Person:

Weisskopf, Marc

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: 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: 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: Research using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson’s disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead. Objectives: We sought to assess the association between bone lead and PD. Methods: Bone lead concentrations were measured using 109Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression. Results: The average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17–8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11–5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01–3.60). We found no association with patella bone lead. Conclusions: These findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD.

Background: High levels of cadmium exposure are known to cause emphysema in occupationally exposed workers, but little has been reported to date on the association between chronic environmental cadmium exposure and pulmonary function. Objective: In this study we examined the association between pulmonary function and cadmium body burden in a subcohort of the Normative Aging Study, a community-based study of aging. Methods: We examined 96 men who had cadmium measured in single 24-hr urinary specimens collected in 1994–1995 and who had one to three tests of pulmonary function between 1994 and 2002 (a total of 222 observations). We used mixed-effect models to predict pulmonary function based on individual 24-hr urinary cadmium output, adjusted for age, height, time elapsed from the baseline, and smoking status. We assessed effect modification by smoking status. Results: Among all subjects, a single log-unit increase in baseline urinary cadmium was inversely associated with forced expiratory volume in 1 sec (FEV1) percent predicted [β = −7.56%; 95% confidence interval (CI) −13.59% to −1.53%]; forced vital capacity (FVC) percent predicted (β = −2.70%; 95% CI −7.39% to 1.99%), and FEV1/FVC ratio (β = −4.13%; 95% CI −7.61% to −0.66%). In models including an interaction between urinary cadmium and smoking status, there was a graded, statistically significant reduction in FEV1/FVC ratio across smoking status in association with urinary cadmium. Conclusions: This study suggests that chronic cadmium exposure is associated with reduced pulmonary function, and cigarette smoking modifies this association. These results should be interpreted with caution because the sample size is small, and further studies are needed to confirm our findings.

Seventy-one-year-old identical twin brothers with chronic lead poisoning were identified from an occupational medicine clinic roster. Both were retired painters, but one brother (J.G.) primarily removed paint and had a history of higher chronic lead exposure. Patella and tibia bone lead concentrations measured by K-X-ray fluorescence in each brother were 5-10 times those of the general population and about 2.5 times higher in J.G. than in his brother (E.G.). Magnetic resonance spectroscopy (MRS) studies examined N-acetylaspartate:creatine ratios, a marker of neuronal density. Ratios were lower in J.G. than in his brother. Scores on neurocognitive tests that assess working memory/executive function were below expectation in both twins. Short-term memory function was dramatically worse in J.G. than in his brother. These results demonstrate some of the more subtle long-term neurologic effects of chronic lead poisoning in adults. In particular, they suggest the presence of frontal lobe dysfunction in both twins, but more dramatic hippocampal dysfunction in the brother with higher lead exposure. The MRS findings are consistent with the hypothesis that chronic lead exposure caused neuronal loss, which may contribute to the impairment in cognitive function. Although a causal relation cannot be inferred, the brothers were genetically identical, with similar life experiences. Although these results are promising, further study is necessary to determine whether MRS findings correlate both with markers of lead exposure and tests of cognitive function. Nevertheless, the results point to the potential utility of MRS in determining mechanisms of neurotoxicity not only for lead but also for other neurotoxicants as well.

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: 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.

Background: Previous studies found effect modification of associations between traffic-related air pollution and cardiovascular outcomes by polymorphisms in the hemochromatosis gene (HFE). As traffic-related air pollution may impact cognition through effects on cardiovascular health or through mechanisms which may also influence cardiovascular outcomes, we hypothesized that HFE polymorphisms would also modify a previously observed association between traffic-related air pollution exposure and cognition in older men. Methods: We considered data from 628 participants of the VA Normative Aging Study. We estimated long term exposure to black carbon (BC), a marker of traffic related air pollution, using a spatio-temporal land use regression model. We assessed cognition using the Mini-Mental State Examination (MMSE), a test of global function, and performance on a battery of other tests, covering a wide range of domains. We investigated whether variants of HFE C282Y and H63D modified the association between BC and having a low MMSE score using logistic models with generalized estimating equations and multiplicative interaction terms. Similarly, we assessed whether HFE variants modified the association between BC and performance on the cognitive battery using linear mixed models with multiplicative interaction terms. Results: Our results suggest modification of the BC-cognition association by HFE C282Y, although the test of interaction did not achieve statistical significance. In multivariable-adjusted models, participants who lacked a HFE C282Y variant (CC) exhibited an adverse association between BC and total cognition z-score (beta for a doubling in BC concentration: -0.061, 95% CI: -0.115, -0.007), while we did not observe an association in participants with at least one variant genotype (CY or YY) (beta for a doubling in BC concentration: 0.073, 95% CI: -0.081, 0.228; p-value for interaction: 0.11). The pattern of association was similar for analyses considering performance on the Mini-Mental State Examination. There was little evidence to support effect modification of the BC-cognition association by the HFE H63D genotype. Conclusions: Our data suggest that older adults who lack an HFE C282Y variant may be more susceptible to an adverse effect of traffic-related air pollution exposure on cognition. This finding and the proposed biological mechanism require confirmation.

Background: Different lines of evidence suggest that low-level lead exposure could be a modifiable risk factor for adverse psychological symptoms, but little work has explored this relation. Objective: We assessed whether bone lead—a biomarker of cumulative lead exposure—is associated with depression and anxiety symptoms among middle-age and elderly women. Methods: Participants were 617 Nurses’ Health Study participants with K-shell X-ray fluorescence bone lead measures and who had completed at last one Mental Health Index 5-item scale (MHI-5) and the phobic anxiety scale of the Crown-Crisp Index (CCI) assessment at mean ± SD age of 59 ± 9 years (range, 41–83 years). With exposure expressed as tertiles of bone lead, we analyzed MHI-5 scores as a continuous variable using linear regression and estimated the odds ratio (OR) of a CCI score ≥ 4 using generalized estimating equations. Results: There were no significant associations between lead and either outcome in the full sample, but associations were found among premenopausal women and women who consistently took hormone replacement therapy (HRT) between menopause and bone lead measurement (n = 142). Compared with women in the lowest tertile of tibia lead, those in the highest scored 7.78 points worse [95% confidence interval (CI): –11.73, –3.83] on the MHI-5 (p-trend = 0.0001). The corresponding OR for CCI ≥ 4 was 2.79 (95% CI: 1.02, 7.59; p-trend = 0.05). No consistent associations were found with patella lead. Conclusions: These results provide support for an association of low-level cumulative lead exposure with increased depressive and phobic anxiety symptoms among older women who are premenopausal or who consistently take postmenopausal HRT.