Early-life risk factors, accelerated biological aging and the late-life risk of mortality and morbidity.

BACKGROUND: Early-life exposure increases health risks throughout an individual's lifetime. Biological aging is influenced by early-life risks as a key process of disease development, but whether early-life risks could accelerate biological aging and elevate late-life mortality and morbidity risks remains unknown. Knowledge is also limited on the potential moderating role of healthy lifestyle. METHODS: We investigate associations of three early-life risks around birth, breastfeeding, maternal smoking and birth weight, with biological aging of 202 580 UK Biobank participants (54.9 ± 8.1 years old). Biological aging was quantified as KDM-BA, PhenoAge and frailty. Moderate alcohol intake, no current smoking, healthy diet, BMI <30 kg/m2 and regular physical activity were considered as healthy lifestyles. Mortality and morbidity data were retrieved from health records. RESULTS: Individual early-life risk factors were robustly associated with accelerated biological aging. A one-unit increase in the 'early-life risk score' integrating the three factors was associated with 0.060 (SE=0.0019) and 0.036-unit (SE = 0.0027) increase in z-scored KDM-BA acceleration and PhenoAge acceleration, respectively, and with 22.3% higher odds (95% CI: 1.185-1.262) of frailty. Increased chronological age and healthy lifestyles could mitigate the accelerations of KDM-BA and PhenoAge, respectively. Associations of early-life risk score with late-life mortality and morbidity were mediated by biological aging (proportions: 5.66-43.12%). KDM-BA and PhenoAge accelerations could significantly mediate the impact on most outcomes except anxiety, and frailty could not mediate the impact on T2D. CONCLUSION: Biological aging could capture and mediate the late-life health risks stemming from the early-life risks, and could be potentially targeted for healthy longevity promotion.

Recombinant human chorionic gonadotropin and gonadotropin-releasing hormone agonist differently affect the profile of extracellular vesicle microRNAs in human follicular fluid.

PURPOSE: To compare the expression profile of extracellular vesicle microRNAs (EV-miRNAs) derived from follicular fluid after a trigger with recombinant human chorionic gonadotropin (r-hCG) or with a gonadotropin-releasing hormone GnRH agonist (GnRH-a) for final oocyte maturation. METHODS: A retrospective analysis of a prospective cohort. Women undergoing in vitro fertilization at a tertiary university-affiliated hospital were recruited between 2014 and 2016. EV-miRNAs were extracted from the follicular fluid of a single follicle, and their expression was assessed using TaqMan Open Array®. Genes regulated by EV-miRNAs were analyzed using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources, Kyoto-Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO). RESULTS: Eighty-two women were included in the r-hCG trigger group and 9 in the GnRH-a group. Of 754 EV-miRNAs screened, 135 were detected in at least 50% of the samples and expressed in both groups and were further analyzed. After adjusting for multiple testing, 41 EV-miRNAs whose expression levels significantly differed between the two trigger groups were identified. Bioinformatics analysis of the genes regulated by these EV-miRNAs showed distinct pathways between the two triggers, including TGF-beta signaling, cell cycle, and Wnt signaling pathways. Most of these pathways regulate cascades associated with apoptosis, embryo development, implantation, decidualization, and placental development. CONCLUSIONS: Trigger with GnRH-a or r-hCG leads to distinct EV-miRNAs expression profiles and to downstream biological effects in ovarian follicles. These findings may provide an insight for the increased apoptosis and the lower implantation rates following GnRH-a trigger vs. r-hCG in cases lacking intensive luteal phase support.

Association between hypertensive disorders of pregnancy and the risk of postpartum hypertension: a cohort study in women with gestational diabetes.

Previous studies in general people indicated that hypertensive disorders of pregnancy (HDP) increased the risk of subsequent hypertension after delivery. Some studies found that women with gestational diabetes mellitus (GDM) had an increased risk of HDP. However, very few studies have assessed the association between HDP and the risk of postpartum hypertension among GDM women. To evaluate the association between HDP and the risk of postpartum hypertension among GDM women, a retrospective cohort study was conducted in 1261 women with prior GDM at their postpartum 1-5 years using the baseline data from Tianjin Gestational Diabetes Mellitus Prevention Program. Cox regression models were applied to assess the single and joint associations of having a history of HDP, maternal pre-pregnancy Body mass index (BMI) (normal weight, overweight and obesity), and weight change from preconception to post-delivery with the risk of subsequent hypertension among the GDM women. We found that GDM women with a history of HDP, high pre-pregnancy BMI and weight gain >7 kg from preconception to post-delivery had an increased risk of postpartum hypertension. Joint effects analysis revealed that the positive association between a history of HDP in the index pregnancy and the risk of postpartum hypertension was consistent in GDM women with different levels of pre-pregnancy BMI or weight gain from preconception to post-delivery. In conclusion, a history of HDP, high pre-pregnancy BMI and weight gain >7 kg from preconception to post-delivery increase the risk of subsequent hypertension in postpartum 1-5 years among GDM women.

Hypertensive disorders of pregnancy in women with gestational diabetes mellitus on overweight status of their children.

Hypertensive disorders of pregnancy (HDP) as a group of medical complications in pregnancy are believed to be associated with an increased risk of poor fetal growth, but the influence on offspring's body composition is not clear. The aim of the present study was to evaluate the association between maternal HDP and overweight status in the offspring of mothers with gestational diabetes mellitus (GDM). A cross-sectional study among 1263 GDM mother-child pairs was performed in Tianjin, China. General linear models and logistic regression models were used to assess the associations of maternal hypertension in pregnancy with anthropometry and overweight status in the offspring from birth to 1-5 years old. Offspring of GDM mothers who were diagnosed with hypertensive disorders during pregnancy had higher mean values of Z-scores for birth weight for gestational age and birth weight for length, and higher mean values of Z-scores for weight for age, weight for length/height, and body mass index for age at 1-5 years old than those of GDM mothers with normal blood pressure during pregnancy. Maternal HDP were associated with increased risks of large for gestational age (OR 1.74, 95% CI 1.08-2.79) and macrosomia (OR 2.02, 95% CI 1.23-3.31) at birth and childhood overweight/obesity at 1-5 years old age (OR 1.88, 95% CI 1.16-3.04). For offspring of mothers with GDM, maternal hypertension during pregnancy was a risk factor for macrosomia at birth and childhood overweight and obesity, and controlling the maternal hypertension may be more important for preventing large-for-gestational-age babies and childhood obesity.

Associations of Maternal Urinary Cadmium with Trimester-Specific Blood Pressure in Pregnancy: Role of Dietary Intake of Micronutrients.

Previous studies revealed associations of urinary Cd (U-Cd), a chronic Cd exposure biomarker, with blood pressure (BP) in non-pregnant adults. However, the evidence regarding trimester-specific blood pressure in pregnancy and U-Cd and effect modification by dietary intake of micronutrients is scarce. We randomly selected 653 women from the Omega Study cohort. U-Cd was quantified by inductively coupled plasma mass spectrometry. Trimester-specific, systolic (SBP) and diastolic blood pressure (DBP) were determined employing standard protocols and mean arterial pressure (MAP) was also calculated. Associations of SBP, DBP, and MAP with U-Cd tertiles (≤0.21; 0.22-0.41; ≥0.42 µg/g Cr) were assessed using multivariable linear regression models. We also explored effect modification by pre-pregnancy BMI (≤25 or >25 kg/m2) or low/high micronutrients intake. After adjusting confounders in women with elevated (upper tertile) as compared with those with low (lowest tertile) U-Cd (≥0.42 vs. ≤0.21 µg/g Cr, respectively) had reduced third trimester MAP (-1.8; 95 % confidence interval (CI) = -3.1, -0.5 mmHg) and second trimester MAP (-1.1; 95 % CI = -2.3, -0.03 mmHg). A significant decrease in third-trimester MAP associated with increased U-Cd was observed only among normal/underweight women (BMI ≤ 25 kg/m2) and women with high dietary intake of micronutrients (calcium, magnesium, zinc, and selenium). Notably, U-Cd concentrations increased with the increased consumption of zinc and non-heme iron food sources. No significant differences in U-Cd concentrations were found in preeclamptic women compared with non-preeclamptic women. Our study provides evidence that dietary intake of micronutrients should be taken into account when assessing the health effects of Cd in pregnant women.

Effects of airborne fine particles (PM2.5 ) on deep vein thrombosis admissions in the northeastern United States.

BACKGROUND: Literature relating air pollution exposure to deep vein thrombosis (DVT) and pulmonary embolism (PE), despite biological plausibility, is sparse. No comprehensive study examining associations between both short- and long-term exposure to particulate matter (PM)2.5 and DVT or PE has been published. Using a novel PM2.5 prediction model, we study whether long- and short-term PM2.5 exposure is associated with DVT and PE admissions among elderly across the northeastern United States. METHODS: We estimated daily exposure of PM2.5 in each ZIP code. We investigated the long- and short-term effects of PM2.5 on DVT and PE hospital admissions. There were 453,413 DVT and 151,829 PE admissions in the study. For short-term exposure, we performed a case crossover analysis matching month and year and defined the hazard period as lag 01 (exposure of day of admission and previous day). For the long-term association, we used a Poisson regression. RESULTS: A 10-µg m(-3) increase in short-term exposure was associated with a 0.63% increase in DVT admissions (95% confidence interval [CI] = 0.03% to 1.25%) and a 6.98% (95% CI = 5.65% to 8.33%) increase in long-term exposure admissions. For PE, the associated risks were 0.38% (95% CI = -0.68% to 1.25%) and 2.67% (95% CI = 5.65% to 8.33%). These results persisted when analyses were restricted to location-periods meeting the current Environmental Protection Agency annual standard of 12 µg m(-3) . CONCLUSIONS: Our findings showed that PM2.5 exposure was associated with DVT and PE hospital admissions and that current standards are not protective of this result.

Variation of DNA methylation in candidate age-related targets on the mitochondrial-telomere axis in cord blood and placenta.

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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Extracellular histones mediate the effects of metal-rich air particles on blood coagulation.

BACKGROUND: Epidemiological studies have shown associations of particulate matter (PM) exposure with hypercoagulability and thrombosis. Extracellular circulating histones have recently been identified as novel mediators of inflammatory and procoagulant responses. The potential roles of extracellular histones in PM-related hypercoagulability have yet not been investigated. OBJECTIVES: In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (H3K4me3 and H3K9ac); and the association of H3K4me3 and H3K9ac with coagulation markers. METHODS: Extracellular H3K4me3 and H3K9ac were determined in plasma through enzyme-linked immunosorbent assays. Coagulation markers included endogenous thrombin potentials (ETPs), tissue-type plasminogen activator antigen (t-PA) and D-dimer. Exposure to PM with aerodynamic diameters <1 µm (PM1) or <10 µm (PM10) and PM10 metal components were estimated for each participant. RESULTS: The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (ß=107.84, p=0.03), PM10 (ß=83.06, p=0.02), and zinc (ß=75.14, p=0.03); and a marginal association with iron (ß=122.58, p=0.07). Additional PM effects were observed on t-PA, D-dimer, and ETP TM+. PM1 exposure was associated with increased plasma H3K4me3 and H3K9ac (ß=0.20, p=0.02; ß=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (ß=0.13, p=0.03) and iron (ß=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (ß=0.50, p=0.05) and H3K9ac (ß=0.54, p=0.05). CONCLUSIONS: This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.

ß-2 adrenergic receptor gene methylation is associated with decreased asthma severity in inner-city schoolchildren: asthma and rhinitis.

BACKGROUND: Genetic variation in the ß-2 adrenergic receptor gene (ADRB2) has been implicated in asthma severity and control with conflicting results. Epigenetic variation in the ADRB2 may play an important role in asthma phenotype. OBJECTIVE: We aimed to evaluate whether DNA methylation of ADRB2 is associated with asthma phenotypes in inner-city school-aged children. METHODS: Multiple CpG sites in the promoter region of ADRB2 gene were analysed in 177 children enrolled in the School Inner-City Asthma Study. Blood- or saliva-derived DNA was measured by bisulphite-polymerase chain reaction pyrosequencing assay. Average percentage DNA methylation across the sites was evaluated for association with asthma severity (report of dyspnoea, night-time symptoms, rescue medication use, and baseline spirometry) and morbidity (school absences and unscheduled healthcare visits). Three clades composed of highly correlated methylation sites within the methylated segment of ADRB2 were further analysed. RESULTS: Methylation of individual sites generally ranged from 0% to 6% with average percentage methylation across sites of 2.4%. Univariate analyses strongly favoured the association of higher percentage methylation with lower asthma severity measured by report of dyspnoea. Furthermore, there was a non-significant trend towards less rescue medication use, night-time symptoms, school absences, activity limitation due to asthma, and improved lung function measurements with increased methylation. Multivariate analysis demonstrated methylation of ADRB2 gene significantly associated with less dyspnoea (odds ratio (OR) 0.2, 95% confidence interval (CI), 0.1-0.6, P = 0.002). Each of the three clades of methylation sites showed a strong, but not statistically significant, effect on decreased dyspnoea. CONCLUSIONS AND CLINICAL RELEVANCE: DNA methylation in the ADRB2 gene is associated with decreased asthma symptom severity, suggesting a role for methylation in asthma phenotypes.