Environmental Epigenetics最新文献

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.

The increasing prevalence of neurodegenerative diseases poses a significant public health challenge, prompting a growing focus on addressing modifiable risk factors of disease (e.g. physical inactivity, mental illness, and air pollution). The environment is a significant contributor of risk factors which are known to impact the brain and contribute to disease risk (e.g. air pollution, noise pollution, green and blue spaces). Epigenetics can offer insights into how various environmental exposures impact the body to contribute to cognitive outcomes. In this systematic review, we examined studies which have associated an environmental exposure to a type of epigenetic modification, DNA methylation, and a cognitive outcome. We searched four databases with keywords "environmental exposures," "epigenetics," and "cognition." We yielded 6886 studies that we screened by title/abstract followed by full text. We included 14 studies which focused on four categories of environmental exposure: air pollution (n = 3), proximity to roads (n = 1), heavy metals (n = 6), and pesticides (n = 4). Overall, n = 10/14 studies provided evidence that DNA methylation is statistically significant in the association between the environment and a cognitive outcome. Furthermore, we identified that n = 5/14 studies performed a type of biological pathway analysis to determine the presence of biological pathways between their environmental exposure and cognitive outcome. Our findings underscore the need for methodological improvements and considerations in future studies, including investigation of other environmental exposures considering tissue-specificity of methylation profiles and stratifying analysis by sex, ethnicity and socioeconomic determinants of disease. This review demonstrates that further investigation is warranted, the findings of which may be of use in the development of preventative measures and risk management strategies for neurodegenerative disease.

Among the various environmental pollutants, dioxin, a highly toxic and widely used compound, is associated with numerous adverse health effects, including a potentially toxic multigenerational effect. Understanding the mechanisms by which dioxin exposure can affect sperm epigenetics is critical to comprehending the potential consequences for offspring health and development. This study investigates the possible association between weighted epimutations, hypothesized as markers of epigenetic drift, and dioxin exposure in sperm tissues. We used a public online methylation dataset consisting of 37 participants: 26 Vietnam veterans exposed to Agent Orange, an herbicide contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and 11 individuals not directly exposed to TCDD but whose serum dioxin levels are equivalent to the background. In our study, conducted at the gene level, 437 epimutated genes were identified as significantly associated with each single-digit increase in serum dioxin levels. We found no significant association between the rise in total epimutation load and serum dioxin levels. The pathway analysis performed on the genes reveals biological processes mainly related to changes in embryonic morphology, development, and reproduction. Results from our current study suggest the importance of further investigations on the consequences of dioxin exposure in humans with specific reference to germinal tissue and related heredity.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by a broad range of symptoms. The etiology of ASD is thought to involve complex gene-environment interactions, which are crucial to understanding its various causes and symptoms. DNA methylation is an epigenetic mechanism that potentially links genetic predispositions to environmental factors in the development of ASD. This review provides a global perspective on ASD, focusing on how DNA methylation studies may reveal gene-environment interactions characteristic of specific geographical regions. It delves into the role of DNA methylation in influencing the causes and prevalence of ASD in regions where environmental influences vary significantly. We also address potential explanations for the high ASD prevalence in North America, considering lifestyle factors, environmental toxins, and diagnostic considerations. Asian and European studies offer insights into endocrine-disrupting compounds, persistent organic pollutants, maternal smoking, and their associations with DNA methylation alterations in ASD. In areas with limited data on DNA methylation and ASD, such as Africa, Oceania, and South America, we discuss prevalent environmental factors based on epidemiological studies. Additionally, the review integrates global and country-specific prevalence data from various studies, providing a comprehensive picture of the variables influencing ASD diagnoses over region and year of assessment. This prevalence data, coupled with regional environmental variables and DNA methylation studies, provides a perspective on the complexities of ASD research. Integrating global prevalence data, we underscore the need for a comprehensive global understanding of ASD's complex etiology. Expanded research into epigenetic mechanisms of ASD is needed, particularly in underrepresented populations and locations, to enhance biomarker development for diagnosis and intervention strategies for ASD that reflect the varied environmental and genetic landscapes worldwide.

Preterm birth (PTB) has dramatically increased within the population (i.e. >10%) and preeclampsia is a significant sub-category of PTB. Currently, there are no practical clinical parameters or biomarkers which predict preeclampsia induced PTB. The current study investigates the potential use of epigenetic (DNA methylation) alterations as a maternal preeclampsia biomarker. Non-preeclampsia term births were compared to preeclampsia PTBs to identify DNA methylation differences (i.e. potential epigenetic biomarker). Maternal buccal cell cheek swabs were used as a marker cell for systemic epigenetic alterations in the individuals, which are primarily due to environmentally induced early life or previous generations impacts, and minimally impacted or associated with the disease etiology or gestation variables. A total of 389 differential DNA methylation regions (DMRs) were identified and associated with the presence of preeclampsia. The DMRs were genome-wide and were predominantly low CpG density (<2 CpG/100 bp). In comparison with a previous PTB buccal cell epigenetic biomarker there was a 15% (60 DMR) overlap, indicating that the majority of the DMRs are unique for preeclampsia. Few previously identified preeclampsia genes have been identified, however, the DMRs had gene associations in the P13 K-Akt signaling pathway and metabolic gene family, such as phospholipid signaling pathway. Preliminary validation of the DMR use as a potential maternal biomarker used a cross-validation analysis on the samples and provided 78% accuracy. Although prospective expanded clinical trials in first trimester pregnancies and clinical comparisons are required, the current study provides the potential proof of concept a preeclampsia epigenetic biomarker may exist. The availability of a preeclampsia PTB maternal susceptibility biomarker may facilitate clinical management and allow preventative medicine approaches to identify and treat the preeclampsia condition prior to its occurrence.

Little is understood about the roles of mitochondria in pregnancy-related adaptations. Therefore, we evaluated associations of maternal early-to-mid pregnancy mitochondrial DNA copy number (mtDNAcn) and mtDNA methylation with birth size and gestational length. Michigan women (n = 396) provided venous bloodspots at median 11 weeks gestation to quantify mtDNAcn marker NADH-ubiquinone oxidoreductase chain 1 (ND1) using real-time quantitative PCR and mtDNA methylation at several regions within four mitochondria-specific genes using pyrosequencing: MTTF (mitochondrially encoded tRNA phenylalanine), DLOOP (D-loop promoter region, heavy strand), CYTB (cytochrome b), and LDLR (D-loop promoter region, light strand). We abstracted gestational length and birthweight from birth certificates and calculated birthweight z-scores using published references. We used multivariable linear regression to evaluate associations of mtDNAcn and mtDNA methylation with birthweight and birthweight z-scores. Cox Proportional Hazards Models (PHMs) and quantile regression characterized associations of mitochondrial measures with gestational length. We also considered differences by fetal sex. Using linear regression and Cox PHMs, mtDNAcn was not associated with birth outcomes, whereas associations of mtDNA methylation with birth outcomes were inconsistent. However, using quantile regression, mtDNAcn was associated with shorter gestation in female newborns at the upper quantiles of gestational length, but with longer gestational length in males at the lower quantiles of gestational length. Maternal LDLR, DLOOP, and MTTF methylation was associated with longer gestational length in females at the upper quantiles and in males at lower gestational length quantiles. Maternal mtDNAcn and mtDNA methylation were associated with gestational length in babies born comparatively early or late, which could reflect adaptations in mitochondrial processes that regulate the length of gestation.

Air pollution is a hazardous contaminant, exposure to which has substantial consequences for health during critical periods, such as pregnancy. MicroRNA (miRNA) is an epigenetic mechanism that modulates transcriptome responses to the environment and has been found to change in reaction to air pollution exposure. The data are limited regarding extracellular-vesicle (EV) miRNA variation associated with air pollution exposure during pregnancy and in susceptible populations who may be disproportionately exposed. This study aimed to identify EV-miRNA expression associated with ambient, residential exposure to PM_2.5, PM₁₀, NO₂, O₃ and with traffic-related NO_x in 461 participants of the MADRES cohort, a low income, predominantly Hispanic pregnancy cohort based in Los Angeles, CA. This study used residence-based modeled air pollution data as well as Nanostring panels for EVmiRNA extracted with Qiagen exoRNeasy kits to evaluate 483 miRNA in plasma in early and late pregnancy. Average air pollution exposures were considered separately for 1-day, 1-week, and 8-week windows before blood collection in both early and late pregnancy. This study identified 63 and 66 EV-miRNA significantly associated with PM_2.5 and PM₁₀, respectively, and 2 miRNA associated with traffic-related NO_X (False Discovery Rate-adjusted P-value < .05). Of 103 unique EV-miRNA associated with PM, 92% were associated with lung conditions according to HMDD (Human miRNA Disease Database) evidence. In particular, EV-miRNA previously identified with air pollution exposure also associated with PM_2.5 and PM₁₀ in this study were: miR-126, miR-16-5p, miR-187-3p, miR200b-3p, miR486-3p, and miR-582-3p. There were no significant differences in average exposures in early vs late pregnancy. Significant EV-miRNAs were only identified in late pregnancy with an 8-week exposure window, suggesting a vulnerable timeframe of exposure, rather than an acute response. These results describe a wide array of EV-miRNA for which expression is affected by PM exposure and may be in part mediating the biological response to ambient air pollution, with potential for health implications in pregnant women and their children.