B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial.

Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 µg/m3) under placebo, and PM2.5 (250 µg/m3) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4+ T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks.

Traffic-Related Air Pollution, Blood Pressure, and Adaptive Response of Mitochondrial Abundance.

BACKGROUND: Exposure to black carbon (BC), a tracer of vehicular-traffic pollution, is associated with increased blood pressure (BP). Identifying biological factors that attenuate BC effects on BP can inform prevention. We evaluated the role of mitochondrial abundance, an adaptive mechanism compensating for cellular-redox imbalance, in the BC-BP relationship. METHODS AND RESULTS: At ≥ 1 visits among 675 older men from the Normative Aging Study (observations=1252), we assessed daily BP and ambient BC levels from a stationary monitor. To determine blood mitochondrial abundance, we used whole blood to analyze mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA) using quantitative polymerase chain reaction. Every standard deviation increase in the 28-day BC moving average was associated with 1.97 mm Hg (95% confidence interval [CI], 1.23-2.72; P<0.0001) and 3.46 mm Hg (95% CI, 2.06-4.87; P<0.0001) higher diastolic and systolic BP, respectively. Positive BC-BP associations existed throughout all time windows. BC moving averages (5-day to 28-day) were associated with increased mtDNA/nDNA; every standard deviation increase in 28-day BC moving average was associated with 0.12 standard deviation (95% CI, 0.03-0.20; P=0.007) higher mtDNA/nDNA. High mtDNA/nDNA significantly attenuated the BC-systolic BP association throughout all time windows. The estimated effect of 28-day BC moving average on systolic BP was 1.95-fold larger for individuals at the lowest mtDNA/nDNA quartile midpoint (4.68 mm Hg; 95% CI, 3.03-6.33; P<0.0001), in comparison with the top quartile midpoint (2.40 mm Hg; 95% CI, 0.81-3.99; P=0.003). CONCLUSIONS: In older adults, short-term to moderate-term ambient BC levels were associated with increased BP and blood mitochondrial abundance. Our findings indicate that increased blood mitochondrial abundance is a compensatory response and attenuates the cardiac effects of BC.

Maternal Lifetime Stress and Prenatal Psychological Functioning and Decreased Placental Mitochondrial DNA Copy Number in the PRISM Study.

Psychosocial stress contributes to placental oxidative stress. Mitochondria are vulnerable to oxidative stress, which can lead to changes in mitochondrial DNA copy number (mtDNAcn). We examined associations of maternal lifetime stress, current negative life events, and depressive and posttraumatic-stress-disorder symptom scores with placental mtDNAcn in a racially/ethnically diverse sample (n = 147) from the Programming of Intergenerational Stress Mechanisms (PRISM) study (Massachusetts, March 2011 to August 2012). In linear regression analyses adjusted for maternal age, race/ethnicity, education, prenatal fine particulate matter exposure, prenatal smoking exposure, and the sex of the child, all measures of stress were associated with decreased placental mtDNAcn (all P values < 0.05). Weighted-quantile-sum (WQS) regression showed that higher lifetime stress and depressive symptoms accounted for most of the effect on mtDNAcn (WQS weights: 0.25 and 0.39, respectively). However, among white individuals, increased lifetime stress and posttraumatic stress disorder symptoms explained the majority of the effect (WQS weights: 0.20 and 0.62, respectively) while among nonwhite individuals, lifetime stress and depressive symptoms accounted for most of the effect (WQS weights: 0.27 and 0.55, respectively). These analyses are first to link increased maternal psychosocial stress with reduced placental mtDNAcn and add to literature documenting racial/ethnic differences in the psychological sequelae of chronic stress that may contribute to maternal-fetal health.

Associations of Annual Ambient Fine Particulate Matter Mass and Components with Mitochondrial DNA Abundance.

BACKGROUND: Fine particulate matter (PM2.5) represents a mixture of components with potentially different toxicities. However, little is known about the relative effects of PM2.5 mass and PM2.5 components on mitochondrial DNA (mtDNA) abundance, which may lie on the pathway of PM2.5-associated disease. METHODS: We studied 646 elderly male participants in the Normative Aging Study from Greater Boston to investigate associations of long-term exposure to PM2.5 mass and PM2.5 components with mtDNA abundance. We estimated concentrations of pollutants for the 365-day preceding examination at each participant's address using spatial- and temporal-resolved chemical transport models. We measured blood mtDNA abundance using RT-PCR. We applied a shrinkage and selection method (adaptive LASSO) to identify components most predictive of mtDNA abundance, and fit multipollutant linear mixed-effects models with subject-specific intercept to estimate the relative effects of individual PM component. RESULTS: MtDNA abundance was negatively associated with PM2.5 mass in the previous year and-after adjusting for PM2.5 mass-several PM2.5 components, including organic carbon, sulfate (marginally), and nitrate. In multipollutant models including as independent variables PM2.5 mass and PM2.5 components selected by LASSO, nitrate was associated with mtDNA abundance. An SD increase in annual PM2.5-associated nitrate was associated with a 0.12 SD (95% confidence intervals [CI] = -0.18, -0.07) decrease in mtDNA abundance. Analyses restricted to PM2.5 annual concentration below the current 1-year U.S. Environmental Protection Agency standard produced similar results. CONCLUSIONS: Long-term exposures to PM2.5-associated nitrate were related to decreased mtDNA abundance independent of PM2.5 mass. Mass alone may not fully capture the potential of PM2.5 to oxidize the mitochondrial genome.See video abstract at, http://links.lww.com/EDE/B274.

Histone 3 modifications and blood pressure in the Beijing Truck Driver Air Pollution Study.

CONTEXT: Histone modifications regulate gene expression; dysregulation has been linked with cardiovascular diseases. Associations between histone modification levels and blood pressure in humans are unclear. OBJECTIVE: We examine the relationship between global histone concentrations and various markers of blood pressure. MATERIALS AND METHODS: Using the Beijing Truck Driver Air Pollution Study, we investigated global peripheral white blood cell histone modifications (H3K9ac, H3K9me3, H3K27me3, and H3K36me3) associations with pre- and post-work measurements of systolic (SBP) and diastolic (DBP) blood pressure, mean arterial pressure (MAP), and pulse pressure (PP) using multivariable mixed-effect models. RESULTS: H3K9ac was negatively associated with pre-work SBP and MAP; H3K9me3 was negatively associated with pre-work SBP, DBP, and MAP; and H3K27me3 was negatively associated with pre-work SBP. Among office workers, H3K9me3 was negatively associated with pre-work SBP, DBP, and MAP. Among truck drivers, H3K9ac and H3K27me were negatively associated with pre-work SBP, and H3K27me3 was positively associated with post-work PP. DISCUSSION AND CONCLUSION: Epigenome-wide H3K9ac, H3K9me3, and H3K27me3 were negatively associated with multiple pre-work blood pressure measures. These associations substantially changed during the day, suggesting an influence of daily activities. Blood-based histone modification biomarkers are potential candidates for studies requiring estimations of morning/pre-work blood pressure.

Impacts of the Mitochondrial Genome on the Relationship of Long-Term Ambient Fine Particle Exposure with Blood DNA Methylation Age.

The mitochondrial genome has long been implicated in age-related disease, but no studies have examined its role in the relationship of long-term fine particle (PM2.5) exposure and DNA methylation age (DNAm-age)-a novel measure of biological age. In this analysis based on 940 observations between 2000 and 2011 from 552 Normative Aging Study participants, we determined the roles of mitochondrial DNA haplogroup variation and mitochondrial genome abundance in the relationship of PM2.5 with DNAm-age. We used the GEOS-chem transport model to estimate address-specific, one-year PM2.5 levels for each participant. DNAm-age and mitochondrial DNA markers were measured from participant blood samples. Nine haplogroups (H, I, J, K, T, U, V, W, and X) were present in the population. In fully adjusted linear mixed-effects models, the association of PM2.5 with DNAm-age (in years) was significantly diminished in carriers of haplogroup V (Pinteraction = 0.01; ß = 0.18, 95%CI: -0.41, 0.78) compared to noncarriers (ß = 1.25, 95%CI: 0.58, 1.93). Mediation analysis estimated that decreases in mitochondrial DNA copy number, a measure of mitochondrial genome abundance, mediated 12% of the association of PM2.5 with DNAm-age. Our data suggests that the mitochondrial genome plays a role in DNAm-age relationships particularly in the context of long-term PM2.5 exposure.

Traffic-derived particulate matter exposure and histone H3 modification: A repeated measures study.

BACKGROUND: Airborne particulate matter (PM) may induce epigenetic changes that potentially lead to chronic diseases. Histone modifications regulate gene expression by influencing chromatin structure that can change gene expression status. We evaluated whether traffic-derived PM exposure is associated with four types of environmentally inducible global histone H3 modifications. METHODS: The Beijing Truck Driver Air Pollution Study included 60 truck drivers and 60 office workers examined twice, 1-2 weeks apart, for ambient PM10 (both day-of and 14-day average exposures), personal PM2.5, black carbon (BC), and elemental components (potassium, sulfur, iron, silicon, aluminum, zinc, calcium, and titanium). For both PM10 measures, we obtained hourly ambient PM10 data for the study period from the Beijing Municipal Environmental Bureau's 27 representatively distributed monitoring stations. We then calculated a 24h average for each examination day and a moving average of ambient PM10 measured in the 14 days prior to each examination. Examinations measured global levels of H3 lysine 9 acetylation (H3K9ac), H3 lysine 9 tri-methylation (H3K9me3), H3 lysine 27 tri-methylation (H3K27me3), and H3 lysine 36 tri-methylation (H3K36me3) in blood leukocytes collected after work. We used adjusted linear mixed-effect models to examine percent changes in histone modifications per each µg/m3 increase in PM exposure. RESULTS: In all participants each µg/m3 increase in 14-day average ambient PM10 exposure was associated with lower H3K27me3 (ß=-1.1%, 95% CI: -1.6, -0.6) and H3K36me3 levels (ß=-0.8%, 95% CI: -1.4, -0.1). Occupation-stratified analyses showed associations between BC and both H3K9ac and H3K36me3 that were stronger in office workers (ß=4.6%, 95% CI: 0.9, 8.4; and ß=4.1%, 95% CI: 1.3; 7.0 respectively) than in truck drivers (ß=0.1%, 95% CI: -1.3, 1.5; and ß=0.9%, 95% CI: -0.9, 2.7, respectively; both pinteraction <0.05). Sex-stratified analyses showed associations between examination-day PM10 and H3K9ac, and between BC and H3K9me3, were stronger in women (ß=10.7%, 95% CI: 5.4, 16.2; and ß=7.5%, 95% CI: 1.2, 14.2, respectively) than in men (ß=1.4%, 95% CI: -0.9, 3.7; and ß=0.9%, 95% CI: -0.9, 2.7, respectively; both pinteraction <0.05). We observed no associations between personal PM2.5 or elemental components and histone modifications. CONCLUSIONS: Our results suggest a possible role of global histone H3 modifications in effects of traffic-derived PM exposures, particularly BC exposure. Future studies should assess the roles of these modifications in human diseases and as potential mediators of air pollution-induced disease, in particular BC exposure.

Mitochondrial haplogroups modify the effect of black carbon on age-related cognitive impairment.

BACKGROUND: 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. METHODS: We investigated 582 older men (72 ± 7 years) in the VA Normative Aging Study cohort with ≤4 visits per participant (1.8 in average) between 1995-2007. Low (≤25) Mini Mental State Examination (MMSE) was used to assess impaired cognition in multiple domains. We fitted repeated-measure logistic regression using validated-LUR BC estimated in the year before their first visit at the participant's address. RESULTS: Mitochondrial haplotyping identified nine haplogroups phylogenetically categorized in four clusters. BC showed larger effect on MMSE in Cluster 4 carriers, including I, W and X haplogroups, [OR = 2.7; 95% CI (1.3-5.6)], moderate effect in Cluster 1, including J and T haplogroups [OR = 1.6; 95% CI: (0.9-2.9)], and no effect in Cluster 2 (H and V haplogroups) [OR = 1.1; 95% CI: (0.8-1.5)] or Cluster 3 (K and U haplogroups) [OR = 1.0; 95% CI: (0.6-1.6)]. BC effect varied only moderately across the I, X, and W haplogroups or across the J and T haplogroups. CONCLUSIONS: The association of BC with impaired cognition was worsened in carriers of phylogenetically-related mtDNA haplogroups in Cluster 4. No BC effects were detected in Cluster 2 and 3 carriers. MtDNA haplotypes may modify individual susceptibility to the particle cognitive effects.

Influence of multiple APOE genetic variants on cognitive function in a cohort of older men - results from the Normative Aging Study.

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 (5th 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.

Long-term exposure to ambient fine particulate matter and carotid intima media thickness at bilateral, left and right in adults from Mexico City: Results from GEA study.

BACKGROUND: PM2.5 exposure has been associated with intima-media thickness (cIMT) increase. However, very few studies distinguished between left and right cIMT in relation to PM2.5 exposure. AIM: To evaluate associations between chronic exposure to PM2.5 and cIMT at bilateral, left, and right in adults from Mexico City. METHODS: This study comprised 913 participants from the control group, participants without personal or family history of cardiovascular disease, of the Genetics of Atherosclerosis Disease Mexican study (GEA acronym in Spanish), recruited at the Instituto Nacional de Cardiología Ignacio Chávez from June 2008 to January 2013. To assess the associations between chronic exposure to PM2.5 (per 5 µg/m3 increase) at different lag years (1-4 years) and cIMT (bilateral, left, and right) we applied distributed lag non-linear models (DLNMs). RESULTS: The median and interquartile range for cIMT at bilateral, left, and right, were 630 (555, 735), 640 (550, 750), and 620 (530, 720) µm, respectively. Annual average PM2.5 exposure was 26.64 µg/m3, with median and IQR, of 24.46 (23.5-25.46) µg/m3. Results from DLNMs adjusted for age, sex, body mass index, low-density lipoproteins, and glucose, showed that PM2.5 exposure for year 1 and 2, were positively and significantly associated with right-cIMT [6.99% (95% CI: 3.67; 10.42) and 2.98% (0.03; 6.01), respectively]. Negative associations were observed for PM2.5 at year 3 and 4 and right-cIMT; however only year 3 was statistically significant [-2.83% (95% CI: 5.12; -0.50)]. Left-cIMT was not associated with PM2.5 exposure at any lag year. The increase in bilateral cIMT followed a similar pattern as that observed for right-cIMT, but with lower estimates. CONCLUSIONS: Our results suggest different susceptibility between left and right cIMT associated with PM2.5 exposure highlighting the need of measuring both, left and right cIMT, regarding ambient air pollution in epidemiological studies.

Environmental polycyclic aromatic hydrocarbon (PAH) exposure and DNA damage in Mexican children.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants presenting a public health risk, particularly to children, a vulnerable population. PAHs have genotoxic and carcinogenic properties, which depend on their metabolism. Many enzymes involved in PAH metabolism, including CYP1A1, CYP1B1, GSTM and GSTT are polymorphic, which may modulate the activation/deactivation of these compounds. We evaluated PAH exposure and DNA damage in children living in the vicinity of the main petrochemical complex located in the Gulf of Mexico, and explored the modulation by genetic polymorphisms of PAH excretion and related DNA damage. The participants (n=82) were children aged 6-10y attending schools near the industrial area. Urinary 1-hydroxypyrene (1-OHP; a biomarker of PAH exposure) was determined by reverse-phase-HPLC; DNA damage by the comet assay (Olive Tail Moment (OTM) parameter); CYP1A1*2C and CYP1B1*3 polymorphisms by real time-PCR; and GSTM1*0 and GSTT1*0 by multiplex PCR. The median value of 1-OHP was 0.37µmol/mol creatinine; 59% of children had higher 1-OHP concentrations than those reported in environmentally exposed adults (0.24µmol/mol creatinine). A stratified analysis showed increased DNA damage in children with 1-OHP concentrations greater than the median value. We observed higher 1-OHP concentrations in children with CYP1A1*2C or GSTM1*0 polymorphisms, and a positive influence of CYP1A1*2C on OTM values in children with the highest PAH exposure. The data indicate that children living in the surroundings of petrochemical industrial areas are exposed to high PAH levels, contributing to DNA damage and suggesting an increased health risk; furthermore, data suggest that polymorphisms affecting activation enzymes may modulate PAH metabolism and toxicity.

Effects of fluoride exposure on mitochondrial function: Energy metabolism, dynamics, biogenesis and mitophagy.

Fluoride is ubiquitous in the environment. Furthermore, drinking water represents the main source of exposure to fluoride for humans. Interestingly, low fluoride concentrations have beneficial effects on bone and teeth development; however, chronic fluoride exposure has harmful effects on human health. Besides, preclinical studies associate fluoride toxicity with oxidative stress, inflammation, and apoptosis. On the other hand, it is well-known that mitochondria play a key role in reactive oxygen species production. By contrast, fluoride's effect on processes such as mitochondrial dynamics, biogenesis and mitophagy are little known. These processes modulate the size, content, and distribution of mitochondria and their depuration help to counter the reactive oxygen species production and cytochrome c release, thereby allowing cell survival. However, a maladaptive response could enhance fluoride-induced toxicity. The present review gives a brief account of fluoride-induced mitochondrial alterations on soft and hard tissues, including liver, reproductive organs, heart, brain, lung, kidney, bone, and tooth.

Long-Term Exposure to Ozone and Fine Particulate Matter and Risk of Premature Coronary Artery Disease: Results from Genetics of Atherosclerotic Disease Mexican Study.

(1) Background: Epidemiological studies have identified associations between fine particulate matter (PM2.5) and ozone exposure with cardiovascular disease; however, studies linking ambient air pollution and premature coronary artery disease (pCAD) in Latin America are non-existing. (2) Methods: Our study was a case−control analysis nested in the Genetics of Atherosclerotic Disease (GEA) Mexican study. We included 1615 participants (869 controls and 746 patients with pCAD), recruited at the Instituto Nacional de Cardiología Ignacio Chávez from June 2008 to January 2013. We defined pCAD as history of myocardial infarction, angioplasty, revascularization surgery or coronary stenosis > 50% diagnosed before age 55 in men and age 65 in women. Controls were healthy individuals without personal or family history of pCAD and with coronary artery calcification equal to zero. Hourly measurements of ozone and PM2.5 from the Atmospheric Monitoring System in Mexico City (SIMAT in Spanish; Sistema de Monitero Atmosférico de la Ciudad de México) were used to calculate annual exposure to ozone and PM2.5 in the study participants. (3) Results: Each ppb increase in ozone at 1-year, 2-year, 3-year and 5-year averages was significantly associated with increased odds (OR = 1.10; 95% CI: 1.03−1.18; OR = 1.17; 95% CI: 1.05−1.30; OR = 1.18; 95% CI: 1.05−1.33, and OR = 1.13; 95% CI: 1.04−1.23, respectively) of pCAD. We observed higher risk of pCAD for each 5 µg/m3 increase only for the 5-year average of PM2.5 exposure (OR = 2.75; 95% CI: 1.47−5.16), compared to controls. (4) Conclusions: Ozone exposure at different time points and PM2.5 exposure at 5 years were associated with increased odds of pCAD. Our results highlight the importance of reducing long-term exposure to ambient air pollution levels to reduce the burden of cardiovascular disease in Mexico City and other metropolitan areas.

Metal exposure and bone remodeling during pregnancy: Results from the PROGRESS cohort study.

Pregnancy is characterized by high bone remodeling and might be a window of susceptibility to the toxic effects of metals on bone tissue. The aim of this study was to assess associations between metals in blood [lead (Pb), cadmium (Cd)and arsenic (As)] and bone remodeling during pregnancy. We studied pregnant woman from the PROGRESS Cohort (Programming Research in Obesity, Growth, and Environment and Social Stress). We measured concentrations of metals in blood and obtained measures of bone remodeling by quantitative ultrasound (QUS) at the radius in the second and third trimester of pregnancy. To account for chronic lead exposure, we measured lead in tibia and patella one-month postpartum with K-shell X-ray fluorescence. We assessed cross-sectional and longitudinal associations between multiple-metal concentrations and QUS z-scores using linear regression models and linear mixed models adjusted for potential confounders. Third trimester blood Cd concentrations were marginal associated with lower QUS z-scores [-0.16 (95% CI: -0.33, 0.007); P-Value = 0.06]. Mixed models showed that blood Cd was longitudinally and marginally associated with an average of -0.10 z-score (95% CI: -0.21, 0.002; P-Value = 0.06) over the course of pregnancy. Associations for Pb and As were all inverse however none reached significance. Additionally, bone Pb concentrations in patella, an index of cumulative exposure, were significantly associated with -0.06 z-score at radius (95% CI: -0.10, -0.01; P-Value = 0.03) during pregnancy. Pb and Cd blood levels are associated with lower QUS distal radius z-scores in pregnant women. Bone Pb concentrations in patella were negatively associated with z-score at radius showing the long-term effects of Pb on bone tissue. However, we cannot exclude the possibility of reverse causality for patella Pb and radius z-score associations. Our results support the importance of reducing women's metal exposure during pregnancy, as metals exposure during pregnancy may have consequences for bone strength later in life. The main finding of our study is the association between Cd blood levels and radius z-score during pregnancy. Bone lead in patella was also negatively associated with radius z-scores.

The rs12617336 and rs17574 Dipeptidyl Peptidase-4 Polymorphisms Are Associated With Hypoalphalipoproteinemia and Dipeptidyl Peptidase-4 Serum Levels: A Case-Control Study of the Genetics of Atherosclerotic Disease (GEA) Cohort.

Dipeptidyl peptidase-4 (DPP4) can influence lipid homeostasis and atherosclerosis progression. We aimed to assess the association of DPP4 gene polymorphisms with hypoalphalipoproteinemia and DPP4 serum levels, in a cohort of Mexican individuals. Five DPP4 polymorphisms (rs12617336, rs12617656, rs1558957, and rs3788979, and rs17574) were genotyped in 748 participants with and 745 without hypoalphalipoproteinemia. The associations were evaluated using logistic regression analyses. Under inheritance models adjusted for confounding variables, the rs12617336 (OR = 0.22, P heterozygote = 0.001) and rs17574 (OR = 0.78, P additive = 0.022; OR = 0.73, P dominant = 0.012; OR = 0.73, P heterozygote = 0.017; OR = 0.72, P codominant 1 = 0.014) minor alleles were associated with a low risk of hypoalphalipoproteinemia. After the correction for multiple comparisons, the associations were marginal except the association of the rs12617336 that remaining significant. Additionally, both DPP4 minor alleles were associated with protection for the presence of insulin resistance (IR) (OR = 0.17, P heterozygote = 0.019 for rs12617336 and OR = 0.75, P additive = 0.049 for rs17574). The rs12617336 minor allele was also associated with a low risk of hyperinsulinemia (OR = 0.11, P heterozygote = 0.006). Differences in DPP4 levels were observed in individuals with rs17574 genotypes, the rs17574 GG genotype individuals had the lowest levels. Our data suggest that rs12617336 and rs17574 DPP4 minor alleles could be envisaged as protective genetic markers for hypoalphalipoproteinemia, IR, and hyperinsulinemia. The rs17574 GG genotype was associated with the lowest DPP4 levels.

Per- and polyfluoroalkyl substances and calcifications of the coronary and aortic arteries in adults with prediabetes: Results from the diabetes prevention program outcomes study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification. METHODS AND RESULTS: This study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14 years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (<10), moderate (11-400) and severe (>400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC > 11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR = 1.26 (95% CI:1.08, 1.47) for moderate CAC and OR = 1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR = 1.67 (95% CI:1.10, 2.54) and OR = 1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes. CONCLUSIONS: Prediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations.

IL-12B Polymorphisms Are Associated with the Presence of Premature Coronary Artery Disease and with Cardiovascular Risk Factors: The Genetics of Atherosclerotic Disease Mexican Study.

The aim of this study was to evaluate the association of the IL-12B polymorphisms with the presence of premature coronary artery disease (pCAD) and with cardiovascular risk factors. The study included 2163 individuals (1133 patients with pCAD and 1030 healthy controls). Seven IL-12B polymorphisms (rs1363670, rs3212220, rs3212227, rs6887695, rs1433048, rs2853694, and rs1368439) were determined by TaqMan assays. The associations were evaluated by logistic regression using inheritance models adjusted for confounding variables. The rs1363670 was associated with a low risk of pCAD (odds ratio [OR] 0.718, pdominant = 0.034; OR 0.701, pheterozygote = 0.024; OR 0.702, pcodominant1 = 0.025). The association of the polymorphisms with cardiovascular risk factors was evaluated independently in each group. In controls, the rs3212227, rs3212220, and rs6887695 polymorphisms were associated with subcutaneous abdominal fat > p75, whereas the rs6887695 was associated with a high risk of central obesity. In pCAD patients, the rs2853694 was associated with a low risk of insulin resistance; and association of rs3212227 and rs3212220 with a low risk of metabolic syndrome was found, and the rs6887695 polymorphism was nominally associated with a high risk of hyperuricemia. In conclusion, the IL-12B rs1363670 polymorphism was associated with a low risk of pCAD, and in both pCAD patients and healthy controls, some IL-12B polymorphisms were associated with cardiovascular risk factors.

Mitochondria and aging in older individuals: an analysis of DNA methylation age metrics, leukocyte telomere length, and mitochondrial DNA copy number in the VA normative aging study.

Population aging is a looming global health challenge. New biological aging metrics based on DNA methylation levels have been developed in addition to traditional aging biomarkers. The prospective relationships of aging biomarkers with mitochondrial changes are still not well understood. Here, we examined the prospective associations of mitochondrial copy number (mtDNAcn) with several aging biomarkers - DNAm-Age, DNAm-PhenoAge, DNAm-GrimAge, and leukocyte telomere length. We analyzed 812 individuals from Veteran Affairs Normative Aging Study (NAS) with available blood samples from 1999-2013. Whole blood mtDNAcn and relative leukocyte telomere length were measured via qPCR. DNA methylation was assessed and used to calculate DNAm-Age, DNAm-GrimAge, and DNAm-PhenoAge. Linear mixed models were used to quantify the associations of mtDNAcn with DNAm-Age, DNAm-GrimAge, DNAm-PhenoAge, and leukocyte telomere length. In multivariable cross-sectional analyses, mtDNAcn is negatively associated with DNAm-Age PhenoAge and DNAm-PhenoAge. In contrast, mtDNAcn is associated with prospective measures of higher DNAm-PhenoAge and shorter leukocyte telomere length. Our study shows that higher mtDNAcn is associated with prospective measures of greater DNAm-PhenoAge and shorter leukocyte telomere length independent of chronological age. This indicates a role for mitochondrial in aging-related disease and mortality, but not the departure of biological age from chronological age.

Age and mitochondrial DNA copy number influence the association between outdoor temperature and cognitive function: Insights from the VA Normative Aging Study.

BACKGROUND: General cognitive function deteriorates with aging, a change that has been linked to outdoor temperature. Older individuals have reduced ability to adapt to changes in outdoor temperature than younger people. However, to what extent short-term changes in outdoor temperature interact with mitochondria to affect cognition in older people has not yet been determined. METHODS: Our study included 591 participants of the Normative Aging Study who underwent multiple examinations between 2000 and 2013. Cognitive function was evaluated via the Mini-Mental State Examination. Outdoor temperature was estimated at residential addresses 1 day before the examination using on a validated spatiotemporal temperature model. Mitochondrial DNA copy number (mtDNAcn) was determined using buffy coat samples. RESULTS: We found an interaction between temperature, age, mtDNAcn, and cognition. In individuals 84 years of age or older, cooler temperature was associated with low cognition (odds ratio = 1.2; 95% confidence interval = 1.05, 1.35 for a 1°C decrease in temperature; P = 0.007). We found higher odds ratio per 1°C decrease in temperature among individuals with lower mtDNAcn (ß3 = 0.12; 95% confidence interval = 0.01, 0.22; P interaction = 0.02). CONCLUSIONS: Our findings, albeit potentially underpowered, suggest that older individuals may be more susceptible to the influence of short-term temperature exposure on cognition. Moreover, the level of mtDNAcn may also modify the association between temperature and cognitive function, indicating a possible role of these cellular elements in this relationship.

Dietary characteristics associated with plasma concentrations of per- and polyfluoroalkyl substances among adults with pre-diabetes: Cross-sectional results from the Diabetes Prevention Program Trial.

Diet is assumed to be the main source of exposure to per- and polyfluoroalkyl substances (PFAS) in non-occupationally exposed populations, but studies on the diet-PFAS relationship in the United States are scarce. We extracted multiple dietary variables, including daily intakes of food group, diet scores, and dietary patterns, from self-reported dietary data collected at baseline (1996-1999) from adults with pre-diabetes enrolled in the Diabetes Prevention Program, and used linear regression models to evaluate relationships of each dietary variable with plasma concentrations of six PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), perfluorononanoic acid (PFNA) adjusting for covariates. Participants (N = 941, 65% female, 58% Caucasian, 68% married, 75% with higher education, 95% nonsmoker) had similar PFAS concentrations compared to the general U.S. population during 1999-2000. Using a single food group approach, fried fish, other fish/shellfish, meat and poultry had positive associations with most PFAS plasma concentrations. The strongest effect estimate detected was between fried fish and PFNA [13.6% (95% CI: 7.7, 19.9) increase in median concentration per SD increase]. Low-carbohydrate and high protein diet score had positive association with plasma PFHxS. Some food groups, mostly vegetables and fruits, and the Dietary Approaches to Stop Hypertension diet score had inverse associations with PFOS and MeFOSAA. A vegetable diet pattern was associated with lower plasma concentrations of MeFOSAA, while high-fat meat and low-fiber and high-fat grains diet patterns were associated with higher plasma concentrations of PFOS, PFHxS, MeFOSAA and PFNA. We summarized four major dietary characteristics associated with variations in PFAS plasma concentrations in this population. Specifically, consuming more meat/fish/shellfish (especially fried fish, and excluding Omega3-rich fish), low-fiber and high-fat bread/cereal/rice/pasta, and coffee/tea was associated with higher plasma concentrations while dietary patterns of vegetables, fruits and Omega-3 rich fish were associated with lower plasma concentrations of some PFAS.