Environmental Epigenetics最新文献

This review article provides a framework for the use of deoxyribonucleic acid (DNA) methylation (DNAm) biomarkers to study the biological embedding of socioeconomic position (SEP) and summarizes the latest developments in the area. It presents the emerging literature showing associations between individual- and neighborhood-level SEP exposures and DNAm across the life course. In contrast to questionnaire-based methods of assessing SEP, we suggest that DNAm biomarkers may offer an accessible metric to study questions about SEP and health outcomes, acting as a personal dosimeter of exposure. However, further work remains in standardizing SEP measures across studies and evaluating consistency across domains, tissue types, and time periods. Meta-analyses of epigenetic associations with SEP are offered as one approach to confirm the replication of DNAm loci across studies. The development of DNAm biomarkers of SEP would provide a method for examining its impact on health outcomes in a more robust way, increasing the rigor of epidemiological studies.

Epidural anesthesia is an effective pain relief modality, widely used for labor analgesia. Childhood asthma is one of the commonest chronic medical illnesses in the USA which places a significant burden on the health-care system. We recently demonstrated a negative association between the duration of epidural anesthesia and the development of childhood asthma; however, the underlying molecular mechanisms still remain unclear. In this study of 127 mother-child pairs comprised of 75 Non-Hispanic Black (NHB) and 52 Non-Hispanic White (NHW) from the Newborn Epigenetic Study, we tested the hypothesis that umbilical cord blood DNA methylation mediates the association between the duration of exposure to epidural anesthesia at delivery and the development of childhood asthma and whether this differed by race/ethnicity. In the mother-child pairs of NHB ancestry, the duration of exposure to epidural anesthesia was associated with a marginally lower risk of asthma (odds ratio = 0.88, 95% confidence interval = 0.76-1.01) for each 1-h increase in exposure to epidural anesthesia. Of the 20 CpGs in the NHB population showing the strongest mediation effect, 50% demonstrated an average mediation proportion of 52%, with directional consistency of direct and indirect effects. These top 20 CpGs mapped to 21 genes enriched for pathways engaged in antigen processing, antigen presentation, protein ubiquitination and regulatory networks related to the Major Histocompatibility Complex (MHC) class I complex and Nuclear Factor Kappa-B (NFkB) complex. Our findings suggest that DNA methylation in immune-related pathways contributes to the effects of the duration of exposure to epidural anesthesia on childhood asthma risk in NHB offspring.

As prenatal and community cannabis exposures have recently been linked with congenital heart disease (CHD), it was of interest to explore these associations in Europe in a causal framework and space-time context. Congenital anomaly data from Eurocat, drug-use data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Countries with rising daily cannabis use had in general higher congenital anomaly rates over time than those without (time: status interaction: β-Est. = 0.0267, P = 0.0059). At inverse probability-weighted panel regression, cannabis terms were positive and significant for CHD, severe CHD, atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, vascular disruptions, double outlet right ventricle, transposition of the great vessels, hypoplastic right heart, and mitral valve anomalies from 1.75 × 10^-19, 4.20 × 10^-11, <2.2 × 10^-16, <2.2 × 10^-16, 1.58 × 10^-12, 4.30 × 10^-9, 4.36 × 10^-16, 3.50 × 10^-8, 5.35 × 10^-12, <2.2 × 10^-16, 5.65 × 10^-5 and 6.06 × 10^-10. At spatial regression, terms including cannabis were positive and significant for this same list of anomalies from 0.0038, 1.05 × 10^-10, 0.0215, 8.94 × 10^-6, 1.23 × 10^-5, 2.05 × 10^-5, 1.07 × 10^-6, 8.77 × 10^-5, 9.11 × 10^-6, 0.0001, 3.10 × 10^-7 and 2.17 × 10^-7. 92.6% and 75.2% of 149 E-value estimates and minimum E-values were in high zone >9; 100.0% and 98.7% >1.25. Data show many congenital cardiac anomalies exhibit strong bivariate relationships with metrics of cannabis exposure. Causal inferential modelling for the twelve anomalies selected demonstrated convincing evidence of robust relationships to cannabis which survived adjustment and fulfilled epidemiological criteria for causal relationships. Space-time regression was similarly confirmatory. Epigenomic pathways constitute viable potential mechanisms. Given exponential genotoxic dose-response effects, careful and astute control of cannabinoid penetration is indicated.

Cannabinoid exposure is increasing in some European nations. Europe therefore provides an interesting test environment for the recently reported link between cannabis exposure and congenital limb anomaly (CLA) rates (CLARs). Exponential genotoxic dose-response relationships make this investigation both intriguing and imperative. Annual CLAR in 14 nations were from Epidemiological Surveillance of Congenital Anomalies. Drug use rates were from European Monitoring Centre for Drugs and Drug Dependency. Median household income was from the World Bank. E-values provide a quantitative measure of robustness of results to confounding by extraneous covariates. Inverse probability weighting is an important technique for equalizing exposures across countries and removing sources of bias. Rates of CLA, hip dysplasia and the whole group of limb anomalies were higher in countries with increasing daily cannabis use (P = 1.81 × 10^-16, 0.0005 and 2.53 × 10^-6, respectively). In additive inverse-probability-weighted panel models, the limb reduction-resin Δ9-tetrahydrocannabinol (THC) concentration E-value estimate was 519.93 [95% lower bound (mEV) 49.56], order Resin > Herb ≫ Tobacco > Alcohol. Elevations were noted in 86% E-value estimates and 70.2% of mEVs from 57 E-value pairs from inverse-probability-weighted panel models and from spatial models. As judged by the mEV the degree of association with metrics of cannabis exposure was hip dysplasia > polydactyly > syndactyly > limb anomalies > limb reductions with median E-value estimates from 3.40 × 10⁶⁵ to 7.06 and median mEVs from 6.14 × 10³³ to 3.41. Daily cannabis use interpolated was a more powerful metric of cannabis exposure than herb or resin THC exposure. Data indicate that metrics of cannabis exposure are closely linked with CLAR and satisfy epidemiological criteria for causality. Along with Hawaii and the USA, Europe now forms the third international population in which this causal link has been demonstrated. Cannabis as a predictor of limb anomalies was more potent than tobacco or alcohol. Cannabinoid access should be restricted to protect public health and the community genome/epigenome transgenerationally.

Exposure to arsenic affects millions of people globally. Changes in the epigenome may be involved in pathways linking arsenic to health or serve as biomarkers of exposure. This study investigated associations between prenatal and early-life arsenic exposure and epigenetic age acceleration (EAA) in adults, a biomarker of morbidity and mortality. DNA methylation was measured in peripheral blood mononuclear cells (PBMCs) and buccal cells from 40 adults (median age = 49 years) in Chile with and without high prenatal and early-life arsenic exposure. EAA was calculated using the Horvath, Hannum, PhenoAge, skin and blood, GrimAge, and DNA methylation telomere length clocks. We evaluated associations between arsenic exposure and EAA using robust linear models. Participants classified as with and without arsenic exposure had a median drinking water arsenic concentration at birth of 555 and 2 μg/l, respectively. In PBMCs, adjusting for sex and smoking, exposure was associated with a 6-year PhenoAge acceleration [B (95% CI) = 6.01 (2.60, 9.42)]. After adjusting for cell-type composition, we found positive associations with Hannum EAA [B (95% CI) = 3.11 (0.13, 6.10)], skin and blood EAA [B (95% CI) = 1.77 (0.51, 3.03)], and extrinsic EAA [B (95% CI) = 4.90 (1.22, 8.57)]. The association with PhenoAge acceleration in buccal cells was positive but not statistically significant [B (95% CI) = 4.88 (-1.60, 11.36)]. Arsenic exposure limited to early-life stages may be associated with biological aging in adulthood. Future research may provide information on how EAA programmed in early life is related to health.

Previous studies have revealed that DNA methylation changes could serve as potential genomic markers for environmental benzo[a]pyrene (BaP) exposure and intergenerational inheritance of various physiological impairments (e.g. obesity and reproductive pathologies). As a typical aromatic hydrocarbon pollutant, direct BaP exposure has been shown to induce neurotoxicity. To unravel the inheritance mechanisms of the BaP-induced bone phenotype in freshwater medaka, we conducted whole-genome bisulfite sequencing of F1 sperm and identified 776 differentially methylated genes (DMGs). Ingenuity pathway analysis revealed that DMGs were significantly enriched in pathways associated with neuronal development and function. Therefore, it was hypothesized that parental BaP exposure (1 μg/l, 21 days) causes offspring neurotoxicity. Furthermore, the possibility for sperm methylation as an indicator for a neurotoxic phenotype was investigated. The F0 adult brains and F1 larvae were analyzed for BaP-induced direct and inherited toxicity. Acetylcholinesterase activity was significantly reduced in the larvae, together with decreased swimming velocity. Molecular analysis revealed that the marker genes associated with neuron development and growth (alpha1-tubulin, mbp, syn2a, shh, and gap43) as well as brain development (dlx2, otx2, and krox-20) were universally downregulated in the F1 larvae (3 days post-hatching). While parental BaP exposure at an environmentally relevant concentration could induce neurotoxicity in the developing larvae, the brain function of the exposed F0 adults was unaffected. This indicates that developmental neurotoxicity in larvae may result from impaired neuronal development and differentiation, causing delayed brain growth. The present study demonstrates that the possible adverse health effects of BaP in the environment are more extensive than currently understood. Thus, the possibility of multigenerational BaP toxicity should be included in environmental risk assessments.

Δ8-Tetrahydrocannabinol (Δ8THC) is marketed in many US states as 'legal weed'. Concerns exist relating to class-wide genotoxic cannabinoid effects. We conducted an epidemiological investigation of Δ8THC-related genotoxicity expressed as 57 congenital anomaly (CA) rates (CARs) in the USA. CARs were taken from the Centers for Disease Control, Atlanta, Georgia. Drug exposure data were taken from the National Survey of Drug Use and Health, with a response rate of 74.1%. Ethnicity and income data were taken from the US Census Bureau. National cannabinoid exposure was taken from Drug Enforcement Agency publications and multiplied by state cannabis use data to derive state-based estimates of Δ8THC exposure. At bivariate continuous analysis, Δ8THC was associated with 23 CAs on raw CA rates, 33 CARs after correction for early termination for anomaly estimates and 41 on a categorical analysis comparing the highest and lowest exposure quintiles. At inverse probability weighted multivariable additive and interactive models lagged to 0, 2 and 4 years, Δ8THC was linked with 39, 8, 4 and 9 CAs. Chromosomal, cardiovascular, gastrointestinal, genitourinary, limb, central nervous system (CNS) and face systems were particularly affected. The minimum E-values ranged to infinity. Both the number of anomalies implicated and the effect sizes demonstrated were much greater for Δ8THC than for tobacco and alcohol combined. Δ8THC appears epidemiologically to be more strongly associated with many CAs than for tobacco and alcohol and is consistent with a cannabinoid class genotoxic/epigenotoxic effect. Quantitative causality criteria were fulfilled, and causal relationships either for Δ8THC or for cannabinoid/s, for which it is a surrogate marker, may be in operation.