Atherogenic Index as a Cardiovascular Biomarker in Mexican Workers from Marginalized Urban Areas Occupationally Exposed to Metals.

BACKGROUND: Cardiovascular disease (CVD) is one of the main causes of death and disability worldwide. The etiology of CVD is often associated with multiple risk factors, with environmental factors receiving considerable attention. Individuals with precarious jobs are among the groups most affected by chronic exposure to environmental pollutants. AIM: This study aimed to evaluate occupational exposure to heavy metals among individuals in precarious job settings and investigate atherogenic indices as biomarkers of cardiovascular risk. METHODS: A total of 137 workers participated in this cross-sectional study conducted in three work environments in San Luis Potosi, Mexico. Urine and blood samples were collected to assess metal exposure and biochemical profiles, including atherogenic indices. RESULTS: The results showed that workers in the brick sector exhibited the highest levels of metal exposure, particularly arsenic (44.06 µg/L), followed by stonecutters and garbage collectors (24.7 and 16.9 µg/L, respectively). Similarly, Castelli risk index (CRI) and the atherogenic index of plasma (AIP) were higher in brickmakers (3.883 and 0.499) compared to stonecutters (3.285 and 0.386) and garbage collectors (3.329 and 0.367). CONCLUSIONS: Evidence of exposure to heavy metals was observed in the three populations, in addition to the fact that individuals with greater exposure to arsenic also exhibited higher CRI and AIP.

Effect of an Arsenic Mitigation Program on Arsenic Exposure in American Indian Communities: A Cluster Randomized Controlled Trial of the Community-Led Strong Heart Water Study Program.

BACKGROUND: Chronic arsenic exposure has been associated with an increased risk of cardiovascular disease; diabetes; cancers of the lung, pancreas and prostate; and all-cause mortality in American Indian communities in the Strong Heart Study. OBJECTIVE: The Strong Heart Water Study (SHWS) designed and evaluated a multilevel, community-led arsenic mitigation program to reduce arsenic exposure among private well users in partnership with Northern Great Plains American Indian Nations. METHODS: A cluster randomized controlled trial (cRCT) was conducted to evaluate the effectiveness of the SHWS arsenic mitigation program over a 2-y period on a) urinary arsenic, and b) reported use of arsenic-safe water for drinking and cooking. The cRCT compared the installation of a point-of-use arsenic filter and a mobile Health (mHealth) program (3 phone calls; SHWS mHealth and Filter arm) to a more intensive program, which included this same program plus three home visits (3 phone calls and 3 home visits; SHWS Intensive arm). RESULTS: A 47% reduction in urinary arsenic [geometric mean (GM)=13.2 to 7.0µg/g creatinine] was observed from baseline to the final follow-up when both study arms were combined. By treatment arm, the reduction in urinary arsenic from baseline to the final follow-up visit was 55% in the mHealth and Filter arm (GM=14.6 to 6.55µg/g creatinine) and 30% in the Intensive arm (GM=11.2 to 7.82µg/g creatinine). There was no significant difference in urinary arsenic levels by treatment arm at the final follow-up visit comparing the Intensive vs. mHealth and Filter arms: GM ratio of 1.21 (95% confidence interval: 0.77, 1.90). In both arms combined, exclusive use of arsenic-safe water from baseline to the final follow-up visit significantly increased for water used for cooking (17% to 53%) and drinking (12% to 46%). DISCUSSION: Delivery of the interventions for the community-led SHWS arsenic mitigation program, including the installation of a point-of-use arsenic filter and a mHealth program on the use of arsenic-safe water (calls only, no home visits), resulted in a significant reduction in urinary arsenic and increases in reported use of arsenic-safe water for drinking and cooking during the 2-y study period. These results demonstrate that the installation of an arsenic filter and phone calls from a mHealth program presents a promising approach to reduce water arsenic exposure among private well users. https://doi.org/10.1289/EHP12548.

Trace element levels: How Substance Use Disorder (SUD) contributes to the alteration of urinary essential and toxic element levels.

Increasing illicit drug use is one of the main problems in most countries or societies. Monitoring heavy metals and trace elements in this vulnerable group seems to be necessary. Therefore, we assessed the urinary trace element and toxic metals/metalloids concentrations (Zinc (Zn), Iron (Fe), Copper (Cu), Chromium (Cr), Lead (Pb), Cadmium (Cd), Arsenic (As), Nickel (Ni), and Mercury (Hg)) in opium, tramadol, and cannabis users compared to healthy subjects. In this cross-sectional study, patients with substance use disorder (SUD) (n = 74) were divided into four groups: cannabis, tramadol, opium, and mixed (simultaneous use of more than one of the three studied substances), along with a healthy group (n = 60). Urine samples were prepared by dispersive liquid-liquid microextraction method so that heavy metals/metalloids could be measured by ICP-MS. The mean urinary concentration of Cu (48.15 vs. 25.45; 89.2%, p<0.001), Hg (1.3 vs. 0.10; 1200%, p < 0.001), and Zn (301.95 vs. 210; 43.8%, p < 0.001) was markedly lower among patients with SUD. The mean urinary concentration of other elements including As (1.9 vs. 4.1; 115.8%), Cd (0.1 vs. 1.10; 1000%), Cr (6.80 vs. 11.65; 71.3%), Ni (2.95 vs. 4.95; 67.8%), and Pb (1.5 vs. 7.9; 426.6%) were significantly higher among patients with SUD compared to healthy subjects. When sub-groups were compared, no significant differences were observed between their trace element levels (Kruskal-Wallis test, p > 0.05). This can be an indication that regardless of the type of drug, the levels of trace elements are changed with respect to healthy individuals. Our results showed that illicit drug use causes changes in urinary trace element/heavy metal/metalloid levels and highlights the need for monitoring heavy metals and trace elements in individuals with substance use disorder. Assessment of different elements in biological samples of drug dependents may be useful for implementing new prevention and treatment protocols. In case of changes in their levels, complementary recommendations, attention to diet, and periodic assessment of toxic metal levels within treatment programs will be needed.

[The study on biological exposure index of occupational exposure to arsenic and its inorganic compounds].

Objective: To establish biological exposure index (BEI) of occupational exposure to arsenic and its inorganic compounds through occupational epidemiology and the regression analysis of internal and external exposure of workers. Methods: In November 2021, 125 workers with occupational exposure to arsenic and its inorganic compounds and 49 office administrators in a non-ferrous metal smelter in Yunnan Province were selected as the exposure group and control group, respectively. Air samples from the workplace of the study subjects on weekdays were collected and arsenic concentrations were determined. Urine samples were collected in end-of-work weekend and high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) was used to detect the levels of trivalent inorganic arsenic (iAs(3+)) , pentavalent inorganic arsenic (iAs(5+)) , monomethyl arsenic (MMA) and dimethyl arsenic (DMA) in urine. The correlations between arsenic concentration in the workplace air and arsenic species in urine of workers were analyzed. Arsenic exposure concentration and the level of urinary arsenic (ΣiAs+MMA+DMA) of workers was analyzed by linear regression and the BEI of arsenic and its inorganic compounds in the workplace was proposed based on the results of micronucleus test. Results: The median of time-weighted average concentration (C(TWA)) of arsenic in the workplace air of the exposure group was 0.0116 mg/m(3), and the over-standard rate was 71.2% (89/125) . The concentrations of iAs(3+), iAs(5+), inorganic arsenic (iAs=ΣiAs(3+)+iAs(5+)) 、MMA、DMA and urinary arsenic in the exposure group were higher than those in the control group at the end of shift, and the differences were statistically significant (P<0.05) . The concentration of arsenic in the workplace air had the strongest correlation with the concentration of urinary arsenic at the end of the shift (r(s)=0.909, P<0.001) . The regression equation was lg (y) =7.662+2.968lg (x) (r=0.821, P<0.05) . According to the occupational exposure limit (OEL) of arsenic in China, the concentration of urinary arsenic in the end-of-work weekend was calculated to be 53.2 µg/L. Combined with the results of micronucleus test, the BEI of occupational exposure to arsenic and its inorganic compounds in the workplace was proposed to be 50 µg/L. Conclusion: The urinary arsenic in the end-of-work weekend can be used as a biomarker of occupational exposure to arsenic, and its BEI is recommended to be 50 µg/L.

[Correlation analysis of urinary arsenic species and health effect indicators of occupational arsenic exposure workers].

Objective: To explore the correlation between urinary arsenic and health effects through the determination and analysis of urinary arsenic levels in occupational arsenic exposed workers. Methods: In November 2021, 95 workers exposed to arsenic and its inorganic compounds and 31 administrative personnel from a non-ferrous metal smelter in Yunnan Province were selected as the contact group and control group, respectively. Urine forms of arsenic, blood tumor markers, liver function were detected, and micronucleus test was used to analyze the chromosome damage. The correlation between urine forms of arsenic and health effects were analyzed. Results: Compared with the control group, the concentrations of urinary trivalent inorganic arsenic (iAs(3+)) , pentavalent inorganic arsenic (iAs(5+)) , inorganic arsenic (iAs=ΣiAs(3+)+iAs(5+)) , monomethyl arsenic (MMA) , dimethyl arsenic (DMA) and urinary arsenic (ΣiAs+MMA+DMA) at the end of class in contact group were higher (P<0.05) . There was no statistically significant difference in blood tumor markers and liver function indicators between the two groups (P>0.05) . Compared with the control group, the peripheral blood micronucleus rate and cell micronucleus rate in the contact group were significantly increased (P<0.05) . The urinary arsenic, iAs(5+), inorganic arsenic and DMA were positively correlated with peripheral blood micronucleus rate in contact group (r(s)=0.48, 0.34, 0.37, 0.23, P<0.05) , and the urinary arsenic, iAs(5+), DMA were positively correlated with peripheral blood micronucleus rate (r(s)=0.48, 0.34, 0.26, P<0.05) . Conclusion: There is a significant correlation between different valence states of arsenic in the urine and abnormal health effects of occupational arsenic exposed workers. It is necessary to strengthen the detection of arsenic species in the urine of occupational arsenic exposed workers to better protect their health.

Associations of urinary metal concentrations with anemia: A cross-sectional study of Chinese community-dwelling elderly.

BACKGROUND: Anemia seriously affects the health and quality of life of the older adult population and may be influenced by various types of environmental metal exposure. Current studies on metals and anemia are mainly limited to single metals, and the association between polymetals and their mixtures and anemia remains unclear. METHODS: We determined 11 urinary metal concentrations and hemoglobin levels in 3781 participants. Binary logistic regression and restricted cubic spline (RCS) model were used to estimate the association of individual metals with anemia. We used Bayesian kernel machine regression (BKMR) and Quantile g-computation (Q-g) regression to assess the overall association between metal mixtures and anemia and identify the major contributing elements. Stratified analyses were used to explore the association of different metals with anemia in different populations. RESULTS: In a single-metal model, nine urinary metals significantly associated with anemia. RCS analysis further showed that the association of arsenic (As) and copper (Cu) with anemia was linear, while cobalt, molybdenum, thallium, and zinc were non-linear. The BKMR model revealed a significant positive association between the concentration of metal mixtures and anemia. Combined Q-g regression analysis suggested that metals such as Cu, As, and tellurium (Te) were positively associated with anemia, with Te as the most significant contributor. Stratified analyses showed that the association of different metals with anemia varied among people of different sexes, obesity levels, lifestyle habits, and blood pressure levels. CONCLUSIONS: Multiple metals are associated with anemia in the older adult population. A significant positive association was observed between metal mixture concentrations and anemia, with Te being the most important factor. The association between urinary metal concentrations and anemia is more sensitive in the non-hypertensive populations.

Method validation for (ultra)-trace element concentrations in urine for small sample volumes in large epidemiological studies: application to the population-based epidemiological multi-ethnic study of atherosclerosis (MESA).

Analysis of essential and non-essential trace elements in urine has emerged as a valuable tool for assessing occupational and environmental exposures, diagnosing nutritional status and guiding public health and health care intervention. Our study focused on the analysis of trace elements in urine samples from the Multi-Ethnic Study of Atherosclerosis (MESA), a precious resource for health research with limited sample volumes. Here we provide a comprehensive and sensitive method for the analysis of 18 elements using only 100 µL of urine. Method sensitivity, accuracy, and precision were assessed. The analysis by inductively coupled plasma mass spectrometry (ICP-MS) included the measurement of antimony (Sb), arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), cobalt (Co), copper (Cu), gadolinium (Gd), lead (Pb), manganese (Mn), molybdenum (Mo), nickel (Ni), selenium (Se), strontium (Sr), thallium (Tl), tungsten (W), uranium (U), and zinc (Zn). Further, we reported urinary trace element concentrations by covariates including gender, ethnicity/race, smoking and location. The results showed good accuracy and sensitivity of the ICP-MS method with the limit of detections rangings between 0.001 µg L-1 for U to 6.2 µg L-1 for Zn. Intra-day precision for MESA urine analysis varied between 1.4% for Mo and 26% for Mn (average 6.4% for all elements). The average inter-day precision for most elements was <8.5% except for Gd (20%), U (16%) and Mn (19%) due to very low urinary concentrations. Urinary mean concentrations of non-essential elements followed the order of Sr > As > Cs > Ni > Ba > Pb > Cd > Gd > Tl > W > U. The order of urinary mean concentrations for essential trace elements was Zn > Se > Mo > Cu > Co > Mn. Non-adjusted mean concentration of non-essential trace elements in urine from MESA participants follow the order Sr > As > Cs > Ni > Ba > Pb > Cd > Gd > Tl > W > U. The unadjusted urinary mean concentrations of essential trace elements decrease from Zn > Se > Mo > Cu > Co > Mn.

Exposure of environmental trace elements in prostate cancer patients: A multiple metal analysis.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men. To elucidate the connection between trace elements (arsenic: As, cadmium: Cd, lead: Pb, chromium: Cr, and nickel: Ni) and the risk of PCa, we analyzed trace element levels in the serum, urine, and tissues of PCa patients, while also examining their smoking status. We correlated these levels with their smoking habits. Notably, levels of Cd (P ≤ 0.05) and As (P ≤ 0.01) were significantly higher in the tumor tissue than in adjacent tissues. No significant differences were observed in the levels of Pb, Cr and Ni. Additionally, urinary Cd levels in 70% and arsenic levels in 2.3% of the PCa cohort were markedly higher than the CDC-reported cutoff (Cd ≤ 0.185 µg/L & As ≤100 µg/L). None displayed elevated levels of urinary Pb, Cr, and Ni. Conversely, in serum samples, the concentration of arsenic exceeded the CDC-determined limit (As ≤1.0 µg/L) in 31.69% of PCa patients. However, only 7.04% of patients had higher serum Cd levels than the CDC standard values (Cd ≤ 0.315 µg/L), while all PCa patients exceeded the Cr CDC limit (Cr ≤ 0.16 µg/L) and the Ni CDC limit (Ni ≤ 0.2 µg/L). On the contrary, no significant differences were observed in serum Pb (Pb ≤ 35.0 µg/L). Our findings establish a positive link between Cd and arsenic tissue concentrations and the risk of PCa. Subsequent studies are essential to determine whether elevated trace element levels pose a risk for the development of prostate carcinogenesis. Interestingly, among the PCa cohort comprising smokers, notably higher Cd levels were observed only in tumor tissues (P ≤ 0.01) and urine (P ≤ 0.05) compared to other elements or in other specimens.

Arsenic exposure was associated with lung fibrotic changes in individuals living near a petrochemical complex.

Individuals residing near petrochemical complexes have been found to have increasing the risk of respiratory distress and diseases. On visit 1 in 2016, all participants underwent urinary arsenic measurement and low-dose computed tomography (LDCT). The same participants had LDCT performed at visit 2 in 2018. Our study revealed that individuals with lung fibrotic changes had significantly higher levels of urinary arsenic compared to the non-lung fibrotic changes group. Moreover, we found that participants with urinary arsenic levels in the highest sextile (> 209.7 µg/g creatinine) had a significantly increased risk of lung fibrotic changes in both visit 1 (OR = 1.87; 95% CI= 1.16-3.02; P = 0.010) and visit 2 (OR = 1.74; 95% CI = 1.06-2.84; P = 0.028) compared to those in the lowest sextile (≤ 41.4 µg/g creatinine). We also observed a significantly increasing trend across urinary arsenic sextile in both visits (Ptrend = 0.015 in visit 1 and Ptrend = 0.026 in visit 2). Furthermore, participants with urinary arsenic levels in the highest sextile had a significantly increased risk of lung fibrotic positive to positive (OR = 2.18; 95% CI: 1.24, 3.82; P = 0.007) compared to the lowest sextile (reference category: lung fibrotic negative to negative). Our findings provide support for the hypothesis that arsenic exposure is significantly associated with an increased risk of lung fibrotic changes. It is advisable to reduce the levels of arsenic exposure for those residing near such petrochemical complexes.

Association between mediterranean diet and metal(loid) exposure in 4-5-year-old children living in Spain.

Even relatively low levels of metals exposure may impact health, particularly among vulnerable populations such as infants and young children. However, little is known about the interplay between simultaneous metal exposures, common in real-life scenarios, and their association with specific dietary patterns. In this study, we have evaluated the association between adherence to Mediterranean diet (MD) and urinary metal concentrations individually and as an exposure mixture in 713 children aged 4-5-years from the INMA cohort study. We used a validated food frequency questionnaire to calculate two MD indexes scores: aMED and rMED. These indexes gather information on various food groups within the MD and score differently. To measure urinary concentrations of cobalt, copper, zinc, molybdenum, selenium, lead, and cadmium as exposure biomarkers, we used inductively coupled plasma mass spectrometry (ICP-MS), coupled with an ion chromatography (IC) equipment for arsenic speciation analysis. We applied linear regression and quantile g-computation, adjusted for confounders, to analyse the association between MD adherence and exposure to the metal mixture. High adherence to MD such as the quintile (Q) 5 MD was associated with higher urinary arsenobetaine (AsB) levels than Q1, with ß values of 0.55 (confidence interval - CI 95% 0.01; 1.09) for aMED and 0.73 (CI 95% 0.13; 1.33) for rMED. Consumption of fish was associated with increased urinary AsB but reduced inorganic arsenic concentrations. In contrast, the aMED vegetables consumption increased urinary inorganic arsenic content. A moderate level of adherence to MD (Q2 and Q3) was associated with lower copper urinary concentrations than Q1, with ß values of -0.42 (CI 95% -0.72; -0.11) for Q2 and -0.33 (CI 95% -0.63; -0.02) for Q3, but only with aMED. Our study, conducted in Spain, revealed that adhering to the MD reduces exposure to certain metals while increasing exposure to others. Specifically, we observed increase in exposure to non-toxic AsB, highlighting the significance of consuming fish/seafood. However, it is crucial to emphasize the necessity for additional efforts in reducing early-life exposure to toxic metals, even when adhering to certain food components of the MD.

Metabolic biomarkers linking urinary arsenic species to gestational diabetes mellitus: A cross-sectional study in Chinese pregnant women.

Environmental arsenic (As) exposure has been associated with gestational diabetes mellitus (GDM) risk. Our recent study found that GDM was positively associated with urinary As3+ level while negatively correlated to As5+. However, the mechanisms underlying the association between arsenic species and GDM remain largely unknown. In the present study, through the measurement of urinary arsenic species and metabolome analysis in 399 pregnant women, we aimed to identify the metabolic biomarkers that may link arsenic exposure to GDM based on a novel systems epidemiology strategy termed meet-in-metabolite-analysis (MIMA). The metabolomics analysis revealed that 20 and 16 urinary metabolites were relevant to arsenic exposure and GDM, respectively. Among them, 12 metabolites were identified to be both arsenic- and GDM-related, which are mainly involved in purine metabolism, one­carbon metabolism (OCM) and glycometabolism. Moreover, it was further showed that the regulation of thiosulfate (AOR: 2.52; 95 % CI: 1.33, 4.77) and phosphoroselenoic acid (AOR: 2.35; 95 % CI: 1.31, 4.22) could significantly contribute to the negative association between As5+ and GDM. Considering the biological functions of these metabolites, it is suggested that As5+ may reduce GDM risk by disturbing OCM in the pregnant women. These data will provide novel insights into the mechanism of action of environmental arsenic exposure on GDM incidence from the aspect of metabolism disorder.

Comparison of the accumulation of toxic metal biomarkers in Asian subgroups and other races in the United States: NHANES 2015-2016.

Toxic metals such as lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) that lead to many visceral organ and nervous system diseases have attracted global attention due to their gradual accumulation in human bodies. The tolerance levels of exposure to toxic metals among race/ethnic groups are different due to the variance of sociodemographic, dietary, and behavioral characteristics. Few studies focused on investigating the biomarker levels of toxic metals in different race/ethnic groups and the potential mechanisms for controlling the accumulation in human bodies. Therefore, we selected eight biomarkers for four toxic metals from the National Health and Nutrition and Examination Survey (NHANES) in the 2-year data cycle of 2015-2016 to reveal the accumulation levels in different races. According to the NHANES rules, we applied probability sampling weights. The geometric mean levels of these biomarkers were calculated in all five race/ethnic groups (Mexican American, white, black, Asian, and other Hispanic) and two Asian subgroups (U.S.-born Asian, and other-born Asian), and compared with each other. The results showed that all the biomarkers in other-born Asians were 1.1-6.7 times in blood and 1.1-3.6 times in urine higher than other race/ethnic groups. Except Hg and As, the lowest biomarker levels were recorded in U.S.-born Asians, only 0.6-0.9 times of lead and 0.3-0.8 times of cadmium than other race/ethnic groups. Furthermore, the major factors of higher Hg and As biomarker levels in Asians were dietary intake of seafood and rice, indicating different accumulation mechanisms among Asians and other race/ethnic groups, especially for U.S.-born Asians. These findings provided new insight into a deeper understanding the accumulation of toxic metals and human health.

The variability of arsenic in blood and urine of humans.

BACKGROUND: Humans are exposed to inorganic and organic arsenic. The total arsenic (As) concentration in urine is a commonly used biomarker of exposure. However, little is known about variability of As in biological fluids and the diurnal variation of As excretion. OBJECTIVES: Main objectives were to assess the variability of As in urine, plasma (P-As), whole blood (B-As), and the blood cell fraction (C-As), and to assess diurnal variation of As excretion. METHODS: Six urine samples were collected at fixed times during 24 h on two different days around one week apart among 29 men and 31 women. Blood samples were collected when the morning urine samples were delivered. The intra-class correlation coefficient (ICC) was calculated as the ratio of the between-individuals variance to the total observed variance. RESULTS: Geometric mean (GM) 24 h urinary excretions of As (U-As24 h) were 41 and 39 µg/24 h on the two days of sampling. Concentrations of B-As, P-As and C-As were highly correlated with U-As24 h and As in first void morning urine. No statistically significant differences were observed for the urinary As excretion rate between the different sampling times. A high ICC was observed for As in the cellular blood fraction (0.803), while ICC for first morning urine corrected for creatine was low (0.316). CONCLUSIONS: The study suggests that C-As is the most reliable biomarker for use in exposure assessment of individual exposure. Morning urine samples have low reliability for such use. No apparent diurnal variation was observed in the urinary As excretion rate.

Association of urinary exposure to multiple metal(loid)s with kidney function from a national cross-sectional study.

BACKGROUND: Arsenic (As), cadmium (Cd) and copper (Cu) are hazardous for kidney function, while the effects of selenium (Se) and zinc (Zn) were unexplored for the narrow safe range of intake. Interactions exists between these multiple metal/metalloid exposures, but few studies have investigated the effects. METHODS: A cross-sectional survey was performed among 2210 adults across twelve provinces in China between 2020 and 2021. Urinary As, Cd, Cu, Se and Zn were measured using inductively coupled plasma-mass spectrometry (ICP-MS). Serum creatinine (Scr) and N-acetyl-beta-D glucosaminidases (urine NAG) were quantified in serum and urine, respectively. Kidney function was evaluated by the estimated glomerular filtration rate (eGFR). We employed logistic regression and Bayesian kernel machine regression (BKMR) models to explore the individual and joint effects of urinary metals/metalloids on the risk of impaired renal function (IRF) or chronic kidney disease (CKD), respectively. RESULTS: Association was found between As (OR = 1.24, 95 % CI: 1.03, 1.48), Cd (OR = 1.65, 95 % CI: 1.35, 2.02), Cu (OR = 1.90, 95 % CI: 1.59, 2.29), Se (OR = 1.51, 95 % CI: 1.24, 1.85) and Zn (OR = 1.33, 95 % CI: 1.09, 1.64) and the risk of CKD. Moreover, we observed association between As (OR = 1.18, 95 % CI: 1.07, 1.29), Cu (OR = 1.14, 95 % CI: 1.04, 1.25), Se (OR = 1.15, 95 % CI: 1.06, 1.26) and Zn (OR = 1.12, 95 % CI: 1.02, 1.22) and the risk of IRF. Additionally, it was found that Se exposure may strength the association of urinary As, Cd and Cu with IRF. Furthermore, it is worth noting that Se and Cu contributed greatest to the inverse association in IRF and CKD, respectively. CONCLUSION: Our findings suggested that metal/metalloid mixtures were associated with kidney dysfunction, Se and Cu were inverse factors. Additionally, interactions between them may affect the association. Further studies are needed to assess the potential risks for metal/metalloid exposures.

Prenatal arsenic exposure, arsenic metabolism and neurocognitive development of 2-year-old children in low-arsenic areas.

BACKGROUND: There is limited evidence on the effects of arsenic species and metabolic capacity on child neurodevelopment, particularly at low levels. Further, little is known about the critical window of exposure. OBJECTIVE: To estimate the associations of arsenic exposure and arsenic metabolism in different pregnancy periods with neurodevelopment of two-year-old children. METHODS: Concentrations of arsenobetaine (AsB), arsenite, arsenate, monomethyl arsenic acid (MMA), and dimethyl arsenic acid (DMA) in urine samples collected in three trimesters from 1006 mothers were measured using HPLC - ICPMS. Inorganic arsenic (iAs) was calculated as the sum of arsenite and arsenate. Total arsenic (tAs) was calculated as the sum of iAs, MMA and DMA. Child neurodevelopment was assessed with the Bayley Scales of Infant Development. RESULTS: The geometric mean (GM) of SG-adjusted tAs in the first, second, third trimester was 16.37, 12.94, 13.04 µg/L, respectively. The mental development index (MDI) score was inversely associated with iAs and tAs. Compared to the 1st quartile, the MDI score decreased 0.43 (95%CI: -4.22, 3.36) for the 2nd, 6.50 (95%CI: -11.73, -1.27) for the 3rd, 5.42 (95%CI: -10.74, -0.10) for the 4th quartiles of iAs, and decreased 4.03 (95%CI: -7.90, -0.15) in the 4th quartile of tAs. In trimester-specific models, negative associations of DMA [-1.94 (95%CI: -3.18, -0.71)] and tAs [-1.61 (95%CI: -3.02, -0.20)] with the psychomotor development index (PDI) were only observed in 1st trimester. CONCLUSIONS: Our study found inverse associations between prenatal arsenic exposure, especially in early pregnancy, and neurodevelopment of children at two years old, even at low exposure levels.

The Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population.

BACKGROUND: Chronic arsenic (As) exposure is a global environmental health issue. Inorganic As (InAs) undergoes methylation to monomethyl (MMAs) and dimethyl-arsenical species (DMAs); full methylation to DMAs facilitates urinary excretion and is associated with reduced risk for As-related health outcomes. Nutritional factors, including folate and creatine, influence one-carbon metabolism, the biochemical pathway that provides methyl groups for As methylation. OBJECTIVE: Our aim was to investigate the effects of supplementation with folic acid (FA), creatine, or the two combined on the concentrations of As metabolites and the primary methylation index (PMI: MMAs/InAs) and secondary methylation index (SMI: DMAs/MMAs) in blood in Bangladeshi adults having a wide range of folate status. METHODS: In a randomized, double-blinded, placebo (PBO)-controlled trial, 622 participants were recruited independent of folate status and assigned to one of five treatment arms: a) PBO (n=102), b) 400µg FA/d (400FA; n=153), c) 800µg FA/d (800FA; n=151), d) 3g creatine/d (creatine; n=101), or e) 3g creatine+400µg of FA/d (creatine+400FA; n=103) for 12 wk. For the following 12 wk, half of the FA participants were randomly switched to the PBO while the other half continued FA supplementation. All participants received As-removal water filters at baseline. Blood As (bAs) metabolites were measured at weeks 0, 1, 12, and 24. RESULTS: At baseline, 80.3% (n=489) of participants were folate sufficient (≥9 nmol/L in plasma). In all groups, bAs metabolite concentrations decreased, likely due to filter use; for example, in the PBO group, blood concentrations of MMAs (bMMAs) (geometric mean±geometric standard deviation) decreased from 3.55±1.89µg/L at baseline to 2.73±1.74 at week 1. After 1 wk, the mean within-person increase in SMI for the creatine+400FA group was greater than that of the PBO group (p=0.05). The mean percentage decrease in bMMAs between baseline and week 12 was greater for all treatment groups compared with the PBO group [400FA: -10.4 (95% CI: -11.9, -8.75), 800FA: -9.54 (95% CI: -11.1, -7.97), creatine: -5.85 (95% CI: -8.59, -3.03), creatine+400FA: -8.44 (95% CI: -9.95, -6.90), PBO: -2.02 (95% CI: -4.03, 0.04)], and the percentage increase in blood DMAs (bDMAs) concentrations for the FA-treated groups significantly exceeded that of PBO [400FA: 12.8 (95% CI: 10.5, 15.2), 800FA: 11.3 (95% CI: 8.95, 13.8), creatine+400FA: 7.45 (95% CI: 5.23, 9.71), PBO: -0.15 (95% CI: -2.85, 2.63)]. The mean decrease in PMI and increase in SMI in all FA groups significantly exceeded PBO (p<0.05). Data from week 24 showed evidence of a reversal of treatment effects on As metabolites from week 12 in those who switched from 800FA to PBO, with significant decreases in SMI [-9.0% (95% CI: -3.5, -14.8)] and bDMAs [-5.9% (95% CI: -1.8, -10.2)], whereas PMI and bMMAs concentrations continued to decline [-7.16% (95% CI: -0.48, -14.3) and -3.1% (95% CI: -0.1, -6.2), respectively] for those who remained on 800FA supplementation. CONCLUSIONS: FA supplementation lowered bMMAs and increased bDMAs in a sample of primarily folate-replete adults, whereas creatine supplementation lowered bMMAs. Evidence of the reversal of treatment effects on As metabolites following FA cessation suggests short-term benefits of supplementation and underscores the importance of long-term interventions, such as FA fortification. https://doi.org/10.1289/EHP11270.

[Association between urinary arsenic level and serum testosterone in Chinese men aged 18 to 79 years].

Objective: To investigate the association between the urinary arsenic level and serum total testosterone in Chinese men aged 18 to 79 years. Methods: A total of 5 048 male participants aged 18 to 79 years were recruited from the China National Human Biomonitoring (CNHBM) from 2017 to 2018. Questionnaires and physical examinations were used to collect information on demographic characteristics, lifestyle, food intake frequency and health status. Venous blood and urine samples were collected to detect the level of serum total testosterone, urinary arsenic and urinary creatinine. Participants were divided into three groups (low, middle, and high) based on the tertiles of creatinine-adjusted urinary arsenic concentration. Weighted multiple linear regression was fitted to analyze the association of urinary arsenic with serum total testosterone. Results: The weighted average age of 5 048 Chinese men was (46.72±0.40) years. Geometric mean concentration (95%CI) of urinary arsenic, creatinine-adjusted urinary arsenic and serum testosterone was 22.46 (20.08, 25.12) µg/L, 19.36 (16.92, 22.15) µg/g·Cr and 18.13 (17.42, 18.85) nmol/L, respectively. After controlling for covariates, compared with the low-level urinary arsenic group, the testosterone level of the participants in the middle-level group and the high-level group decreased gradually. The percentile ratio (95%CI) was -5.17% (-13.14%, 3.54%) and -10.33% (-15.68%, -4.63). The subgroup analysis showed that the association between the urinary arsenic level and testosterone level was more obvious in the group with BMI<24 kg/m2 group (Pinteraction=0.023). Conclusion: There is a negative association between the urinary arsenic level and serum total testosterone in Chinese men aged 18 to 79 years.

Maternal DNA methylation signatures of arsenic exposure is associated with adult offspring insulin resistance in the Strong Heart Study.

Exposure to low to moderate arsenic (As) levels has been associated with type 2 diabetes (T2D) and other chronic diseases in American Indian communities. Prenatal exposure to As may also increase the risk for T2D in adulthood, and maternal As has been associated with adult offspring metabolic health measurements. We hypothesized that T2D-related outcomes in adult offspring born to women exposed to low to moderate As can be evaluated utilizing a maternally-derived molecular biosignature of As exposure. Herein, we evaluated the association of maternal DNA methylation with incident T2D and insulin resistance (Homeostatic model assessment of insulin resistance [HOMA2-IR]) in adult offspring. For DNA methylation, we used 20 differentially methylated cytosine-guanine dinucleotides (CpG) previously associated with the sum of inorganic and methylated As species (ΣAs) in urine in the Strong Heart Study (SHS). Of these 20 CpGs, we found six CpGs nominally associated (p < 0.05) with HOMA2-IR in a fully adjusted model that included clinically relevant covariates and offspring adiposity measurements; a similar model that adjusted instead for maternal adiposity measurements found three CpGs nominally associated with HOMA2-IR, two of which overlapped the offspring adiposity model. After adjusting for multiple comparisons, cg03036214 remained associated with HOMA2-IR (q < 0.10) in the offspring adiposity model. The odds ratio of incident T2D increased with an increase in maternal DNA methylation at one HOMA2-IR associated CpG in the model adjusting for offspring adiposity, cg12116137, whereas adjusting for maternal adiposity had a minimal effect on the association. Our data suggests offspring adiposity, rather than maternal adiposity, potentially influences the effects of maternal DNAm signatures on offspring metabolic health parameters. Here, we have presented evidence supporting a role for epigenetic biosignatures of maternal As exposure as a potential biomarker for evaluating risk of T2D-related outcomes in offspring later in life.

Chronic Kidney Disease: Combined Effects of Gene Polymorphisms of Tissue Inhibitors of Metalloproteinase 3, Total Urinary Arsenic, and Blood Lead Concentration.

The tissue inhibitor of metalloproteinase 3 (TIMP3) is known to be an anti-fibrotic factor. Arsenic, lead, and cadmium exposure and selenium intake may affect TIMP3 expression. The downregulation of TIMP3 expression is related to kidney fibrosis. Genotypes of TIMP3 are related to hypertension and cardiovascular diseases. Therefore, this study explored whether TIMP3 polymorphism is associated with hypertension-related chronic kidney disease (CKD). In addition, the combined effects of TIMP3 polymorphism and total urinary arsenic, blood lead and cadmium, and plasma selenium concentrations on CKD, were investigated. This was a case-control study, with 213 CKD patients and 423 age- and sex-matched controls recruited. Polymerase chain reaction-restriction fragment length polymorphism was used to determine TIMP3 gene polymorphisms. The concentrations of urinary arsenic species, plasma selenium, and blood lead and cadmium were measured. The odds ratio (OR) of CKD in the TIMP3rs9609643 GA/AA genotype was higher than that of the GG genotype at high levels of total urinary arsenic and blood lead; the OR and 95% confidence interval (CI) were 0.57 (0.31-1.05) and 0.52 (0.30-0.93), respectively, after multivariate adjustment. High blood lead levels tended to interact with the TIMP3rs9609643 GG genotype to increase the OR of CKD, and gave the highest OR (95% CI) for CKD of 5.97 (2.60-13.67). Our study supports a possible role for the TIMP3rs9609643 risk genotype combined with high total urinary arsenic or with high blood lead concentration to increase the OR of CKD.