Long-term exposure to ambient fine particulate components and leukocyte epigenome-wide DNA Methylation in older men: the Normative Aging Study.

BACKGROUND: Epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, few have examined PM2.5 components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources. METHODS: We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000-2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM2.5 sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM2.5 sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways. RESULTS: We included 669 men with 1,178 visits between 2000-2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic. CONCLUSIONS: Our findings showed that the effects of PM2.5 on DNAm varied by its PMCs and sources.

Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study.

BACKGROUND: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. OBJECTIVES: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. METHODS: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. RESULTS: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. CONCLUSIONS: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.

Maternal exposure to black carbon and nitrogen dioxide during pregnancy and birth weight: Using machine-learning methods to achieve balance in inverse-probability weights.

BACKGROUND: Low birth weight is associated with increased risks of health problems in infancy and later life. Among the epidemiological analyses suggesting an association between air pollution and birth weight, few have estimated the effects of black carbon (BC) or together with nitrogen dioxide (NO2), and even fewer studies have used causal modelling. METHODS: We examined 1,119,011 birth records between 2001/01/01 and 2015/12/31 from the Massachusetts Birth Registry to investigate causal associations between prenatal exposure to BC and NO2 and birth weight. We calculated mean residential BC and NO2 exposures 0-30, and 31-280 days prior to birth from validated spatial-temporal models. We fit generalized propensity score models with gradient boosting tuned by a new algorithm to achieve covariate balance, then fit marginal structural models with stabilized inverse-probability weights. RESULTS: Throughout pregnancy, the average birth weight would drop by 17.0 g (95% CI: 15.4, 18.6) for an IQR increase of 0.14 µg/m3 in BC and would independently drop by 19.9 g (95% CI: 18.6, 21.3) for an IQR increase of 9.8 ppb in NO2. Most of the negative effects of BC on birth weight are from 0 to 30 days before the delivery date. The estimated odds ratio of low birth weight for every IQR increase during the entire pregnancy was 1.131 (95% CI: 1.106, 1.156) for BC and 1.082 (95% CI: 1.062, 1.103) for NO2. CONCLUSIONS: We found that prenatal exposures to both BC and NO2 were associated with lower birth weight.

Short- and intermediate-term exposure to ambient fine particulate elements and leukocyte epigenome-wide DNA methylation in older men: the Normative Aging Study.

BACKGROUND: Several epigenome-wide association studies (EWAS) of ambient particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) have been reported. However, EWAS of PM2.5 elements (PEs), reflecting different emission sources, are very limited. OBJECTIVES: We performed EWAS of short- and intermediate-term exposure to PM2.5 and 13 PEs. We hypothesized that significant changes in DNAm may vary by PM2.5 mass and its elements. METHODS: We repeatedly collected blood samples in the Normative Aging Study and measured leukocyte DNA methylation (DNAm) with the Illumina HumanMethylation450K BeadChip. We collected daily PM2.5 and 13 PEs at a fixed central site. To estimate the associations between each PE and DNAm at individual cytosine-phosphate-guanine (CpG) sites, we incorporated a distributed-lag (0-27 d) term in the setting of median regression with subject-specific intercept and examined cumulative lag associations. We also accounted for selection bias due to loss to follow-up and mortality prior to enrollment. Significantly differentially methylated probes (DMPs) were identified using Bonferroni correction for multiple testing. We further conducted regional and pathway analyses to identify significantly differentially methylated regions (DMRs) and pathways. RESULTS: We included 695 men with 1,266 visits between 1999 and 2013. The subjects had a mean age of 75 years. The significant DMPs, DMRs, and pathways varied by to PM2.5 total mass and PEs. For example, PM2.5 total mass was associated with 2,717 DMPs and 10,470 DMRs whereas Pb was associated with 3,173 DMPs and 637 DMRs. The identified pathways by PM2.5 mass were mostly involved in mood disorders, neuroplasticity, immunity, and inflammation, whereas the pathways associated with motor vehicles (BC, Cu, Pb, and Zn) were related with cardiovascular disease and cancer (e.g., "PPARs signaling"). CONCLUSIONS: PM2.5 and PE were associated with methylation changes at multiple probes and along multiple pathways, in ways that varied by particle components.

DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4.

BACKGROUND: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. METHODS: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. FINDINGS: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. INTERPRETATION: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. FUNDING: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.

Not just smoking and high-tech medicine: socioeconomic inequities in U.S. mortality rates, overall and by race/ethnicity, 1960-2006.

Recent research on the post-1980 widening of U.S. socioeconomic inequalities in mortality has emphasized the contribution of smoking and high-tech medicine, with some studies treating the growing inequalities as effectively inevitable. No studies, however, have analyzed long-term trends in U.S. mortality rates and inequities unrelated to smoking or due to lack of basic medical care, even as a handful have shown that U.S. socioeconomic inequalities in overall mortality shrank between the mid-1960s and 1980. The authors accordingly analyzed U.S. mortality data for 1960-2006, stratified by county income quintile and race/ethnicity, for mortality unrelated to smoking and preventable by 1960s' standards of medical care. Key findings are that relative and absolute socioeconomic inequalities in U.S. mortality unrelated to smoking and preventable by 1960s' medical care standards shrank between the 1960s and 1980 and then increased and stagnated, with absolute rates on a par with several leading causes of death, and with the burden greatest for U.S. populations of color. None of these findings can be attributed to trends in smoking-related deaths and access to high-tech medicine, and they also demonstrate that socioeconomic inequities in mortality can shrink and need not inevitably rise.

Prostate cancer mortality and birth or adult residence in the southern United States.

PURPOSE: Although there are few confirmed risk factors for prostate cancer (PCa), mortality rates are known to vary geographically across the United States. PCa mortality is higher among black and younger white men in a band of states spanning from Washington DC to Louisiana (the "PCa belt"). This study assessed the associations of birth and adult residence in the PCa belt with PCa mortality among black and white men and trends in these associations over time. METHODS: PCa-specific mortality rates in 1980, 1990, and 2000 for black and white men born in the continental US, aged 40-89, were calculated by linking national mortality records with population data based on birth state, state of residence at the census, race, and age. PCa belt (Washington DC, Virginia, North Carolina, South Carolina, Georgia, Mississippi, Alabama, and Louisiana) birth was cross-classified against PCa belt adult residence. RESULTS: Black men born in the PCa belt had elevated PCa mortality in 1980, 1990, and 2000. Associations were independent of adult residence in the PCa belt. For example, in 2000, black men aged 65-89 who were born in the PCa belt but no longer lived there in adulthood had an odds ratio of 1.19 (1.14-1.24) for PCa mortality compared to black men born and residing outside the PCa belt. The PCa belt was not associated with PCa mortality among whites. CONCLUSIONS: Geographically patterned childhood exposures, for example, differences in social or environmental conditions, or behavioral norms, may influence PCa mortality.

Shrinking, widening, reversing, and stagnating trends in US socioeconomic inequities in cancer mortality for the total, black, and white populations: 1960-2006.

OBJECTIVES OF STUDY: To test recent claims that cancer inequities are bound to increase as population health improves. METHODS: We analyzed 1960-2006 age-standardized US county cancer mortality data, total and site-specific (lung, prostate, colorectal, breast, cervix, stomach), stratified by county income quintile for the US total, black, and white populations. RESULTS: Between 1960 and 2006, US socioeconomic inequities in cancer mortality variously shrunk, widened, reversed, and stagnated, depending on time period and cancer site. For all cancers combined and most, but not all, sites, absolute, but not relative, socioeconomic gaps were greater for the black compared to white population. Compared to the yearly age-specific mortality rates among whites in the most affluent counties, the percent of excess cancer deaths among whites in the lower four county income quintiles first rose above 0 in 1990 and in 2006 equaled 5.4% (95% CI 4.8, 6.0); among blacks, it rose from 6.0% (95% CI 4.5, 7.4) in 1960 to 24.7% (95% CI 23.9, 25.5) in 1990 and remained at this level through 2006. CONCLUSIONS: The hypothesis that cancer mortality inequities are bound to increase is refuted by long-term data on total and site-specific cancer mortality stratified by socioeconomic position and race/ethnicity.

Exposing racial discrimination: implicit & explicit measures--the My Body, My Story study of 1005 US-born black & white community health center members.

BACKGROUND: To date, research on racial discrimination and health typically has employed explicit self-report measures, despite their potentially being affected by what people are able and willing to say. We accordingly employed an Implicit Association Test (IAT) for racial discrimination, first developed and used in two recent published studies, and measured associations of the explicit and implicit discrimination measures with each other, socioeconomic and psychosocial variables, and smoking. METHODOLOGY/PRINCIPAL FINDINGS: Among the 504 black and 501 white US-born participants, age 35-64, randomly recruited in 2008-2010 from 4 community health centers in Boston, MA, black participants were over 1.5 times more likely (p<0.05) to be worse off economically (e.g., for poverty and low education) and have higher social desirability scores (43.8 vs. 28.2); their explicit discrimination exposure was also 2.5 to 3.7 times higher (p<0.05) depending on the measure used, with over 60% reporting exposure in 3 or more domains and within the last year. Higher IAT scores for target vs. perpetrator of discrimination occurred for the black versus white participants: for "black person vs. white person": 0.26 vs. 0.13; and for "me vs. them": 0.24 vs. 0.19. In both groups, only low non-significant correlations existed between the implicit and explicit discrimination measures; social desirability was significantly associated with the explicit but not implicit measures. Although neither the explicit nor implicit discrimination measures were associated with odds of being a current smoker, the excess risk for black participants (controlling for age and gender) rose in models that also controlled for the racial discrimination and psychosocial variables; additional control for socioeconomic position sharply reduced and rendered the association null. CONCLUSIONS: Implicit and explicit measures of racial discrimination are not equivalent and both warrant use in research on racial discrimination and health, along with data on socioeconomic position and social desirability.

Occupational, social, and relationship hazards and psychological distress among low-income workers: implications of the 'inverse hazard law'.

BACKGROUND: Few studies have simultaneously included exposure information on occupational hazards, relationship hazards (eg, intimate partner violence) and social hazards (eg, poverty and racial discrimination), especially among low-income multiracial/ethnic populations. METHODS: A cross-sectional study (2003-2004) of 1202 workers employed at 14 worksites in the greater Boston area of Massachusetts investigated the independent and joint association of occupational, social and relationship hazards with psychological distress (K6 scale). RESULTS: Among this low-income cohort (45% were below the US poverty line), exposure to occupational, social and relationship hazards, per the 'inverse hazard law,' was high: 82% exposed to at least one occupational hazard, 79% to at least one social hazard, and 32% of men and 34% of women, respectively, stated they had been the perpetrator or target of intimate partner violence (IPV). Fully 15.4% had clinically significant psychological distress scores (K6 score ≥ 13). All three types of hazards, and also poverty, were independently associated with increased risk of psychological distress. In models including all three hazards, however, significant associations with psychological distress occurred among men and women for workplace abuse and high exposure to racial discrimination only; among men, for IPV; and among women, for high exposure to occupational hazards, poverty and smoking. CONCLUSIONS: Reckoning with the joint and embodied reality of diverse types of hazards involving how people live and work is necessary for understanding determinants of health status.

Prenatal and postnatal tobacco smoke exposure and respiratory health in Russian children.

BACKGROUND: Only few studies have assessed the relative impact of prenatal and postnatal exposure to tobacco smoke on the child's later asthma or chronic respiratory symptoms and to our knowledge no studies have elaborated respiratory infections and allergies in this context. OBJECTIVE: To assess the effects of prenatal and postnatal exposure to tobacco smoke on respiratory health of Russian school children. METHODS: We studied a population of 5951 children (8 to 12 years old) from 9 Russian cities, whose parents answered a questionnaire on their children's respiratory health, home environment, and housing characteristics. The main health outcomes were asthma, allergies, chronic respiratory symptoms, chronic bronchitis, and upper respiratory infections. We used adjusted odds ratios (ORs) from logistic regression analyses as measures of effect. RESULTS: Prenatal exposure due to maternal smoking had the strongest effects on asthma (adjusted OR 2.46, 95% CI 1.19-5.08), chronic bronchitis (adjusted OR 1.45, 95% CI 1.08-1.96) and respiratory symptoms, such as wheezing (adjusted OR 1.30, 95% CI 0.90-1.89). The associations were weaker for exposure during early-life (adjusted ORs 1.38/1.27/1.15 respectively) and after 2 years of age (adjusted ORs 1.45/1.34/1.18) compared to prenatal exposure and the weakest or non-existent for current exposure (adjusted ORs 1.05/1.09/1.06). Upper respiratory infections were associated more strongly with early-life exposure (adjusted OR 1.25, 95% CI 1.09-1.42) than with prenatal (adjusted OR 0.74, 95% CI 0.54-1.01) or current exposure (adjusted OR1.05, 95% CI 0.92-1.20). The risk of allergies was also related to early life exposure to tobacco smoke (adjusted OR 1.26, 95% CI 1.13-1.42). CONCLUSION: Adverse effects of tobacco smoke on asthma, chronic bronchitis, and chronic respiratory symptoms are strongest when smoking takes place during pregnancy. The relations are weaker for exposure during early-life and after 2 years of age and weakest or non-existent for current exposure.

Housing characteristics and children's respiratory health in the Russian Federation.

OBJECTIVES: We studied housing characteristics, parental factors, and respiratory health conditions in Russian children. METHODS: We studied a population of 5951 children from 9 Russian cities, whose parents answered a questionnaire on their children's respiratory health, home environment, and housing characteristics. The health outcomes were asthma conditions, current wheeze, dry cough, bronchitis, and respiratory allergy. RESULTS: Respiratory allergy and dry cough increased in association with the home being adjacent to traffic. Consistent positive associations were observed between some health conditions and maternal smoking during pregnancy, many health conditions and lifetime exposure to environmental tobacco smoke (ETS), and nearly all health conditions and water damage and molds in the home. CONCLUSIONS: Vicinity to traffic, dampness, mold, and ETS are important determinants of children's respiratory health in Russia.