Environmental Epigenetics最新文献

Exposure to air pollution and an unhealthy built environment increase disease risk by impacting metabolic risk factors and inflammation, potentially via epigenetic modifications and effects on gene expression. We aimed to explore associations between fine particulate matter (PM_2.5), black carbon, ozone, nitrogen dioxide, distance to nearest water body, normalized difference vegetation index, and impervious surface and gene expression profiles in adults. This study is a part of the LongITools project and includes cross-sectional data from the Rotterdam Study, a population-based cohort study, and NoMa, a randomized controlled trial. Environmental exposures were assigned using land-use regression (LUR) models and satellite data. Gene expression was assessed with whole blood RNA sequencing (Rotterdam Study, n = 758) and microarray analyses in peripheral blood mononuclear cells (NoMa, n = 100). We analysed transcriptomic profiles and enriched pathways associated with each of the environmental exposures. PM_2.5 had the strongest gene expression associations, while only a few significant associations were observed for the other environmental exposures. In both populations, exposure to PM_2.5 was associated with genes and pathways related to inflammation, oxidative stress, DNA metabolism, cell cycle regulation, histones, electron transport chain, oxidative phosphorylation, and neural signalling. This study is limited by different methods for RNA quantification, a cross-sectional design, and a small sample size. However, in both populations, exposure to PM_2.5 resulted in the maximum number of associations with gene expression. In conclusion, PM_2.5 is strongly associated with various gene expression profiles, which provide information about the underlying mechanisms of the detrimental health effects of exposure to PM_2.5.

Paternal exposure to drugs of abuse can impact addiction-related behaviours in progeny via germline epigenome remodelling. Previously, we found that offspring of morphine-exposed male rats showed increased morphine-taking, diminished adolescent social play, and increased sensitivity to morphine-derived analgesia. Here, we first tested the impact of a 90-day paternal abstinence period following morphine self-administration on the transmission of the aforementioned phenotypes. The previously observed changes in morphine-related behaviours were no longer present in offspring of morphine-abstinent sires. We next compared small RNA (smRNA) content in sperm collected from four sire intravenous self-administration groups: morphine, saline, abstinent morphine, and abstinent saline. Two smRNAs (rno-miR-150-5p and an snoRNA annotated to Snora42/Noc3l) were differentially expressed specifically between morphine- and saline-treated sperm. No differential expression between abstinent morphine and saline sperm was observed. These data begin to delineate the temporal limits of heritable germline modifications associated with morphine exposure, in addition to identifying F0 germline factors coinciding with the manifestation of F1 multigenerational phenotypes. Furthermore, these data suggest that paternal abstinence at conception can prevent inheritance of germline factors that may alter offspring susceptibility to addiction-related endophenotypes.

Previous studies have demonstrated that ten-eleven translocation methylcytosine dioxygenase 1 (TET1) plays a protective role against house dust mite (HDM)-induced allergic airway inflammation. TET1 transcriptionally responded to HDM extract and regulated the expression of genes involved in asthma in human bronchial epithelial cells (HBECs). How TET1 regulates the expression of these genes, however, is unknown. To this end, we measured mRNA expression, DNA methylation, chromatin accessibility, and histone modifications in control and TET1 knockdown HBECs treated or untreated with HDM extract. Throughout our analyses of multiomics data, we detected significant similarities between the effects of TET1 knockdown alone and the effects of HDM treatment alone, all enriched for asthma-related genes and pathways. One especially striking pattern was that both TET1 knockdown and HDM treatment generally led to decreased chromatin accessibility at many of the same genomic loci. Transcription factor enrichment analyses indicated that altered chromatin accessibility following the loss of TET1 may affect, or be affected by, CCCTC-binding factor and CCAAT-enhancer-binding protein binding. Analysis of H3K27ac levels and comparison with existing datasets suggested a potential impact of TET1 on enhancer activity. TET1 loss also led to changes in DNA methylation, but these changes were generally in regions where accessibility was not changing. Lastly, more significant transcriptomic changes were observed in HBEC cells with TET1 knockdown compared to control cells following HDM challenges. Collectively, our data suggest that TET1 regulates gene expression through distinct mechanisms across various genomic regions in airway epithelial cells, restricting transcriptomic responses to allergen and potentially protecting against the development of asthma.

The relationship between circadian rhythm disorders and the development of various diseases appears to be significant, with limited current interventions available. Research literature suggests that hypoxia may influence the expression of clock genes and the shifting of rhythm phases. However, the precise mechanisms underlying the modulation of circadian rhythm through circulating exosomes by hypoxia preconditioning remain unclear. In this study, the mice were exposed to hypobaric conditions, simulating an altitude of 5000 m, for 1 h daily over the course of 1 week in order to achieve hypoxia preconditioning. Compared to the control group, no significant alteration was observed in the concentration, modal size, and mean size of circulating exosomes in hypoxia preconditioning mice. Exosomes derived from hypoxia preconditioning effectively suppressed the expression of Per1, Clock, and Bmal1 in NIH 3T3 cells. The miRNA sequencing analysis revealed miR-34b-3p as a potential regulator of the Clock, resulting in the downregulation of clock gene expression and subsequent promotion of proliferation and migration in NIH 3T3 cells. This study elucidated a novel mechanism of hypoxia preconditioning in the regulation of circadian rhythm, proposing that exosomal miR-34b-3p functions as an unrecognized molecule entity involved in the modulation of circadian rhythm. These findings offer a new avenue for developing protective strategies and therapeutic targets for circadian rhythm disorders.

A Bhas42 cell transformation assay is a method used to detect the tumour-promoting activities of chemicals. However, the mechanisms underlying tumour transformations mediated by non-genotoxic carcinogens (NGCs) are poorly understood. This study aimed to examine the correlation between 12-O-tetradecanoylphorbol 13-acetate (TPA) or mezerein and the initiation of tumourous transformations by epigenetic regulation in Bhas42 cells. We found that TPA and mezerein prompted tumourous transformations by stimulating cell proliferation and migration in Bhas42 cells. Furthermore, we observed alterations in the expression levels of 134 genes, with 87 genes being upregulated and 47 genes being downregulated, following exposure to either TPA or mezerein. Among the differentially regulated genes, we identified 17 upregulated genes and 8 downregulated genes corresponding to differentially expressed genes in TNM [primary tumour (T), regional nodes (N), and metastasis (M)]. Importantly, we found that TPA and mezerein triggered the expression of Hmga2 and Ezh2 by loss of miRNA let-7 (miR let-7) in Bhas42 cells. Finally, the microRNA (miRNA) mimic of let-7 prevented the TPA- and mezerein-induced activation of Hmga2 and Ezh2 in Bhas42 cells. Our findings reveal a connection between tumourous transformations and the epigenetic regulator miR let-7 in NGCs, such as TPA and mezerein in Bhas42 cells. This highlights miR let-7 as a promising therapeutic target for mitigating tumourous transformations induced by NGCs.

Nutritional challenges and obesity can contribute to the transmission of metabolic diseases through epigenetic mechanisms. Among them, DNA methylation stands out as a potential carrier of information because germline cytosine methylation responds to environmental factors and can be transmitted across generations. Yet, it remains unclear whether inherited DNA methylation plays an active role in the inheritance of metabolic phenotypes or solely influences expression of a few genes that cannot recapitulate the whole metabolic spectrum in the next generation offspring. Previously, we established a mouse model of childhood obesity by reducing litter size at birth. Mice raised in small litters (SL) developed obesity, insulin resistance, and hepatic steatosis. The offspring (SL-F1) and grand-offspring (SL-F2) of SL males also exhibited hepatic steatosis. Here, we aimed to investigate whether germline DNA methylation could serve as a carrier of phenotypic information, hepatic steatosis, between generations. Litter size reduction significantly altered global DNA methylation profile in the sperm of SL-F0 males. Remarkably, 8% of these methylation marks remained altered in the sperm of SL-F1 mice and in the liver of SL-F2 mice. These data suggest that germline DNA methylation is sensitive to environmental challenges and holds significant heritability, either through direct germline transmission and/or through sequential erasure and reestablishment of the marks in the following generations. Yet, DNA methylation did not strongly correlate with the hepatic transcriptome in SL-F2 mice, suggesting that it does not directly drive phenotypes in the F2. As an alternative, germline DNA methylation could potentially influence the phenotype of the next generation by modulating the expression of a reduced number of key transcription factors that, through an amplification cascade, drive phenotypic outcomes in subsequent generations.

Mesoamerican nephropathy (MeN) is a leading cause of morbidity and mortality in Central America, yet its aetiology remains unclear. Environmental exposures including heat stress, pesticides, and heavy metals have all been suggested as possible causes or exacerbating factors of the disease, but intermittent and cumulative exposures are difficult to capture using conventional biomonitoring. Locus-specific differential DNA-methylation (DNAm) which is known to occur in association with these environmental exposures can be readily measured in peripheral blood leucocytes, and therefore have the potential to be used as biomarkers of these exposures. In this study, we aimed first to perform a hypothesis-free epigenome-wide association study of MeN to identify disease-specific methylation signatures, and second to explore the association of DNAm changes associated with potentially relevant environmental exposures and MeN onset. Whole-blood epigenome-wide DNAm was analysed from a total of 312 blood samples: 53 incident cases (pre- and post-evidence of disease onset), 61 matched controls and 16 established cases, collected over a 5-year period. Mixed-effect models identified three unique differentially methylated regions that associated with incident kidney injury, two of which lie within the intron of genes (Amphiphysin on chromosome 7, and SLC29A3 chromosome 10), none of which have been previously reported with any other kidney disease. Next, we conducted a hypothesis-driven analysis examining the coefficients of CpG sites reported to be associated with ambient temperature, pesticides, arsenic, cadmium, and chromium. However, none showed an association with MeN disease onset. Therefore, we did not observe previously reported patterns of DNA methylation that might support a role of pesticides, temperature, or the examined metals in causing MeN.

Fine particulate matter (PM_2.5), an atmospheric pollutant that settles deep in the respiratory tract, is highly harmful to human health. Despite its well-known impact on lung function and its ability to exacerbate asthma, the molecular basis of this effect is not fully understood. This integrated transcriptomic and epigenomic data analysis from publicly available datasets aimed to determine the impact of PM_2.5 exposure and its association with asthma in human airway epithelial cells. Differential gene expression and binding analyses identified 349 common differentially expressed genes and genes associated with differentially enriched H3K27ac regions in both conditions. Co-expression network analysis revealed three preserved modules (Protein Folding, Cell Migration, and Hypoxia Response) significantly correlated with PM_2.5 exposure and preserved in asthma networks. Pathways dysregulated in both conditions included epithelial function, hypoxia response, interleukin-17 and TNF signaling, and immune/inflammatory processes. Hub genes like TGFB2, EFNA5, and PFKFB3 were implicated in airway remodeling, cell migration, and hypoxia-induced glycolysis. These findings elucidate common altered expression patterns and processes between PM_2.5 exposure and asthma, helping to understand their molecular connection. This provides guidance for future research to utilize them as potential biomarkers or therapeutic targets and generates evidence supporting the need for implementing effective air quality management strategies.

Environmental exposures, including air pollutants and lack of natural spaces, are associated with suboptimal health outcomes in children. We aimed to study the associations between environmental exposures and gene expression in children. Associations of exposure to particulate matter (PM) with diameter <2.5 (PM_2.5) and < 10 (PM₁₀) micrometers, nitrogen dioxide, green spaces, and blue space, with whole-blood gene expression were explored in children from the Dutch Generation R Study (n = 172). Analyses were adjusted for age, sex, batch, maternal education, and area socioeconomic status. Follow-up analysis was carried out using lymphoblastoid cell line gene expression in children from the ALSPAC Study (n = 946). Gene set enrichment analysis (GSEA) using hallmark and immune gene sets from the molecular signature database was carried out to identify significantly over-represented gene sets for insights into biological mechanisms Exposure to PM_2.5 was associated with expression of 86 genes in discovery analyses in the Generation R Study [false discovery rate (FDR)-adjusted P-value < .25]. Of these, PM_2.5 was also associated with GNG11 expression in the same direction in follow-up analysis (FDR-adjusted P-value < .05). The remaining exposures showed much fewer associations in the discovery analyses. GSEA using PM_2.5 association results for both cohorts indicated suppression of gene sets related to interferon response and response to bacterial and viral exposure. In conclusion, gene expression analysis performed in two independent cohorts suggests that PM_2.5 exposure in children may be involved in interferon and microbial infection responses.