Potential health impacts of heavy metals on HIV-infected population in USA.

Noninfectious comorbidities such as cardiovascular diseases have become increasingly prevalent and occur earlier in life in persons with HIV infection. Despite the emerging body of literature linking environmental exposures to chronic disease outcomes in the general population, the impacts of environmental exposures have received little attention in HIV-infected population. The aim of this study is to investigate whether individuals living with HIV have elevated prevalence of heavy metals compared to non-HIV infected individuals in United States. We used the National Health and Nutrition Examination Survey (NHANES) 2003-2010 to compare exposures to heavy metals including cadmium, lead, and total mercury in HIV infected and non-HIV infected subjects. In this cross-sectional study, we found that HIV-infected individuals had higher concentrations of all heavy metals than the non-HIV infected group. In a multivariate linear regression model, HIV status was significantly associated with increased blood cadmium (p=0.03) after adjusting for age, sex, race, education, poverty income ratio, and smoking. However, HIV status was not statistically associated with lead or mercury levels after adjusting for the same covariates. Our findings suggest that HIV-infected patients might be significantly more exposed to cadmium compared to non-HIV infected individuals which could contribute to higher prevalence of chronic diseases among HIV-infected subjects. Further research is warranted to identify sources of exposure and to understand more about specific health outcomes

Association of single and joint metals with albuminuria and estimated glomerular filtration longitudinal change in middle-aged adults from Spain: The Aragon workers health study

The nephrotoxicity of low-chronic metal exposures is unclear, especially considering several metals simultaneously. We assessed the individual and joint association of metals with longitudinal change in renal endpoints in Aragon Workers Health Study participants with available measures of essential (cobalt [Co], copper [Cu], molybdenum [Mo] and zinc [Zn]) and non-essential (As, barium [Ba], Cd, chromium [Cr], antimony [Sb], titanium [Ti], uranium [U], vanadium [V] and tungsten [W]) urine metals and albumin-to-creatinine ratio (ACR) (N = 707) and estimated glomerular filtration rate (eGFR) (N = 1493) change. Median levels were 0.24, 7.0, 18.6, 295, 3.1, 1.9, 0.28, 1.16, 9.7, 0.66, 0.22 μg/g for Co, Cu, Mo, Zn, As, Ba, Cd, Cr, Sb, Ti, V and W, respectively, and 52.5 and 27.2 ng/g for Sb and U, respectively. In single metal analysis, higher As, Cr and W concentrations were associated with increasing ACR annual change. Higher Zn, As and Cr concentrations were associated with decreasing eGFR annual change. The shape of the longitudinal dose-responses, however, was compatible with a nephrotoxic role for all metals, both in ACR and eGFR models. In joint metal analysis, both higher mixtures of Cu–Zn–As–Ba–Ti–U–V–W and Co–Cd–Cr–Sb–V–W showed associations with increasing ACR and decreasing eGFR annual change. As and Cr were main drivers of the ACR change joint metal association. For the eGFR change joint metal association, while Zn and Cr were main drivers, other metals also contributed substantially. We identified potential interactions for As, Zn and W by other metals with ACR change, but not with eGFR change. Our findings support that Zn, As, Cr and W and suggestively other metals, are nephrotoxic at relatively low exposure levels. Metal exposure reduction and mitigation interventions may improve prevention and decrease the burden of renal disease in the population

Blood DNA methylation and liver cancer in American Indians: evidence from the Strong Heart Study

Purpose: Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer. Methods: We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations. Results: We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39). Conclusions: Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer.This work was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) (Contract Numbers 75N92019D00027, 75N92019D00028, 75N92019D00029 and 75N92019D00030) and previous Grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and Cooperative Agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520 and U01HL65521); by the National Institute of Environmental Health Sciences (Grant Numbers R25ES025505, R01ES032638, R01ES021367, R01ES025216, P42ES033719, P30ES009089); by the Chilean CONICYT/FONDECYT-POSTDOCTORADO Nº 3180486 and by a fellowship from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). The funders had no role in the planning, conducting, analysis, interpretation, or writing of this study. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the ofcial views of the National Institutes of Health (United States) or the National Health Institute Carlos III (Spain).S

Selenium and impaired physical function in US and Spanish older adults

Background: Selenium (Se) is a trace element with a narrow safety margin. Objectives: To evaluate the cross-sectional and longitudinal dose-response association between Se exposure and measures of impaired physical function and disability in older adults. Design: NHANES 2011–2014 cross-sectional (US, n = 1733, age ≥60 years) and Seniors-ENRICA-2 2017–2019 cross-sectional and longitudinal (Spain, n = 2548 and 1741, respectively, age ≥65 years) data were analyzed. Whole blood and serum Se levels were measured using inductively coupled plasma-mass spectrometry. Lowerextremity performance was assessed with the Short Physical Performance Battery, and muscle weakness with a dynamometer. Incident mobility and agility limitations, and disability in instrumental activities of daily living (IADL) were ascertained with standardized questionnaires. Analyses were adjusted for relevant confounders, including physical activity. Results across studies were pooled using random-effects meta-analysis. Results: Meta-analyzed odds ratios (95% confidence interval) per log2 increase in whole blood Se were 0.54 (0.32; 0.76) for weakness, 0.59 (0.34; 0.83) for impaired lower-extremity performance, 0.48 (0.31; 0.68) for mobility limitations, 0.71 (0.45; 0.97) for agility limitations, and 0.34 (0.12; 0.56) for disability in at least one IADL. Analyses for serum Se in NHANES showed similar results. Findings suggest the inverse association with grip strength is progressive below 140 μg/L (p-value for non-linear trend in the Seniors-ENRICA-2 study = 0.13), and above 140 μg/L (p-value for non-linear trend in NHANES = 0.11). In the Seniors-ENRICA-2 cohort, with a 2.2 year follow-up period, a doubling in baseline Se levels were associated with a lower incidence of weakness [odds ratio (95% confidence interval): 0.45 (0.22; 0.91)], impaired lower-extremity performance [0.63 (0.32; 1.23)], mobility [0.43 (0.21; 0.91)] and agility [0.38 (0.18; 0.78)] limitations. Discussion: In US and Spanish older adults, Se concentrations were inversely associated with physical function limitations. Further studies are needed to elucidate underlying mechanisms.Instituto de Salud Carlos III European Commission PI18/287 16/609State Secretary of R + D + I PID2019-108973RB-C21/C22European Social Fund (ESF) European Commissio

Mortality and cardiovascular disease burden of uncontrolled diabetes in a registry-based cohort: the ESCARVAL-risk study

BACKGROUND: Despite the epidemiological evidence about the relationship between diabetes, mortality and cardiovascular disease, information about the population impact of uncontrolled diabetes is scarce. We aimed to estimate the attributable risk associated with HbA1c levels for all-cause mortality and cardiovascular hospitalization. METHODS: Prospective study of subjects with diabetes mellitus using electronic health records from the universal public health system in the Valencian Community, Spain 2008-2012. We included 19,140 men and women aged 30 years or older with diabetes who underwent routine health examinations in primary care. RESULTS: A total of 11,003 (57%) patients had uncontrolled diabetes defined as HbA1c ≥6.5%, and, among those, 5325 participants had HbA1c ≥7.5%. During an average follow-up time of 3.3 years, 499 deaths, 912 hospitalizations for coronary heart disease (CHD) and 786 hospitalizations for stroke were recorded. We observed a linear and increasingly positive dose-response of HbA1c levels and CHD hospitalization. The relative risk for all-cause mortality and CHD and stroke hospitalization comparing patients with and without uncontrolled diabetes was 1.29 (95 CI 1.08,1.55), 1.38 (95 CI 1.20,1.59) and 1.05 (95 CI 0.91, 1.21), respectively. The population attributable risk (PAR) associated with uncontrolled diabetes was 13.6% (95% CI; 4.0-23.9) for all-cause mortality, 17.9% (95% CI; 10.5-25.2) for CHD and 2.7% (95% CI; - 5.5-10.8) for stroke hospitalization. CONCLUSIONS: In a large general-practice cohort of patients with diabetes, uncontrolled glucose levels were associated with a substantial mortality and cardiovascular disease burden

Arsenic exposure, diabetes-related genes and diabetes prevalence in a general population from Spain

Inorganic arsenic exposure may be associated with diabetes, but the evidence at low-moderate levels is not sufficient. Polymorphisms in diabetes-related genes have been involved in diabetes risk. We evaluated the association of inorganic arsenic exposure on diabetes in the Hortega Study, a representative sample of a general population from Valladolid, Spain. Total urine arsenic was measured in 1451 adults. Urine arsenic speciation was available in 295 randomly selected participants. To account for the confounding introduced by non-toxic seafood arsenicals, we designed a multiple imputation model to predict the missing arsenobetaine levels. The prevalence of diabetes was 8.3%. The geometric mean of total arsenic was 66.0 µg/g. The adjusted odds ratios (95% confidence interval) for diabetes comparing the highest with the lowest tertile of total arsenic were 1.76 (1.01, 3.09) and 2.14 (1.47, 3.11) before and after arsenobetaine adjustment, respectively. Polymorphisms in several genes including IL8RA, TXN, NR3C2, COX5A and GCLC showed suggestive differential associations of urine total arsenic with diabetes. The findings support the role of arsenic on diabetes and the importance of controlling for seafood arsenicals in populations with high seafood intake. Suggestive arsenic-gene interactions require confirmation in larger studies

Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.

The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein-protein interaction networks to explore the biological relevance of the findings. At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345.This work was supported by grants by the National Heart, Lung, and Blood Institute (NHLBI) (under contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, & 75N92019D00030) and previous grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and cooperative agreements U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521), by the National Institute of Health Sciences (R01ES021367, R01ES025216, P42ES010349, P30ES009089), by the Spanish Funds for Research In Health Sciences, Carlos III Health Institute, co-funded by European Regional Development Fund (CP12/03080 and PI15/00071), by Chilean CONICYT/FONDECYT-POSTDOCTORADO Nº3180486 (A.L.R.-C) and a fellowship from “La Caixa” Foundation (ID 100010434). The fellowship code is “LCF/BQ/DR19/11740016.”S

Gene-environment interaction analysis of redox-related metals and genetic variants with plasma metabolic patterns in a general population from Spain: The Hortega Study

Background: Limited studies have evaluated the joint influence of redox-related metals and genetic variation on metabolic pathways. We analyzed the association of 11 metals with metabolic patterns, and the interacting role of candidate genetic variants, in 1145 participants from the Hortega Study, a population-based sample from Spain. Methods: Urine antimony (Sb), arsenic, barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), molybdenum (Mo) and vanadium (V), and plasma copper (Cu), selenium (Se) and zinc (Zn) were measured by ICP-MS and AAS, respectively. We summarized 54 plasma metabolites, measured with targeted NMR, by estimating metabolic principal components (mPC). Redox-related SNPs (N = 291) were measured by oligo-ligation assay. Results: In our study, the association with metabolic principal component (mPC) 1 (reflecting non-essential and essential amino acids, including branched chain, and bacterial co-metabolism versus fatty acids and VLDL subclasses) was positive for Se and Zn, but inverse for Cu, arsenobetaine-corrected arsenic (As) and Sb. The association with mPC2 (reflecting essential amino acids, including aromatic, and bacterial co-metabolism) was inverse for Se, Zn and Cd. The association with mPC3 (reflecting LDL subclasses) was positive for Cu, Se and Zn, but inverse for Co. The association for mPC4 (reflecting HDL subclasses) was positive for Sb, but inverse for plasma Zn. These associations were mainly driven by Cu and Sb for mPC1; Se, Zn and Cd for mPC2; Co, Se and Zn for mPC3; and Zn for mPC4. The most SNP-metal interacting genes were NOX1, GSR, GCLC, AGT and REN. Co and Zn showed the highest number of interactions with genetic variants associated to enriched endocrine, cardiovascular and neurological pathways. Conclusions: Exposures to Co, Cu, Se, Zn, As, Cd and Sb were associated with several metabolic patterns involved in chronic disease. Carriers of redox-related variants may have differential susceptibility to metabolic alterations associated to excessive exposure to metals.This work was supported by the Strategic Action for Research in Health sciences [CP12/03080, PI15/00071, PI10/0082, PI13/01848, PI14/00874, PI16/01402, PI21/00506 and PI11/00726], CIBER Fisio patología Obesidad y Nutrición (CIBEROBN) (CIBER-02-08-2009, CB06/03 and CB12/03/30,016), the State Agency for Research (PID2019-108973RB- C21 and C22), the Valencia Government (GRUPOS 03/101; PROMETEO/2009/029 and ACOMP/2013/039, IDI FEDER/2021/072 and GRISOLIAP/2021/119), the Castilla-Leon Government (GRS/279/A/08) and European Network of Excellence Ingenious Hypercare (EPSS-037093) from the European Commission. The Strategic Action for Research in Health sciences, CIBERDEM and CIBEROBN are initiatives from Carlos III Health Institute Madrid and cofunded with European Funds for Regional Development (FEDER). The State Agency for Research and Carlos III Health Institute belong to the Spanish Ministry of Science and Innovation. ADR received the support of a fellowship from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). MGP received the support of a fellowship from “la Caixa” Foundation (ID 100010434, fellowship code LCFLCF/BQ/DI18/11660001). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.S

Cadmium body burden and increased blood pressure in middle-aged American Indians: the Strong Heart Study

Cadmium (Cd) is an environmental pollutant that has been associated with cardiovascular disease in populations, but the relationship of Cd with hypertension has been inconsistent. We studied the association between urinary Cd concentrations, a measure of total body burden, and blood pressure in American Indians, a US population with above national average Cd burden. Urinary Cd was measured using inductively coupled plasma mass spectrometry, and adjusted for urinary creatinine concentration. Among 3714 middle-aged American Indian participants of the Strong Heart Study (mean age 56 years, 41% male, 67% ever-smokers, 23% taking antihypertensive medications), urinary Cd ranged from 0.01 to 78.48 μg g$^{-1}$ creatinine (geometric mean=0.94 μg g$^{-1}$) and it was correlated with smoking pack-year among ever-smokers (r$^{2}$=0.16, P<0.0001). Participants who were smokers were on average light-smokers (mean 10.8 pack-years), and urinary Cd was similarly elevated in light- and never-smokers (geometric means of 0.88 μg g$^{-1}$ creatinine for both categories). Log-transformed urinary Cd was significantly associated with higher systolic blood pressure in models adjusted for age, sex, geographic area, body mass index, smoking (ever vs never, and cumulative pack-years) and kidney function (mean blood pressure difference by lnCd concentration (β)=1.64, P=0.002). These associations were present among light- and never-smokers (β=2.03, P=0.002, n=2627), although not significant among never-smokers (β=1.22, P=0.18, n=1260). Cd was also associated with diastolic blood pressure among light- and never-smokers (β=0.94, P=0.004). These findings suggest that there is a relationship between Cd body burden and increased blood pressure in American Indians, a population with increased cardiovascular disease risk.This research is supported by the NHLBI HL123677-02 to NF and the NIEHS training grant (ES007141-32) to PB. MTP was supported by the Strategic Action for Research in Health sciences [CP12/03080], which is an initiatives from Carlos III Health Institute Madrid and the Spanish Ministry of Economy and Competitiveness and are co-funded with European Funds for Regional Development (FEDER)