual cycle length and regularity, menstrual bleeding length, menstrual blood loss and dysmenorrhea were assessed by self-reported questionnaires, and hypertension was diagnosed by physician. Multiple logistic regression models were used to assess the relationships between menstrual characteristics and hypertension.ResultsNormal length menstrual cycle (OR = 1.21, 95% CI: 1.03–1.41), oligomenorrhea (OR = 1.54, 95% CI: 1.12–2.07), irregular cycle (OR = 1.54, 95% CI: 1.22–1.93), and light menstrual blood loss (OR = 1.36, 95% CI: 1.06–1.72) were associated with hypertension among women who are overweight or obese, but not among women who are normal weight. Longer menstrual bleeding duration (OR = 1.44, 95% CI: 1.24–1.67) and dysmenorrhea were associated with increased prevalence of hypertension (OR = 1.20, 95% CI: 1.14–1.41) in all young women.ConclusionsThe prevalence of hypertension is higher among women with menstrual abnormalities, and this association is modified by overweight and obesity.