[Show abstract][Hide abstract] ABSTRACT: BackgroundDNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age.ResultsHere we test whether differences between people¿s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age, (¿age), was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between ¿age and mortality. A 5-year higher ¿age is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher ¿age. A pedigree-based heritability analysis of ¿age was conducted in a separate cohort. The heritability of ¿age was 0.43.ConclusionsDNA methylation-derived measures of accelerated ageing are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.
[Show abstract][Hide abstract] ABSTRACT: Abstract Preterm birth is a leading cause of infant mortality and can lead to poor life-long health and adverse neurodevelopmental outcomes. The pathophysiologic mechanisms that precede preterm labor remain elusive, and the role that epigenetic phenomena play is largely unstudied. The objective of this study was to assess the association between microRNA (miRNA) expression levels in cervical cells obtained from swabs collected during pregnancy and the length of gestation. We analyzed cervical samples obtained between 16 and 19 weeks of gestation from 53 women in a prospective cohort from Mexico City, and followed them until delivery. Cervical miRNA was extracted and expression was quantified using the NanoString nCounter Analysis System. Linear regression models were used to examine the association between miRNA expression levels and gestational age at delivery, adjusted for maternal age, education, parity, body mass index, smoke exposure, and inflammation assessed on a Papanicolaou smear. We identified six miRNAs that were significantly associated with gestational age at the time of delivery, including miR-21, 30e, 142, 148b, 29b, and 223. Notably, per each doubling in miR-21 expression, gestations were 0.9 (95% CI: 0.2-1.5) days shorter on average (P = 0.009). Per each doubling in miR-30e, 142, 148b, 29b, and 223 expression, gestations were shorter by 1.0 to 1.6 days. The predicted targets of the miRNAs were enriched for molecules involved in DNA replication and inflammatory processes. The levels of specific miRNAs in the human cervix during pregnancy are predictive of gestational age at delivery, and should be validated in future studies as potential biomarkers of preterm birth risk.
Epigenetics: official journal of the DNA Methylation Society 01/2015; · 5.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are known endocrine disrupting chemicals used commonly as flame retardants in everything from electronics to furniture. Exposure to PBDEs during early development has been linked to neurodevelopmental delays. Despite mounting evidence of neurological harm from PBDE exposure, the molecular mechanisms underlying these effects on brain function remain unknown. We examined the effects of perinatal exposure to BDE-47, the most biologically active and prevalent BDE congener in North America, on epigenetic patterns in the frontal lobe of Wistar rats. Dams were gavaged with BDE-47 (0.002 and 0.2 mg/kg body weight) at gestation days 9 and 16, and postnatal days 1, 8, and 15. Frontal lobes from offspring at postnatal day 41 were collected to measure 5-methylcytosine (5mC) in mitochondrial cytochrome c oxidase genes (Mt-co1, Mt-co2, and Mt-co3), global nuclear 5-hydroxymethylcytosine (5hmC) content, 5mC in repetitive elements L1Rn, and 5mC in nuclear genes (Bdnf, Crhr1, Mc2r, Nr3c1, and Snca) related to behavioral and brain functions in the nuclear genome. We observed a significant decrease in %5mC in Mt-co2 (difference from control = −0.68%, p = 0.01 at the 0.2 mg/kg BDE-47). 5mC in repetitive elements L1Rn decreased at 0.002 mg/kg BDE-47 (difference = −1.23%, p = 0.02). Decreased nuclear 5mC was observed in Bdnf and Nr3c1 in BDE-47 exposed rats. However, we did not observe significant effects of PBDE toxicity on DNA methylation patterns for the majority of genes in the brain.
[Show abstract][Hide abstract] ABSTRACT: In occupational settings, boilermakers are exposed to high levels of metallic fine particulate matter (PM2.5) generated during the welding process. The effect of welding PM2.5 on heart rate variability (HRV) has been described, but the relationship between PM2.5, DNA methylation, and HRV is not known.
In this repeated-measures panel study, we recorded resting HRV and measured DNA methylation levels in transposable elements Alu and long interspersed nuclear element-1 (LINE-1) in peripheral blood leukocytes under ambient conditions (pre-shift) and right after a welding task (post-shift) among 66 welders. We also monitored personal PM2.5 level in the ambient environment and during the welding procedure.
The concentration of welding PM2.5 was significantly higher than background levels in the union hall (0.43 mg/m3 vs. 0.11 mg/m3, p < 0.0001). The natural log of transformed power in the high frequency range (ln HF) had a significantly negative association with PM2.5 exposure (beta = -0.76, p = 0.035). pNN10 and pNN20 also had a negative association with PM2.5 exposure (beta = -0.16%, p = 0.006 and beta = -0.13%, p = 0.030, respectively). PM2.5 was positively associated with LINE-1 methylation [beta = 0.79%, 5-methylcytosince (%mC), p = 0.013]; adjusted for covariates. LINE-1 methylation did not show an independent association with HRV.
Acute decline of HRV was observed following exposure to welding PM2.5 and evidence for an epigenetic response of transposable elements to short-term exposure to high-level metal-rich particulates was reported.
BMC Public Health 12/2014; 14(1):1279. · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to air particulate matter is known to elevate blood biomarkers of inflammation and to increase cardiopulmonary morbidity and mortality. Major components of airborne particulate matter typically include black carbon from traffic and sulfates from coal-burning power plants. DNA methylation is thought to be sensitive to these environmental toxins and possibly mediate environmental effects on clinical outcomes via regulation of gene networks. The underlying mechanisms may include epigenetic modulation of major inflammatory pathways, yet the details remain unclear.
Environmental Health 11/2014; 13(1):94. · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies. The aim of this study was to validate the role of intralesional interleukin (IL)-2, to understand its mechanism of action, and to better understand factors that may influence its response.
Annals of Surgical Oncology 11/2014; · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Exposure to ambient particulate matter (PM) has been associated with reduced lung function. Elemental components of PM have been suggested to have critical roles in PM toxicity, but their contribution to respiratory effects remains under-investigated. We evaluated the effects of traffic-related PM2.5 and its elemental components on lung function in two highly exposed groups of healthy adults in Beijing, China.Methods
The Beijing Truck-Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers evaluated in 2008. On two days separated by 1-2 weeks, we measured lung function at the end of the work day, personal PM2.5, and nine elemental components of PM2.5 during eight hours of work, i.e., elemental carbon (EC), potassium (K), sulfur (S), iron (Fe), silicon (Si), aluminum (Al), zinc (Zn), calcium (Ca), and titanium (Ti). We used covariate-adjusted mixed-effects models including PM2.5 as a covariate to estimate the percentage change in lung function associated with an inter-quartile range (IQR) exposure increase.ResultsThe two groups had high and overlapping exposure distributions with mean personal PM2.5 of 94.6 ¿g/m3 (IQR: 48.5-126.6) in office workers and 126.8 ¿g/m3 (IQR: 73.9-160.5) in truck drivers. The distributions of the nine elements showed group-specific profiles and generally higher levels in truck drivers. In all subjects combined, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) did not significantly correlate with PM2.5. However, FEV1 showed negative association with concentrations of four elements: Si (-3.07%, 95%CI: -5.00; -1.11, IQR: 1.54), Al (-2.88%, 95%CI: -4.91; -0.81, IQR: 0.86), Ca (-1.86%, 95%CI: -2.95; -0.76, IQR: 1.33), and Ti (-2.58%, 95%CI: -4.44; -0.68, IQR: 0.03), and FVC showed negative association with concentrations of three elements: Si (-3.23%, 95%CI: -5.61; -0.79), Al (-3.26%, 95%CI: -5.73; -0.72), and Ca (-1.86%, 95%CI: -3.23; -0.47). In stratified analysis, Si, Al, Ca, and Ti showed associations with lung function only among truck drivers, and no significant association among office workersConclusion
Selected elemental components of PM2.5 showed effects on lung function that were not found in analyses of particle levels alone.
Particle and Fibre Toxicology 10/2014; 11(1):51. · 6.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks.
In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation.
The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated.
A significant sex interaction was observed for AluYb8 (p-value for interaction < 0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value < 0.001), while no significant effects were found in girls (p-value = 0.134).
Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.
Environment International 10/2014; 71:81–87. · 5.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Epigenetics is tissue-specific and potentially even cell-specific, but little information is available from human reproductive studies about the concordance of DNA methylation patterns in cord blood and placenta, as well as within-placenta variations. We evaluated methylation levels at promoter regions of candidate genes in biological ageing pathways (SIRT1, TP53, PPARG, PPARGC1A, and TFAM), a subtelomeric region (D4Z4) and the mitochondrial genome (MT-RNR1, D-loop).
Ninety individuals were randomly chosen from the ENVIRONAGE birth cohort to evaluate methylation concordance between cord blood and placenta using highly quantitative bisulfite-PCR pyrosequencing. In a subset of nineteen individuals, a more extensive sampling scheme was performed to examine within-placenta variation.
The DNA methylation levels of the subtelomeric region and mitochondrial genome showed concordance between cord blood and placenta with correlation coefficients ranging from r = 0.31 to 0.43, p ≤ 0.005, and also between the maternal and foetal sides of placental tissue (r = 0.53 to 0.72, p ≤ 0.05). For the majority of targets, an agreement in methylation levels between four foetal biopsies was found (with intra-class correlation coefficients ranging from 0.16 to 0.72), indicating small within-placenta variation.
The methylation levels of the subtelomeric region (D4Z4) and mitochondrial genome (MT-RNR1, D-loop) showed concordance between cord blood and placenta, suggesting a common epigenetic signature of these targets between tissues. Concordance was lacking between the other genes that were studied. In placental tissue, methylation patterns of most targets on the mitochondrial-telomere axis were not strongly influenced by sample location.
[Show abstract][Hide abstract] ABSTRACT: Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways, not only through energetics and ATP production but also through metabolites generated in the Tricarboxylic Acid (TCA) cycle, and mitochondria-nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Objectives: This review investigates the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. Methods: NIEHS sponsored a workshop on Mitochondria, Energetics, Epigenetics, Environment and DNA Damage Response on March 25-26, 2013. Key points and ideas emerging from this meeting are summarized. Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. Conclusions: Understanding mitochondrial-cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors.
Environmental Health Perspectives 08/2014; · 7.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background APOE is the biomarker with the greatest known influence on cognitive function; however, the effect of complex haplotypes involving polymorphisms rs449647, rs405509, rs440446, rs429358 and rs7412 has never been studied in older populations.Methods
We evaluated APOE polymorphisms using multiplex PCR for genotyping and Mini-Mental State Examination (MMSE) to evaluate cognitive function in 819 individuals from VA Normative Aging Study.ResultsCombinatorial analysis of all polymorphisms and individual analysis of polymorphisms rs449647, rs405509, rs440446 and rs7412 did not show any association with cognitive performance. Polymorphism rs429358 was associated with better cognitive performance (odds of MMSE¿¿¿25¿=¿0.63, 95%CI 0.42-0.95; p¿=¿0.03) in the oldest subsample (5th quintile of age) (odds of MMSE¿¿¿25¿=¿0.34; 95%CI 0.13-0.86; p¿=¿0.02). APOE allele ¿4 was also associated with better cognitive performance (odds of MMSE¿¿¿25¿=¿0.61, 95%CI 0.40-0.94; p¿=¿0.02), also in the oldest subsample (odds of MMSE¿¿¿25¿=¿0.35, 95%CI 0.14-0.90; p¿=¿0.03).Conclusions
These results suggest a beneficial effect of polymorphism rs429358 in the oldest men.
[Show abstract][Hide abstract] ABSTRACT: Background: APOE is the biomarker with the greatest known influence on cognitive function; however, the effect of complex haplotypes involving polymorphisms rs449647, rs405509, rs440446, rs429358 and rs7412 has never been studied in older populations. Methods: We evaluated APOE polymorphisms using multiplex PCR for genotyping and Mini-Mental State Examination (MMSE) to evaluate cognitive function in 819 individuals from VA Normative Aging Study. Results: Combinatorial analysis of all polymorphisms and individual analysis of polymorphisms rs449647, rs405509, rs440446 and rs7412 did not show any association with cognitive performance. Polymorphism rs429358 was associated with better cognitive performance (odds of MMSE ≤ 25 = 0.63, 95% CI 0.42-0.95; p = 0.03) in the oldest subsample (5 th quintile of age) (odds of MMSE ≤ 25 = 0.34; 95% CI 0.13-0.86; p = 0.02). APOE allele ε4 was also associated with better cognitive performance (odds of MMSE ≤ 25 = 0.61, 95% CI 0.40-0.94; p = 0.02), also in the oldest subsample (odds of MMSE ≤ 25 = 0.35, 95% CI 0.14-0.90; p = 0.03). Conclusions: These results suggest a beneficial effect of polymorphism rs429358 in the oldest men.
[Show abstract][Hide abstract] ABSTRACT: Motivation: MicroRNAs (miRNAs) are short single-stranded non-coding molecules that usually function as negative regulators to silence or suppress gene expression. Owning to the dynamic nature of miRNA and reduced microarray and sequencing costs, a growing number of researchers are now measuring high-dimensional miRNA expression data using repeated or multiple measures in which each individual has more than one sample collected and measured over time. However, the commonly used univariate association testing or the site-by-site (SBS) testing may underutilize the longitudinal feature of the data, leading to underpowered results and less biologically meaningful results.
Results: We propose a penalized regression model incorporating grid search method (PGS), for analyzing associations of high-dimensional miRNA expression data with repeated measures. The development of this analytical framework was motivated by a real-world miRNA dataset. Comparisons between PGS and the SBS testing revealed that PGS provided smaller phenotype prediction errors and higher enrichment of phenotype-related biological pathways than the SBS testing. Our extensive simulations showed that PGS provided more accurate estimates and higher sensitivity than the SBS testing with comparable specificities.
Availability and implementation: R source code for PGS algorithm, implementation example and simulation study are available for download at https://github.com/feizhe/PGS.
[Show abstract][Hide abstract] ABSTRACT: To determine gene-specific methylation levels (promoter region) on genes from critical cellular pathways in persons occupationally exposed to a single volatile organic compound (VOC) or to a mixture of them
Occupational and environmental medicine 06/2014; 71 Suppl 1:A36. · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiologic studies have linked pesticide use to various health outcomes, including cancer, but underlying mechanisms remain unclear. In a previous analysis from the Agricultural Health Study (AHS), a prospective cohort study of pesticide applicators in the US, use of certain pesticides was linked to shorter relative telomere length (RTL) measured in buccal cell DNA. In this analysis we examined the associations between occupational pesticide use and RTL measured in blood DNA.
Occupational and Environmental Medicine 06/2014; 71 Suppl 1:A14-5. · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Traffic-related air pollution has been linked with impaired cognition in older adults, possibly due to effects of oxidative stress on the brain. Mitochondria are the main source of cellular oxidation. Haplogroups in mitochondrial DNA (mtDNA) mark individual differences in oxidative potential and are possible determinants of neurodegeneration. The aim of this study was to investigate whether mtDNA haplogroups determined differential susceptibility to cognitive effects of long-term exposure to black carbon (BC), a marker of traffic-related air pollution.
Environmental Health 05/2014; 13(1):42. · 2.71 Impact Factor