Person:

Sparrow, David

Background: Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave). Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis ((HFE)), transferrin ((TF)) C2, and heme oxygenase-1 ((HMOX-1))] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men. Methods: We used standard 12-lead electrocardiograms, K-shell X-ray fluorescence, and graphite furnace atomic absorption spectrometry to measure QT interval, bone lead, and blood lead levels, respectively. Results: A one-interquartile-range increase in tibia lead level (13 μg/g) was associated with a 11.35-msec [95% confidence interval (CI), 4.05–18.65 msec] and a 6.81-msec (95% CI, 1.67–11.95 msec) increase in the heart-rate–corrected QT interval among persons carrying long (HMOX-1) alleles and at least one copy of an (HFE) variant, respectively, but had no effect in persons with short and middle (HMOX-1) alleles and the wild-type HFE genotype. The lengthening of the heart-rate–corrected QT interval with higher tibia lead and blood lead became more pronounced as the total number (0 vs. 1 vs. ≥2) of gene variants increased (tibia, (p)-trend = 0.01; blood, (p)-trend = 0.04). This synergy seems to be driven by a joint effect between (HFE) variant and (HMOX-1) L alleles. Conclusion: We found evidence that gene variants related to iron metabolism increase the impacts of low-level lead exposure on the prolonged QT interval. This is the first such report, so these results should be interpreted cautiously and need to be independently verified.

Background and Objectives: We have previously shown that reduced defenses against oxidative stress due to glutathione S-transferase M1 (GSTM1) deletion modify the effects of PM[2.5] (fine-particulate air pollution of < 2.5 μm in aerodynamic diameter) on heart rate variability (HRV) in a cross-sectional analysis of the Normative Aging Study, an elderly cohort. We have extended this to include a longitudinal analysis with more subjects and examination of the GT short tandem repeat polymorphism in the heme oxygenase-1 (HMOX-1) promoter. Methods: HRV measurements were taken on 539 subjects. Linear mixed effects models were fit for the logarithm of HRV metrics—including standard deviation of normal-to-normal intervals (SDNN), high frequency (HF), and low frequency (LF)—and PM2.5 concentrations in the 48 hr preceding HRV measurement, controlling for confounders and a random subject effect. Results: PM2.5 was significantly associated with SDNN (p = 0.04) and HF (p = 0.03) in all subjects. There was no association in subjects with GSTM1, whereas there was a significant association with SDNN, HF, and LF in subjects with the deletion. Similarly, there was no association with any HRV measure in subjects with the short repeat variant of HMOX-1, and significant associations in subjects with any long repeat. We found a significant three-way interaction of PM[2.5] with GSTM1 and HMOX-1 determining SDNN (p = 0.008), HF (p = 0.01) and LF (p = 0.04). In subjects with the GSTM1 deletion and the HMOX-1 long repeat, SDNN decreased by 13% [95% confidence interval (CI), −21% to −4%], HF decreased by 28% (95% CI, −43% to −9%), and LF decreased by 20% (95% CI, −35% to −3%) per 10 μg/m3 increase in PM. Conclusions: Oxidative stress is an important pathway for the autonomic effects of particles.

Background: Cumulative lead exposure is associated with a widened pulse pressure (PP; the difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function. Objectives: We examined whether the HFE mutations modify the impact of lead on PP in community-dwelling older men. Methods: We examined 619 participants with a total of 1,148 observations of PP from a substudy of bone lead levels (a measure of cumulative exposure, measured by in vivo K-shell X-ray fluorescence) and health in the Normative Aging Study between 1991 and 2001. Linear mixed-effects regression models with random intercepts were constructed. Results: Of the 619 subjects, 138 and 72 carried the HFE H63D and C282Y variants, respectively. After adjusting for age; education; alcohol intake; smoking; daily intakes of calcium, sodium, and potassium; total calories; family history of hypertension; diabetes; height; heart rate; high-density lipoprotein (HDL); total cholesterol:HDL ratio; and waist circumference, baseline bone lead levels were associated with steeper increases in PP in men with at least one H63D allele (p-interaction = 0.03 for tibia and 0.02 for patella) compared with men with only the wild types or C282Y variant. Conclusions: The HFE H63D polymorphism, but not the C282Y mutation, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.

Background: Pulse pressure increases with age in industrialized societies as a manifestation of arterial stiffening. Lead accumulates in the vasculature and is associated with vascular oxidative stress, which can promote functional and structural vascular disease. Objectives: We tested the hypothesis that cumulative community-level lead exposure, measured with K-X-ray fluorescence, is associated with pulse pressure in a cohort of adult men. Methods and results: In a cross-sectional analysis of 593 men not treated with antihypertensive medication, tibia lead was positively associated with pulse pressure (p < 0.001). Adjusting for age, race, diabetes, family history of hypertension, education, waist circumference, alcohol intake, smoking history, height, heart rate, fasting glucose, and total cholesterol-to-HDL ratio, increasing quintiles of tibia lead remained associated with increased pulse pressure (ptrend = 0.02). Men with tibia lead above the median (19.0 μg/g) had, on average, a 4.2-mmHg (95% confidence interval, 1.9–6.5) higher pulse pressure than men with tibia lead level below the median. In contrast, blood lead level was not associated with pulse pressure. Conclusions: These data indicate that lead exposure may contribute to the observed increase in pulse pressure that occurs with aging in industrialized societies. Lead accumulation may contribute to arterial aging, perhaps providing mechanistic insight into the observed association of low-level lead exposure with cardiovascular mortality.

Background: Exposure to lead is known to have adverse effects on cognition in several different populations. Little is known about the underlying structural and functional correlates of such exposure in humans. Objectives: We assessed the association between cumulative exposure to lead and levels of different brain metabolite ratios in vivo using magnetic resonance spectroscopy (MRS). Methods: We performed MRS on 15 men selected from the lowest quintile of patella bone lead within the Department of Veterans Affairs’ Normative Aging Study (NAS) and 16 from the highest to assess in the hippocampal levels of the metabolites N-acetylaspartate, myoinositol, and choline, each expressed as a ratio with creatine. Bone lead concentrations—indicators of cumulative lead exposure—were previously measured using K-X-ray fluorescence spectroscopy. MRS was performed on the men from 2002 to 2004. Results: A 20-μg/g bone and 15-μg/g bone higher patella and tibia bone lead concentration—the respective interquartile ranges within the whole NAS—were associated with a 0.04 [95% confidence interval (CI), 0.00–0.08; p = 0.04] and 0.04 (95% CI, 0.00–0.08; p = 0.07) higher myoinositol-to-creatine ratio in the hippocampus. After accounting for patella bone lead declines over time, analyses adjusted for age showed that the effect of a 20-μg/g bone higher patella bone lead level doubled (0.09; 95% CI, 0.01–0.17; p = 0.03). Conclusions: Cumulative lead exposure is associated with an increase in the myinositol-to-creatine ratio. These data suggest that, as assessed with MRS, glial effects may be more sensitive than neuronal effects as an indicator of cumulative exposure to lead in adults.

Background: Altered heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with sudden cardiac death and heart failure. Objective: We examined the association of low-level lead exposure measured in bone by K-X-ray fluorescence with alterations in HRV, and whether metabolic syndrome (MetS) or its individual components modify those associations. Methods: HRV measures [power in high-frequency (HF({norm})) and low-frequency (LF({norm})) in normalized units, and LF/HF] were taken among 413 elderly men from the Normative Aging Study. MetS was defined as subjects having three or more of the following criteria: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein, high blood pressure, and high fasting glucose. Results: Of the subjects, 32% were identified as having MetS. Inverse but nonstatistically significant associations of both tibia and patella lead levels with HF({norm}) and nonstatistically significant positive relations with LF({norm}) and LF/HF were found in the entire cohort. There was a graded, statistically significant reduction in HF({norm}) and increases in LF({norm}) and LF/HF in association with an increase in patella lead as the number of metabolic abnormalities increased. We also observed that higher patella lead was consistently associated with lower HFnorm and higher LF(_{norm}) and LF/HF among subjects with MetS or its individual components. No statistically significant interaction between MetS and tibia lead was observed. Conclusion: The results suggest that elderly men with MetS were more susceptible to autonomic dysfunction in association with chronic lead exposure as measured in patella. The modification by MetS is consistent with a role for oxidative stress in lead toxicity on the cardiovascular system.

Background: Particulate matter (PM) air pollution has been associated with cardiovascular morbidity and mortality, and elevated blood pressure (BP) is a known risk factor for cardiovascular disease. A small number of studies have investigated the relationship between PM and BP and found mixed results. Evidence suggests that traffic-related air pollution contributes significantly to PM-related cardiovascular effects. Objectives: We hypothesized that black carbon (BC), a traffic-related combustion by-product, would be more strongly associated with BP than would fine PM [aerodynamic diameter ≤ 2.5 μm (PM({2.5}))], a heterogeneous PM mixture, and that these effects would be larger among participants with genetic variants associated with impaired antioxidative defense. Methods: We performed a repeated-measures analysis in elderly men to analyze associations between PM({2.5}) and BC exposure and BP using mixed-effects models with random intercepts, adjusting for potential confounders. We also examined statistical interaction between BC and genetic variants related to oxidative stress defense: GSTM1, GSTP1, GSTT1, NQO1, catalase, and HMOX-1. Results: A 1-SD increase in BC concentration was associated with a 1.5-mmHg increase in systolic BP [95% confidence interval (CI), 0.1–2.8] and a 0.9-mmHg increase in diastolic BP (95% CI, 0.2–1.6). We observed no evidence of statistical interaction between BC and any of the genetic variants examined and found no association between PM({2.5}) and BP. Conclusions: We observed positive associations between BP and BC, but not between BP and PM({2.5}), and found no evidence of effect modification of the association between BC and BP by gene variants related to antioxidative defense.

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 less than 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.

Background: Fine particulate matter [aerodynamic diameter ≤ 2.5 μm (PM2.5)] has been associated with autonomic dysregulation.Objective We hypothesized that PM2.5 influences postural changes in systolic blood pressure (ΔSBP) and in diastolic blood pressure (ΔDBP) and that this effect is modified by genes thought to be related to chronic lung disease. Methods: We measured blood pressure in participants every 3–5 years. ΔSBP and ΔDBP were calculated as sitting minus standing SBP and DBP. We averaged PM2.5 over 48 hr before study visits and analyzed 202 single nucleotide polymorphisms (SNPs) in 25 genes. To address multiple comparisons, data were stratified into a split sample. In the discovery cohort, the effects of SNP × PM2.5 interactions on ΔSBP and ΔDBP were analyzed using mixed models with subject-specific random intercepts. We defined positive outcomes as p < 0.1 for the interaction; we analyzed only these SNPs in the replicate cohort and confirmed them if p < 0.025 with the same sign. Confirmed associations were analyzed within the full cohort in models adjusted for anthropometric and lifestyle factors. Results: Nine hundred forty-five participants were included in our analysis. One interaction with rs9568232 in PHD finger protein 11 (PHF11) was associated with greater ΔDBP. Interactions with rs1144393 in matrix metalloprotease 1 (MMP1) and rs16930692, rs7955200, and rs10771283 in inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) were associated with significantly greater ΔSBP. Because SNPs associated with ΔSBP in our analysis are in genes along the renin–angiotensin pathway, we then examined medications affecting that pathway and observed significant interactions for angiotensin receptor blockers but not angiotensin-converting enzyme inhibitors with PM2.5. Conclusions: PM2.5 influences blood pressure and autonomic function. This effect is modified by genes and drugs that also act along this pathway.

Background: Lead exposure has been associated with cardiovascular disease (CVD) in animal and human studies. However, the mechanisms of action have not been fully elucidated. We therefore examined the relationship between lead and multiple biomarkers of CVD. Methods: Participants were older men from the Normative Aging Study without preexisting coronary heart disease, diabetes, or active infection at baseline (n = 426). Serum biomarkers included lipid profile [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides] and inflammatory markers [C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and tumor necrosis factor receptor-2 (TNF-R2)]. We measured lead in blood and in bone by K-shell X-ray fluorescence. In this sample, 194 men (44.3%) had two or more repeated measures, resulting in 636 observations for analysis. We conducted analyses using mixed effects models with random subject intercepts. Results: Lead levels were associated with several CVD biomarkers, including levels of TNF-R2 and lipid markers. Specifically, in multivariable models, a 50% increase in blood lead level was associated with 26% increased odds of high TNF-R2 levels (> 5.52 ng/mL; odds ratio = 1.26; 95% confidence interval: 1.09, 1.45). There were positive associations of blood lead level with total cholesterol and HDL levels, and these associations were more evident when modeled as continuous outcomes than when categorized using clinically relevant cut points. In addition, longitudinal analyses indicated a significant increase in TNF-R2 levels over time to be associated with high blood lead level at the preceding visit. Conclusions: Blood lead level may be related with CVD in healthy older men through its association with TNF-R2 levels. In addition, the magnitude of the association of blood lead level with TNF-R2 level increased with age in the study population.