Sung Kyun Park

Biomarkers of Lead Exposure and DNA Methylation within Retrotransposons

Background DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead. Objective In this study we compared associations between lead biomarkers and DNA methylation. Methods We measured global methylation in participants of the Normative Aging Study (all men) who had archived DNA samples. We measured patella and tibia lead levels by K-X-Ray fluorescence and blood lead by atomic absorption spectrophotometry. DNA samples from blood were used to determine global methylation averages within CpG islands of long interspersed nuclear elements-1 (LINE-1) and Alu retrotransposons. A mixed-effects model using repeated measures of Alu or LINE-1 as the dependent variable and blood/bone lead (tibia or patella in separate models) as the primary exposure marker was fit to the data. Results Overall mean global methylation (± SD) was 26.3 ± 1.0 as measured by Alu and 76.8 ± 1.9 as measured by LINE-1. In the mixed-effects model, patella lead levels were inversely associated with LINE-1 (β = −0.25; p < 0.01) but not Alu (β = −0.03; p = 0.4). Tibia lead and blood lead did not predict global methylation for either Alu or LINE-1. Conclusion Patella lead levels predicted reduced global DNA methylation within LINE-1 elements. The association between lead exposure and LINE-1 DNA methylation may have implications for the mechanisms of action of lead on health outcomes, and also suggests that changes in DNA methylation may represent a biomarker of past lead exposure.

Urinary Bisphenol A and Type-2 Diabetes in U.S. Adults: Data from NHANES 2003-2008

Objective Bisphenol A (BPA) is found in plastics and other consumer products; exposure may lead to insulin resistance and development of type-2 diabetes mellitus (T2DM) through over-activation of pancreatic β-cells. Previous studies using data from the National Health and Nutrition Examination Survey (NHANES) showed an inconsistent association between prevalence of self-reported T2DM and urinary BPA. We used a different diagnosis method of T2DM (hemoglobin A1c (HbA1c)) with a larger subset of NHANES. Methods and Findings We analyzed data from 4,389 adult participants who were part of a sub-study of environmental phenol measurements in urine from three NHANES cycles from 2003 to 2008. T2DM was defined as having a HbA1c ≥6.5% or use of diabetes medication. The weighted prevalence of T2DM was 9.2%. Analysis of the total sample revealed that a two-fold increase in urinary BPA was associated with an odds ratio (OR) of 1.08 of T2DM (95% confidence interval (CI), 1.02 to 1.16), after controlling for potential confounders. However, when we examined each NHANES cycle individually, we only found a statistically significant association in the 2003/04 cycle (n = 1,364, OR = 1.23 (95% CI, 1.07 to 1.42) for each doubling in urinary BPA). We found no association in either the NHANES cycle from 2005/06 (n = 1,363, OR = 1.05 (95% CI, 0.94 to 1.18)); or 2007/08 (n = 1,662, OR = 1.06 (95% CI, 0.91 to 1.23)). Similar patterns of associations between BPA and continuous HbA1c were also observed. Conclusions Although higher urinary BPA was associated with elevated HbA1c and T2DM in the pooled analysis, it was driven by data from only one NHANES cycle. Additional studies, especially of a longitudinal design with repeated BPA measurements, are needed to further elucidate the association between BPA and T2DM.

Cardiac autonomic dysfunction: effects from particulate air pollution and protection by dietary methyl nutrients and metabolic polymorphisms.

Background— Particulate air pollution is associated with cardiovascular mortality and morbidity. To help identify mechanisms of action and protective/susceptibility factors, we evaluated whether the effect of particulate matter <2.5 &mgr;m in aerodynamic diameter (PM2.5) on heart rate variability was modified by dietary intakes of methyl nutrients (folate, vitamins B6 and B12, methionine) and related gene polymorphisms (C677T methylenetetrahydrofolate reductase [MTHFR] and C1420T cytoplasmic serine hydroxymethyltransferase [cSHMT]). Methods and Results— Heart rate variability and dietary data were obtained between 2000 and 2005 from 549 elderly men from the Normative Aging Study. In carriers of [CT/TT] MTHFR genotypes, the SD of normal-to-normal intervals was 17.1% (95% CI, 6.5 to 26.4; P=0.002) lower than in CC MTHFR subjects. In the same [CT/TT] MTHFR subjects, each 10-&mgr;g/m3 increase in PM2.5 in the 48 hours before the examination was associated with a further 8.8% (95% CI, 0.2 to 16.7; P=0.047) decrease in the SDNN. In [CC] cSHMT carriers, PM2.5 was associated with an 11.8% (95% CI, 1.8 to 20.8; P=0.02) decrease in SDNN. No PM2.5-SSDN association was found in subjects with either [CC] MTHFR or [CT/TT] cSHMT genotypes. The negative effects of PM2.5 were abrogated in subjects with higher intakes (above median levels) of B6, B12, or methionine. PM2.5 was negatively associated with heart rate variability in subjects with lower intakes, but no PM2.5 effect was found in the higher intake groups. Conclusion— Genetic and nutritional variations in the methionine cycle affect heart rate variability either independently or by modifying the effects of PM2.5.

Ambient Temperature, Air Pollution, and Heart Rate Variability in an Aging Population

Studies show that ambient temperature and air pollution are associated with cardiovascular disease and that they may interact to affect cardiovascular events. However, few epidemiologic studies have examined mechanisms through which ambient temperature may influence cardiovascular function. The authors examined whether temperature was associated with heart rate variability (HRV) in a Boston, Massachusetts, study population and whether such associations were modified by ambient air pollution concentrations. The population was a cohort of 694 older men examined between 2000 and 2008. The authors fitted a mixed model to examine associations between temperature and air pollution and their interactions with repeated HRV measurements, adjusting for covariates selected a priori on the basis of their previous studies. Results showed that higher ambient temperature was associated with decreases in HRV measures (standard deviation of normal-to-normal intervals, low-frequency power, and high-frequency power) during the warm season but not during the cold season. These warm-season associations were significantly greater when ambient ozone levels were higher (>22.3 ppb) but did not differ according to levels of ambient fine (≤2.5 μm) particulate matter. The authors conclude that temperature and ozone, exposures to both of which are expected to increase with climate change, might act together to worsen cardiovascular health and/or precipitate cardiovascular events via autonomic nervous system dysfunction.

HFE Genotype, Particulate Air Pollution, and Heart Rate Variability A Gene-Environment Interaction

Background— Particulate air pollution has been associated with cardiovascular mortality and morbidity. Transition metals such as iron bound to the particles may be responsible for those associations. The protein product of the hemochromatosis (HFE) gene modulates uptake of iron and divalent cations from pulmonary sources and reduces their toxicity. Two HFE polymorphisms (C282Y and H63D) associated with increased iron uptake may modify the effect of metal-rich particles on the cardiovascular system. Methods and Results— We investigated the association between particulate matter ≤2.5 &mgr;m in aerodynamic diameter and heart rate variability in 518 older men from the Normative Aging Study who were examined between November 2000 and December 2004. Linear regression models were fit to evaluate interactions between HFE genotype and particulate matter ≤2.5 &mgr;m in aerodynamic diameter in relation to heart rate variability, controlling for potential confounders. A 10-&mgr;g/m3 increase in particulate matter ≤2.5 &mgr;m in aerodynamic diameter during the 48 hours before heart rate variability measurement was associated with a 31.7% (95% CI, 10.3% to 48.1%) decrease in the high-frequency component of heart rate variability in persons with the wild-type genotype, whereas no relationship in the high-frequency component was observed in persons with either HFE variant. The difference in effect of particulate matter ≤2.5 &mgr;m in aerodynamic diameter on the high-frequency component between persons with and without HFE variants was significant (P for interaction=0.02). Conclusions— The effect of particles on cardiac autonomic function was shielded in subjects with at least 1 copy of an HFE variant compared with wild-type subjects. Transition metals, including iron, bound to ambient particles and the related oxidative stress may play an important role in cardiac toxicity of particles.

Particulate Air Pollution, Metabolic Syndrome, and Heart Rate Variability: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background Cardiac autonomic dysfunction has been suggested as a possible biologic pathway for the association between fine particulate matter ≤ 2.5 μm in diameter (PM2.5) and cardiovascular disease (CVD). We examined the associations of PM2.5 with heart rate variability, a marker of autonomic function, and whether metabolic syndrome (MetS) modified these associations. Methods We used data from the Multi-Ethnic Study of Atherosclerosis to measure the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences (rMSSD) of 5,465 participants 45–84 years old who were free of CVD at the baseline examination (2000–2002). Data from the U.S. regulatory monitor network were used to estimate ambient PM2.5 concentrations at the participants’ residences. MetS was defined as having three or more of the following criteria: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, high blood pressure, and high fasting glucose. Results After controlling for confounders, we found that an interquartile range (IQR) increase in 2-day average PM2.5 (10.2 μg/m3) was associated with a 2.1% decrease in rMSSD [95% confidence interval (CI), −4.2 to 0.0] and nonsignificantly associated with a 1.8% decrease in SDNN (95% CI, −3.7 to 0.1). Associations were stronger among individuals with MetS than among those without MetS: an IQR elevation in 2-day PM2.5 was associated with a 6.2% decrease in rMSSD (95% CI, −9.4 to −2.9) among participants with MetS, whereas almost no change was found among participants without MetS (p-interaction = 0.005). Similar effect modification was observed in SDNN (p-interaction = 0.011). Conclusion These findings suggest that autonomic dysfunction may be a mechanism through which PM exposure affects cardiovascular risk, especially among persons with MetS.

Cadmium exposure and cardiovascular disease in the 2005 Korea National Health and Nutrition Examination Survey

BACKGROUND Limited epidemiologic data are available concerning the cardiovascular effects of cadmium exposure, although recent studies suggest associations with myocardial infarction and peripheral arterial disease. We examined the associations of cadmium exposure with cardiovascular disease in nationally representative general Korean adults. METHODS We used cross-sectional data on blood cadmium and self-reported diagnoses of ischemic heart disease (IHD), stroke, and hypertension in a sub-sample of 1908 adults, aged 20 years and older, who participated in the 2005 Korea National Health and Nutrition Examination Survey (KNHANES). We used survey logistic regression models accounting for the complex sampling design to estimate the odds ratios (OR), adjusting for age, education, income, alcohol, smoking, body mass index, waist circumference, family history of hypertension, blood pressure, and blood lead. RESULTS The geometric mean of blood cadmium was 1.53 μg/L. After adjusting for potential confounders, an interquartile range (IQR) increase in blood cadmium (0.91 μg/L) was found to be associated with an increased risk for IHD (OR 2.1, 95% confidence interval (CI) 1.3-3.4). An IQR increase in blood cadmium was found to be associated with an elevated risk for hypertension only among men (OR 1.4, 95% CI 1.1-1.8) but not among women. No association was observed with stroke in both genders. CONCLUSIONS These findings suggest that cadmium in blood may be associated with an increased risk for IHD and hypertension in the general Korean adult population.

Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution.

Background: Ambient particles are associated with cardiovascular events and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biologic mechanisms are not fully understood. One of the putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367, and rs2300181), NQO1 (rs1800566), GSTP1 I105V, GSTM1, GSTT1 (deletion vs. nondeletion), and HMOX-1 (any short vs. both long). We attempted to replicate identified genes in an analysis of heart rate variability and in other outcomes reported in the literature. Methods: Study subjects were 1000 white non-Hispanic men in the Boston area, participating in a cohort study of aging. PM2.5, black carbon, total plasma homocysteine, and other covariates were measured at several points in time between 1995 and 2006. We fit mixed models to examine effect modification of genes on associations of pollution with total plasma homocysteine. Results: Interquartile range increases in PM2.5 and black carbon (7-day moving averages) were associated with 1.5% (95% confidence interval = 0.2% to 2.8%) and 2.2% (0.6% to 3.9%) increases in total plasma homocysteine, respectively. GSTT1 and HFE C282Y modified effects of black carbon on total plasma homocysteine, and HFE C282Y and CAT (rs2300181) modified effects of PM2.5 on homocysteine. Several genotypes marginally modified effects of PM2.5 and black carbon on various endpoints. All genes with significant interactions with particulate air pollution had modest main effects on total plasma homocysteine. Conclusions: Effects of PM2.5 and black carbon on various endpoints appeared to be mediated by genes related to oxidative stress pathways.

Traffic-related Particles Are Associated with Elevated Homocysteine The VA Normative Aging Study

RATIONALE Recent epidemiologic studies have shown that homocysteine, a sulfur-containing amino acid formed during the metabolism of methionine, is a risk factor for atherosclerosis, myocardial infarction, stroke, and thrombosis. Particulate air pollution has been related to cardiovascular death and hospital admission, but the underlying mechanisms are not fully elucidated. OBJECTIVES We examined the associations between ambient particulate air pollution and plasma concentrations of homocysteine among 960 community-residing older men (mean age, 73.6 +/- 6.9 yr). METHODS Total homocysteine in plasma, measured using high-performance liquid chromatography with fluorescence detection, was regressed on each ambient particulate pollutant (black carbon, organic carbon, sulfate or PM(2.5)), and effect modification by plasma and dietary B vitamins (folate, B6, and B12) was examined. MEASUREMENTS AND MAIN RESULTS The median concentration of total homocysteine was 10.6 micromol/L. Statistically significant positive associations of total homocysteine were observed with traffic-related particles (black carbon and organic carbon). No association was observed with sulfate, an indicator of coal combustion particles, or PM(2.5) (particulate matter < or = 2.5 microm in aerodynamic diameter). The effects of black carbon and organic carbon were more pronounced in persons with low concentrations of plasma folate and vitamin B12. CONCLUSIONS Exposures to ambient particles, particularly from traffic, are associated with elevated plasma total homocysteine. Homocysteine may be a component or biological marker of the oxidation pathways underlying the effect of ambient particles on the cardiovascular system.

Environmental cadmium and lead exposures and hearing loss in U.S. adults: The National Health and Nutrition Examination Survey, 1999 to 2004

Background: Although cadmium and lead are known risk factors for hearing loss in animal models, few epidemiologic studies have been conducted on their associations with hearing ability in the general population. Objectives: We investigated the associations between blood cadmium and lead exposure and hearing loss in the U.S. general population while controlling for noise and other major risk factors contributing to hearing loss. Methods: We analyzed data from 3,698 U.S. adults 20–69 years of age who had been randomly assigned to the National Health and Nutrition Examination Survey (NHANES) 1999–2004 Audiometry Examination Component. Pure-tone averages (PTA) of hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz were computed, and hearing loss was defined as a PTA > 25 dB in either ear. Results: The weighted geometric means of blood cadmium and lead were 0.40 [95% confidence interval (CI): 0.39. 0.42] µg/L and 1.54 (95% CI: 1.49, 1.60) µg/dL, respectively. After adjusting for sociodemographic and clinical risk factors and exposure to occupational and nonoccupational noise, the highest (vs. lowest) quintiles of cadmium and lead were associated with 13.8% (95% CI: 4.6%, 23.8%) and 18.6% (95% CI: 7.4%, 31.1%) increases in PTA, respectively (p-trends < 0.05). Conclusions: Our results suggest that low-level exposure to cadmium and lead found in the general U.S. population may be important risk factors for hearing loss. The findings support efforts to reduce environmental cadmium and lead exposures.