Total Urinary Arsenic Research Articles

Long-term effects of arsenic on glucose-insulin homeostasis: A gene-environment interaction study

Abstract Background Arsenic exposure and genetic factors are associated with an increased risk of type 2 diabetes, yet study of environment-gene interaction on glucose-insulin homeostasis remains scarce. We aimed to investigate the associations and interactions of urinary total arsenic (UTAs) and genetic susceptibility with glucose-insulin homeostasis through a longitudinal epidemiological study. Methods A total of 6136 observations (3063 participants) from the baseline, 3-year follow-up, and 6-year follow-up of the Wuhan-Zhuhai cohort were included in this study. In each study period, we repeatedly measured UTAs, fasting plasma glucose (FPG), fasting plasma insulin (FPI), and homeostasis model-assessed insulin resistance (HOMA-IR) and β-cell function (HOMA-β). Polygenic risk scores (PRSs) specific for all traits were constructed by corresponding genome-wide association summary statistics. Linear mixed models were used to assess associations and interactions of UTAs and PRSs with four indicators of glucose-insulin homeostasis. Results After adjustment for all covariates, the βs (95% CIs) for the annual growth rates of FPG, FPI, and HOMA-IR were 0.020 (0.008, 0.032), 0.007 (0.002, 0.013), and 0.011 (0.004, 0.017), respectively, associated with each ln-unit increase in UTAs. Compared to subjects with the first-quartile PRS and low UTAs, participants with the fourth-quartile PRS and high UTAs had a 0.029 (0.012, 0.047) or 0.032 (0.012, 0.051) ln-unit increase in the annual growth rate of FPI or HOMA-IR, respectively. UTAs and PRS had significant interactions on the longitudinal progressive increases of FPI and HOMA-IR (P interaction < 0.05). Conclusions Arsenic exposure and genetic variants are significantly synergistic risk factors for dysregulation and progressive deterioration of glucose-insulin homeostasis. Our findings emphasize the importance of reducing arsenic exposure to maintain normal glucose-insulin metabolism, especially for those at higher genetic risk. Key messages • Arsenic exposure was associated with annual increased rates of FPG, FPI, and HOMA-IR. • Arsenic exposure and trait-specific PRSs are synergistic risk factors for glucose-insulin homeostasis impairment.

Associations among global long interspersed nuclear element-1 DNA methylation, metal exposure, and chronic kidney disease.

Long interspersed nuclear element-1 (LINE-1) methylation serves as an indicator of global DNA methylation. This study explored the correlation between LINE-1 methylation and chronic kidney disease (CKD). We also evaluated whether LINE-1 methylation could modify the association between CKD and metal exposure. A total of 213 patients with clinically defined CKD, without hemodialysis and 416 age and sex matched controls were recruited. Levels of LINE-1 methylation, total urinary arsenic, blood lead, blood cadmium, and plasma selenium were assessed. The results reveal a positive association between LINE-1 methylation and CKD, with an odds ratio (OR) of 5.30 (95% confidence interval: 2.81 to 9.99). Total urinary arsenic and blood cadmium concentrations were positively related with LINE-1 methylation. This study was the first to observe that low plasma selenium, high blood cadmium, and high blood lead levels significantly and additively interact with increased LINE-1 methylation to increase the OR of CKD. Additionally, high LINE-1 methylation interacted multiplicatively with low plasma selenium to increase the OR of CKD (p < 0.001). This study highlighted the significant association between LINE-1 hypermethylation and CKD. Furthermore, the results demonstrate that LINE-1 methylation can interact with high blood cadmium or low plasma selenium to affect CKD risk.

Influence of folic acid and vitamin B12 supplementation on arsenic methylation: A double-blinded, placebo-controlled trial in Bangladeshi children

BackgroundInorganic arsenic is metabolized to monomethyl- (MMAs) and dimethyl- (DMAs) species via one-carbon metabolism (OCM); this facilitates urinary arsenic elimination. OCM is influenced by folate and vitamin B12 and previous randomized control trials (RCTs) showed that folic acid (FA) supplementation increases arsenic methylation in adults. This RCT investigated the effects of FA + B12 supplementation on arsenic methylation in children, a key developmental stage where OCM supports growth. MethodsA total of 240 participants (8–11 years, 53 % female) drinking from wells with arsenic concentrations > 50 μg/L, were encouraged to switch to low arsenic wells and were randomized to receive 400 μg FA + 5 μg B12 or placebo daily for 12-weeks. Urine and blood samples were collected at baseline, week 1 (only urine) and week 12. Generalized estimated equation (GEE) models were used to assess treatment effects on arsenic species in blood and urine. ResultsAt baseline, the mean ± SD total blood and urinary arsenic were 5.3 ± 2.9 μg/L and 91.2 ± 89.5 μg/L. Overall, total blood and urine arsenic decreased by 11.7% and 17.6%, respectively, at the end of follow up. Compared to placebo, the supplementation group experienced a significant increase in the concentration of blood DMAs by 14.0% (95% CI 5.0, 25.0) and blood secondary methylation index (DMAs/MMAs) by 0.19 (95% CI: 0.09, 0.35) at 12 weeks. Similarly, there was a 1.62% (95% CI: 0.43, 20.83) significantly higher urinary %DMAs and −1.10% (95% CI: −1.73, −0.48) significantly lower urinary %MMAs in the supplementatio group compared to the placebo group after 1 week. The direction of the changes in the urinary %iAs, %MMAs, and %DMAs at week 12 were consistent with those at week 1, though estimates were not significant. Treatment effects were stronger among participants with higher baseline blood arsenic concentrations. Results were consistent across males and females, and participants with higher and lower folate and B12 status at baseline. ConclusionThis RCT confirms that FA + B12 supplementation increases arsenic methylation in children as reflected by decreased MMAs and increased DMAs in blood and urine. Nutritional interventions may improve arsenic methylation and elimination in children, potentially reducing arsenic toxicity while also improving nutritional status.

Interplay of arsenic exposure and cigarette smoking on oxidative DNA damage in healthy males

BackgroundLong-term exposure to inorganic arsenic (As) and cigarette smoking has been associated with adverse health effects such as cancer, cardiovascular disease, and respiratory disease. Oxidative stress is one of the most well-known damage mechanisms for both. However, studies on the association with induced 8-hydroxy-2-deoxyguanosine (8-OHdG) in Iran are scarce, with no study on the interactive effect of As exposure and smoking in the literature.ObjectiveThis stratified cross-sectional study aimed to assess urinary and serum 8-OHdG levels in the relation to As exposure from drinking water, smoking and their interaction effect.MethodsThis study was based on 132 healthy male subjects living in villages of Hashtroud County, Iran (2021). All participants were categorized into four groups: (i) non-As exposed, never smokers (n = 33); (ii) non-As exposed, active smokers (n = 33); (iii) As exposed, never smokers (n = 33); and (iv) As exposed, active smokers (n = 33). Data on demographic and lifestyle factors were collected, and urinary and serum levels of 8-OHdG were determined by enzyme-linked immunosorbent assay (ELISA). The smoker's daily cigarette consumption and the duration of smoking were self-reported data.ResultsParticipants consuming drinking water with an As concentration > 10 µg/L had significantly higher urinary total arsenic (U-tAs) concentrations (median 26.96, IQR 21.35–37.17) µg/g Cr compared to the reference group (median 19.33, IQR 17.29–23.26) µg/g Cr. There was a significant difference in the serum concentration of 8-OHdG between groups (i) and (iii), (iv) and also between groups (ii) and (iv). We did not find a significant interaction effect of As exposure and smoking on the both urinary and serum 8-OHdG levels (P > 0.05). Serum 8-OHdG (S-8OHdG) was associated with average daily intake of As (As-ADI) (β = 0.32; 95% CI 0.01, 0.04, P-value = 0.001) and cigarettes smoked per day (β = 0.3; 95% CI 0.00, 0.043, P-value = 0.046). While As-ADI (β = 0.16; 95% CI 0.001, 0.004, P-value = 0.01) and U-tAs (β = 0.6; 95% CI 0.006, 0.009, P-value < 0.001) were associated with increased urinary 8-OHdG (U-8OHdG), moderate physical activity (β = − 0.15; 95% CI − 0.07, − 0.008, P-value < 0.015) inversely decreased biomarker levels.ConclusionOur findings suggest that As exposure and smoking are potential risk factors for oxidative DNA damage, and it is strongly recommended to pay more attention to the role of lifestyle factors in future studies.

Associations of Urinary Total Arsenic and Arsenic Species and Periodontitis

AimsArsenic exposure is a significant global public health concern and has been implicated in endocrine disruption and increased oxidative stress, both of which are crucial pathogenic mechanisms of periodontitis. This study aimed to investigate the association of urinary total arsenic and arsenic species with periodontitis and to further explore the potential mediating roles of sex hormones and oxidative stress indicators. MethodsData used in this study were derived from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) in the US population. In all, 1063 participants with complete data were included in this study. Weighted logistic regression analyses were used to evaluate the relationship between urinary arsenic and periodontitis. Mediation analyses were used to explore the effects of potential mediators on these associations. ResultsHigh concentrations of urinary dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), 2 types of toxic urinary arsenic (TUA2), and 4 types of toxic urinary arsenic (TUA4) were positively related to periodontitis (P < .05). After adjusting for potential confounders, the positive association remained significant (odds ratio, 1.32; 95% confidence interval, 1.01–1.71). Testosterone may partially mediate the relationship between MMA and periodontitis, with mediating effects of 21.78% and 39.73% of the total effect. No significant mediation effect of oxidative stress indicators was found for this relationship. ConclusionsThis study reports a positive association between urinary MMA and periodontitis, and testosterone may mediate this relationship. Our findings serve as a call for action to avoid the deployment of arsenic-containing therapeutic agents as treatment modalities for oral afflictions.

Analysis of Relationships between Metabolic Changes and Selected Nutrient Intake in Women Environmentally Exposed to Arsenic.

Nutrients involved in the metabolism of inorganic arsenic (iAs) may play a crucial role in mitigating the adverse health effects associated with such exposure. Consequently, the objective of this study was to analyze the association between the intake levels of nutrients involved in iAs metabolism and alterations in the metabolic profile during arsenic exposure. The study cohort comprised environmentally exposed women: WL (lower total urinary arsenic (As), n = 73) and WH (higher As, n = 73). The analysis included urinary untargeted metabolomics (conducted via liquid chromatography-mass spectrometry) and the assessment of nutrient intake involved in iAs metabolism, specifically methionine, vitamins B2, B6, and B12, folate, and zinc (based on 3-day dietary records of food and beverages). In the WL group, the intake of all analyzed nutrients exhibited a negative correlation with 5 metabolites (argininosuccinic acid, 5-hydroxy-L-tryptophan, 11-trans-LTE4, mevalonic acid, aminoadipic acid), while in the WH group, it correlated with 10 metabolites (5-hydroxy-L-tryptophan, dihyroxy-1H-indole glucuronide I, 11-trans-LTE4, isovalerylglucuronide, 18-oxocortisol, 3-hydroxydecanedioic acid, S-3-oxodecanoyl cysteamine, L-arginine, p-cresol glucuronide, thromboxane B2). Furthermore, nutrient intake demonstrated a positive association with 3 metabolites in the WL group (inosine, deoxyuridine, glutamine) and the WH group (inosine, N-acetyl-L-aspartic acid, tetrahydrodeoxycorticosterone). Altering the intake of nutrients involved in iAs metabolism could be a pivotal factor in reducing the negative impact of arsenic exposure on the human body. This study underscores the significance of maintaining adequate nutrient intake, particularly in populations exposed to arsenic.

Arsenic exposure and oxidative damage to lipid, DNA, and protein among general Chinese adults: A repeated-measures cross-sectional and longitudinal study

Arsenic-related oxidative stress and resultant diseases have attracted global concern, while longitudinal studies are scarce. To assess the relationship between arsenic exposure and systemic oxidative damage, we performed two repeated measures among 5236 observations (4067 participants) in the Wuhan-Zhuhai cohort at the baseline and follow-up after 3 years. Urinary total arsenic, biomarkers of DNA oxidative damage (8-hydroxy-2′-deoxyguanosine (8-OHdG)), lipid peroxidation (8-isoprostaglandin F2alpha (8-isoPGF2α)), and protein oxidative damage (protein carbonyls (PCO)) were detected for all observations. Here we used linear mixed models to estimate the cross-sectional and longitudinal associations between arsenic exposure and oxidative damage. Exposure-response curves were constructed by utilizing the generalized additive mixed models with thin plate regressions. After adjusting for potential confounders, arsenic level was significantly and positively related to the levels of global oxidative damage and their annual increased rates in dose-response manners. In cross-sectional analyses, each 1% increase in arsenic level was associated with a 0.406% (95% confidence interval (CI): 0.379% to 0.433%), 0.360% (0.301% to 0.420%), and 0.079% (0.055% to 0.103%) increase in 8-isoPGF2α, 8-OHdG, and PCO, respectively. More importantly, arsenic was further found to be associated with increased annual change rates of 8-isoPGF2α (β: 0.147; 95% CI: 0.130 to 0.164), 8-OHdG (0.155; 0.118 to 0.192), and PCO (0.050; 0.035 to 0.064) in the longitudinal analyses. Our study suggested that arsenic exposure was not only positively related with global oxidative damage to lipid, DNA, and protein in cross-sectional analyses, but also associated with annual increased rates of these biomarkers in dose-dependent manners.

Interactions of arsenic exposure, arsenic metabolism with red blood cell folate on the risk of hypertension: NHANES 2007-2016.

Arsenic exposure was associated with hypertension, and arsenic metabolism might be influenced by folate concentrations. Thus, this study aimed to explore the interaction between arsenic exposure and metabolism with folate concentrations on hypertension. We studied 6643 adults aged 20 years and older who participated in the National Health and Nutrition Examination Survey from 2007 through 2016. Urinary total arsenic (UTAs), the percentage of urinary dimethylarsinic acid (DMA%), serum and red blood cell (RBC) folate were collected. Logistic regression and restricted cubic spline (RCS) analyses were performed to determine the association and dose-response relationship. Interaction analyses were conducted on both additive and multiplicative scales. UTAs (median: 7.05μg/L) was positively associated with hypertension risk, and the adjusted OR was 1.44 (95% CI: 1.06-1.95) when comparing the third with the lowest quartile. And participants with the highest quintile of RBC folate had increased hypertension risk than those with the lowest quintile (adjusted OR=1.43, 95% CI: 1.06-1.94). Significant additive interaction was observed between excessive RBC folate with high UTAs (AP=0.323, 95% CI: 0.083-0.564) and low DMA% (AP=0.381, 95% CI: 0.119-0.643) on hypertension risk. Our results suggested significant interactions between high UTAs and low DMA% with excessive RBC folate on hypertension risk.

Association between arsenic (+3 oxidation state) methyltransferase gene polymorphisms and arsenic methylation capacity in rural residents of northern China: a cross-sectional study.

Arsenic is a toxic metal-like element. The toxic reaction of the body to arsenic is related to the ability of arsenic methylation metabolism. As the rate-limiting enzyme of arsenic methylation metabolism, the genetic single nucleotide polymorphisms (SNPs) of arsenic (+ 3 oxidation state) methyltransferase (AS3MT) gene are related to capacity of arsenic methylation. In this paper, we investigated the association of five SNPs (rs7085104, rs3740390, 3740393, rs10748835, and rs1046778) in AS3MT with arsenic methylation metabolizing using the data and samples from a cross-sectional case-control study of arsenic and Type 2 diabetes mellitus conducted in Shanxi, China. A total of 340 individuals were included in the study. Urinary total arsenic (tAs, μg/L) was detected by liquid chromatography-atomic fluorescence spectrometry (LC-AFS). According to "safety guidance value of urinary arsenic for population" as specified in WS/T665-2019 (China), participants were divided into the control group (tAs ≤ 32μg/L, n = 172) and arsenic-exposed group (tAs > 32μg/L, n = 168). iAs%, MMA%, and DMA% are as the indicator of arsenic methylation capacity. The genotypes of AS3MT SNPs were examined by Multiple PCR combined sequencing. Linear regression analysis showed that AG + GG genotype in rs7085104 was associated with decreased iAs% and increased DMA%. Moreover, AG + AA genotype in rs10748835 and TC + CC genotype in rs1046778 were associated with decreased iAs% and MMA% and increased DMA%. The interaction between rs7085104 and arsenic is associated with iAs% and DMA%. The interaction of rs3740390 and rs10748835 with arsenic is associated with iAs%. Haplotype CTAC (rs3740393-rs3740390-rs10748835-rs1046778) was associated with lower iAs% and higher DMA%, but this association disappeared after adjusting for age, gender, drink, smoking, BMI and tAs. Haplotype GCAC was associated with decreased MMA%. Our study provides additional support for revealing the factors influencing the metabolic capacity of arsenic methylation and might be helpful to identify the population susceptible to arsenic exposure through individualized screening in the future.

Ecological Risk Assessment of Inorganic Arsenic and Mercuric Fungicides Through Biological Tools

This review discusses the use, mode of action, biomarkers, and bioindicators of inorganic arsenic and mercuric fungicides, as well as their effects on the environment and human health. The most prevalent indicator of exposure to arsenic is the measurement of total arsenic in urine. Biomarkers of exposure for arsenic and inorganic fungicides incudes the analysis of hair, urine, blooda and nails. Bio indicators are species or group of species that are used to indicate adverse effect of contamination. Freshwater fish species act as a very good bio indicator for inorganic arsenic. Tree bark, rice fields and sea birds could be a valuable indicator of inorganic arsenic contamination. Black Piranha, fish and earthworms are an ideal bio indicator of inorganic mercury. Inorganic arsenic compounds are known to be highly carcinogenic and toxic compounds. Mercuric fungicide is very toxic when inhaled by humans or animals it causes severe health issues and when absorbed by plants it retards their growth. To estimate the daily dose of arsenic exposure to humans through absorption, ingestion and other pathways, Average daily dose is implemented by using two equations from the US EPA. To determine the ecological risk assessment a simplified equation was proposed by FDA i.e. HQ = E/RfD. Overall, the review emphasizes the need for heightened awareness, regulation, and alternative approaches to fungicide use, with a focus on minimizing the use of inorganic arsenic and mercuric fungicides to safeguard the environment and promote sustainable agricultural practices.

A State-of-the-Science Review on Metal Biomarkers.

Biomarkers are commonly used in epidemiological studies to assess metals and metalloid exposure and estimate internal dose, as they integrate multiple sources and routes of exposure. Researchers are increasingly using multi-metal panels and innovative statistical methods to understand how exposure to real-world metal mixtures affects human health. Metals have both common and unique sources and routes of exposure, as well as biotransformation and elimination pathways. The development of multi-element analytical technology allows researchers to examine a broad spectrum of metals in their studies; however, their interpretation is complex as they can reflect different windows of exposure and several biomarkers have critical limitations. This review elaborates on more than 500 scientific publications to discuss major sources of exposure, biotransformation and elimination, and biomarkers of exposure and internal dose for 12 metals/metalloids, including 8 non-essential elements (arsenic, barium, cadmium, lead, mercury, nickel, tin, uranium) and 4 essential elements (manganese, molybdenum, selenium, and zinc) commonly used in multi-element analyses. We conclude that not all metal biomarkers are adequate measures of exposure and that understanding the metabolic biotransformation and elimination of metals is key to metal biomarker interpretation. For example, whole blood is a good biomarker of exposure to arsenic, cadmium, lead, mercury, and tin, but it is not a good indicator for barium, nickel, and uranium. For some essential metals, the interpretation of whole blood biomarkers is unclear. Urine is the most commonly used biomarker of exposure across metals but it should not be used to assess lead exposure. Essential metals such as zinc and manganese are tightly regulated by homeostatic processes; thus, elevated levels in urine may reflect body loss and metabolic processes rather than excess exposure. Total urinary arsenic may reflect exposure to both organic and inorganic arsenic, thus, arsenic speciation and adjustment for arsebonetaine are needed in populations with dietary seafood consumption. Hair and nails primarily reflect exposure to organic mercury, except in populations exposed to high levels of inorganic mercury such as in occupational and environmental settings. When selecting biomarkers, it is also critical to consider the exposure window of interest. Most populations are chronically exposed to metals in the low-to-moderate range, yet many biomarkers reflect recent exposures. Toenails are emerging biomarkers in this regard. They are reliable biomarkers of long-term exposure for arsenic, mercury, manganese, and selenium. However, more research is needed to understand the role of nails as a biomarker of exposure to other metals. Similarly, teeth are increasingly used to assess lifelong exposures to several essential and non-essential metals such as lead, including during the prenatal window. As metals epidemiology moves towards embracing a multi-metal/mixtures approach and expanding metal panels to include less commonly studied metals, it is important for researchers to have a strong knowledge base about the metal biomarkers included in their research. This review aims to aid metals researchers in their analysis planning, facilitate sound analytical decision-making, as well as appropriate understanding and interpretation of results.

Urinary arsenic and spontaneous pregnancy loss – a hypothesis-generating case-control investigation in western Romania

Arsenic occurs as a natural contaminant of drinking water supplies in arsenic endemic areas, posing a threat to public health. Our aim was to evaluate the relationship between urinary arsenic concentrations and spontaneous pregnancy loss in a population with low-moderate level drinking water arsenic exposure (mostly <10 μg/L). We enrolled 150 women with incident spontaneous pregnancy losses and 150 controls with ongoing pregnancies matched by gestational age. We measured arsenic species in urine using high performance liquid chromatography paired to inductively coupled plasma mass spectrometry. Urinary arsenic was not related to spontaneous pregnancy loss in conditional logistic regression models adjusted for confounding factors. However, a 10 μg/L increase in urinary arsenic (III + V) salt concentrations was associated with 8.00-fold (95% CI: 0.68, 3.35 × 105) greater odds of spontaneous loss among women using prenatal vitamins in an interaction model (P for interaction = 0.07), although the effect estimate was imprecise. In an additional interaction model, prenatal vitamin use was associated with lower odds of loss (OR = 0.30; 95% CI: 0.13, 0.66), although the association was diminished in the presence of a 10 μg/L increase in urinary inorganic arsenic (OR = 0.44; 95% CI: 0.70, 3.22). Total urinary arsenic was associated with 1.48-fold (95% CI: 0.20, 11.35) greater odds for loss among women with urinary cotinine >50 μg/L in another interaction model (P for interaction = 0.07). These results suggest a potential modest increase in the odds of pregnancy loss associated with increased total urinary arsenic among women smoking during pregnancy (urinary cotinine >50 μg/L). Prenatal vitamin use may act as a protective factor for arsenic exposure associated pregnancy loss, but appears to be less protective with increasing urinary inorganic arsenic concentrations.

Relationship between urinary biomarkers of early kidney damage and exposure to inorganic toxins in a pediatric population of Apizaco, Tlaxcala, Mexico.

In recent years, chronic kidney disease has increased in the pediatric population and has been related to environmental factors. In the diagnosis of kidney damage, in addition to the traditional parameters, early kidney damage biomarkers, such as kidney injury molecule 1, cystatin C, and osteopontin, among others, have been implemented as predictors of early pathologicalprocesses. This study aimed to evaluate the relationship between exposure to environmental pollutants and early kidney damage biomarkers. A cross-sectional pilot study was conducted in February 2016 and involved 115 apparently healthy children aged 6-15 residing in Apizaco, Tlaxcala. Participant selection was carried out randomly from among 16,472 children from the municipality of Apizaco.A socio-demographic questionnaire includedage, sex, education, durationof residence in the area, occupation, water consumption and dietary habits, pathological history, and some non-specific symptoms. Physical examination includedbloodpressure, weight, and height.The urineconcentrations of urinary aluminum, total arsenic, boron, calcium, chromium, copper, mercury, potassium, sodium, magnesium, manganese, molybdenum, lead, selenium, silicon, thallium, vanadium, uranium, and zinc, were measured.Four of the 115 participants selected for the study were excluded due to an incomplete questionnaire or lack of a medical examination, leaving a final sample population of 111 participants. The results showed a mean estimated glomerular filtration rate of 89.1 ± 9.98mL/min/1.73m2 and a mean albumin/creatinine ratio of 12.9 ± 16.7mg/g urinary creatinine. We observed a positive and significant correlation between estimated glomerular filtration rate with fluoride, total arsenic and lead, and a correlation of albumin/creatinine ratio with fluoride, vanadium, and total arsenic. There was also a significant correlation between the early kidney damage biomarkers and fluoride, vanadium, and total arsenic, except for cystatin C. In conclusion, our results show that four urinary biomarkers: α1-microglobulin, cystatin C, kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin are related to environmental exposure to urinary fluoride, vanadium, and total arsenic in our pediatric population.

Gut Microbiota Control the Bioavailability and Metabolism of Organoarsenicals of Seaweeds in Mice after Oral Ingestion.

Edible seaweed consumption is an essential route of human exposure to complex organoarsenicals, including arsenosugars and arsenosugar phospholipids. However, the effects of gut microbiota on the metabolism and bioavailability of arsenosugars in vivo are unknown. Herein, two nori and two kelp samples with phosphate arsenosugar and sulfonate arsenosugar, respectively, as the predominant arsenic species, were administered to normal mice and gut microbiota-disrupted mice treated with the broad-spectrum antibiotic cefoperazone for 4 weeks. Following exposure, the community structures of the gut microbiota, total arsenic concentrations, and arsenic species in excreta and tissues were analyzed. Total arsenic excreted in feces and urine did not differ significantly between normal and antibiotic-treated mice fed with kelp samples. However, the total urinary arsenic of normal mice fed with nori samples was significantly higher (p < 0.05) (urinary arsenic excretion factor, 34-38 vs 5-7%), and the fecal total arsenic was significantly lower than in antibiotic-treated mice. Arsenic speciation analysis revealed that most phosphate arsenosugars in nori were converted to arsenobetaine (53.5-74.5%) when passing through the gastrointestinal tract, whereas a large portion of sulfonate arsenosugar in kelp was resistant to speciation changes and was excreted in feces intact (64.1-64.5%). Normal mice exhibited greater oral bioavailability of phosphate arsenosugar from nori than sulfonate arsenosugar from kelp (34-38 vs 6-9%). Our work provides insights into organoarsenical metabolism and their bioavailability in the mammalian gut.

Global DNA methylation and the association between metal exposure and chronic kidney disease.

Prior studies indicate that exposure to metals may alter DNA methylation. Evidence also shows that global DNA methylation is associated with chronic kidney disease (CKD). This study aimed to examine the association between CKD and 5-methyl-2-deoxycytidine (5mdC, %), a marker of global DNA methylation, and to evaluate the interaction between metal exposures and 5mdC (%) on CKD. We also explored the mediation effect of 5mdC (%) on the association between metal exposures and renal function (i.e., estimated glomerular filtration rate, eGFR). A total of 218 CKD patients and 422 controls were recruited in this case-control study. 5mdC (%), concentrations of blood lead and cadmium, plasma selenium, and total urinary arsenic were measured. CKD cases were clinically defined among patients with eGFR <60 mL/min/1.73 m2 for at least 3 months and without hemodialysis. Odds ratio (OR) and 95% confidence interval (CI) were estimated by logistic regression models to examine the association between metal exposures, 5mdC (%), and CKD, adjusted for confounders. Multivariable linear regression models were used to examine associations between metal exposures, 5mdC (%), and eGFR. CKD cases compared to controls had 6.06-fold (95% CI: 3.11-11.81) higher odds of having high blood cadmium and high 5mdC (%) levels. A positive interaction on an additive scale was identified between blood cadmium and 5mdC (%) on CKD. Cases compared to controls had 4.73-fold (95% CI: 2.65-8.45) higher odds of having low plasma selenium and high 5mdC (%) levels; and a significant multiplicative interaction between plasma selenium and 5mdC (%) on CKD was observed. In addition, we found that blood lead and cadmium concentrations were positively associated, while plasma selenium concentrations were inversely associated, with 5mdC (%). The associations of blood lead and plasma selenium with eGFR were partially mediated by 5mdC (%). Our results suggest that 5mdC (%) may interact with plasma selenium and blood cadmium to influence the risk of CKD. The 5mdC (%) also potentially mediates the associations between exposure to metals and renal function.

Chronic Kidney Disease: Interaction of Adiponectin Gene Polymorphisms and Diabetes.

Adiponectin is an adipokine multipeptide hormone with insulin-sensitizing; anti-atherosclerotic; and anti-inflammatory properties. Chronic kidney disease (CKD) may be associated with low adiponectin. The adiponectin gene ADIPOQ is thought to be the only major gene responsible for plasma adiponectin levels; which are associated with diabetes and diabetic nephropathy. The purpose of this study was to investigate the association between ADIPOQ polymorphism and CKD. In addition; the combined effects of ADIPOQ polymorphism and diabetes and levels of total urinary arsenic and blood cadmium on CKD were also explored. This study included 215 CKD patients and 423 age-sex matched controls. The ADIPOQ polymorphisms were determined using the Agena Bioscience Mass ARRAY System. The levels of blood cadmium and urinary arsenic species were measured. The ADIPOQ rs182052 GA/AA genotype had a marginally lower odds ratio (OR) for CKD than the GG genotype. The OR (95% confidence interval; CI) was 16.33 (5.72-46.66) of CKD in subjects carrying the ADIPOQ rs182052 GG genotype and diabetes compared to non-diabetes subjects carrying the ADIPOQ rs182052 GA/AA genotype; the interaction term had p = 0.015; and the synergy index was 6.64 (1.81-24.36) after multivariate adjustment. A significant interaction of diabetes and ADIPOQ rs1501299 risk genotype increased the OR of CKD after multivariate adjustment with a synergy index of 0.31 (0.11-0.86) and a multiplicative interaction with p = 0.001. These results suggest that ADIPOQ rs182052 and rs1501299 risk genotypes may significantly modify the association between diabetes and CKD but not the association between total urinary arsenic and blood cadmium and CKD.

Arsenic exposure incurs hyperglycemia mediated by oxidative damage in urban adult population: A prospective cohort study with three repeated measures

The associations and potential mechanisms of low to moderate arsenic exposure with fasting plasma glucose (FPG) and type 2 diabetes mellitus (T2DM) are still unclear. To assess the effects of short-term and long-term arsenic exposure on hyperglycemia and the mediating effect of oxidative damage on such association, three repeated-measures studies with 9938 observations were conducted in the Wuhan-Zhuhai cohort. The levels of urinary total arsenic, FPG, urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2α), urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), and plasma protein carbonyls (PCO) were measured. Generalized linear mixed models were used to evaluate the exposure-response relationships of urinary total arsenic with FPG and the prevalent risks of impaired fasting glucose (IFG), T2DM, and abnormal glucose regulation (AGR). Cox regression models were applied to assess the associations of arsenic exposure with incident risks of IFG, T2DM, and AGR. Mediation analyses were performed to assess the mediating effects of 8-iso-PGF2α, 8-OHdG, and PCO. In cross-sectional analyses, each one-unit increase in natural log-transformed urinary total arsenic was associated with a 0.082 (95% CI: 0.047 to 0.118) mmol/L increase in FPG, as well as a 10.3% (95% CI: 1.4%–20.0%), 4.4% (95% CI: 5.3%–15.2%), and 8.7% (95% CI: 1.2%–16.6%) increase in prevalent risks of IFG, T2DM, and AGR, respectively. In longitudinal analyses, arsenic exposure was further associated with the annual increased rate of FPG with a β (95% CI) of 0.021 (95% CI: 0.010 to 0.033). The incident risks of IFG, T2DM, and AGR were increased without statistical significance when arsenic levels increased. Mediation analyses showed that 8-iso-PGF2α and PCO mediated 30.04% and 10.02% of the urinary total arsenic-associated FPG elevation, respectively. Our study indicated that arsenic exposure was associated with elevated level and progression rate of FPG among general Chinese adults, where lipid peroxidation and oxidative protein damage might be the potential mechanisms.

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.

Fate of arsenicals in mice carrying the human AS3MT gene exposed to environmentally relevant levels of arsenite in drinking water

Although mice are widely used to study adverse effects of inorganic arsenic (iAs), higher rates of iAs methylation in mice than in humans may limit their utility as a model organism. A recently created 129S6 mouse strain in which the Borcs7/As3mt locus replaces the human BORCS7/AS3MT locus exhibits a human-like pattern of iAs metabolism. Here, we evaluate dosage dependency of iAs metabolism in humanized (Hs) mice. We determined tissue and urinary concentrations and proportions of iAs, methylarsenic (MAs), and dimethylarsenic (DMAs) in male and female Hs and wild-type (WT) mice that received 25- or 400-ppb iAs in drinking water. At both exposure levels, Hs mice excrete less total arsenic (tAs) in urine and retain more tAs in tissues than WT mice. Tissue tAs levels are higher in Hs females than in Hs males, particularly after exposure to 400-ppb iAs. Tissue and urinary fractions of tAs present as iAs and MAs are significantly greater in Hs mice than in WT mice. Notably, tissue tAs dosimetry in Hs mice resembles human tissue dosimetry predicted by a physiologically based pharmacokinetic model. These data provide additional support for use of Hs mice in laboratory studies examining effects of iAs exposure in target tissues or cells.

Associations of arsenic exposure with liver injury in US adults: NHANES 2003-2018.

Arsenic is a natural element with complex toxicity. Long-term exposure to arsenic can cause a variety of health damage. In recent years, there are some studies on arsenic exposure and liver injury. But few of them tried to measure the quantitative relationship between arsenic exposure and indicators of liver injury in adult. Therefore, this study aimed to elucidate the relationship between them. This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) in 2003-2018. Arsenic exposure was assessed using total urinary arsenic and dimethylarsenate acid (DMA). We selected alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total protein (TP), ALT/AST, total bilirubin (TBIL), and albumin (ALB) as markers of liver injury. Multiple linear regression was used to explore the relationship between urinary arsenic concentrations and these markers of liver function injury. In addition, six covariables (age, sex, smoker, alcohol user, BMI, diabetes) were further analyzed in subgroups. A total of 13,420 adults were included in the analysis. The multivariate linear regression analyses showed that urinary DMA was positively correlated with ALT (β 0.135, 95%CI 0.090, 0.180, p < 0.001), AST (β 0.053, 95%CI 0.014, 0.092, p < 0.01), ALT/AST (β 0.052, 95%CI 0.030, 0.074, p < 0.001), TBIL (β 0.061, 95%CI 0.034, 0.089, p < 0.001), and GGT (β 0.178, 95%CI 0.110, 0.246, p < 0.001). Similar results were observed for total urinary arsenic, suggesting a positive association with AST (β 0.048, 95%CI 0.016, 0.081, p < 0.01), ALT (β 0.090, 95%CI 0.049, 0.132, p < 0.001), and TBIL (β 0.062, 95%CI 0.037, 0.088, p < 0.001). In subgroup analysis, sex and smoker showed significant differences between subgroups. Our results demonstrate a positive association between urinary arsenic exposure and liver injury in adults. Sex and smokers may be related to arsenic pathogenicity.