Arsenic Exposure-Related Hypertension in Bangladesh and Reduced Circulating Nitric Oxide Bioavailability.

BACKGROUND: Hypertension is a major cause of death worldwide. Although arsenic exposure has been associated with the risk of hypertension, this association appears nonuniform due to inconsistent results from studies conducted in different populations. Moreover, hypertension is a complex condition with multiple underlying mechanisms and factors. One factor is impaired production and bioavailability of vascular nitric oxide (NO). However, the implications of the effects of arsenic exposure on circulating NO and its association with hypertension in humans are largely unknown. OBJECTIVE: We investigated the dose-response relationship between arsenic exposure and hypertension with vascular NO levels as a potential mediator of arsenic-related hypertension in individuals exposed to a broad range of arsenic. METHODS: A total of 828 participants were recruited from low- and high-arsenic exposure areas in Bangladesh. Participants' drinking water, hair, and nail arsenic concentrations were measured by inductively coupled plasma mass spectroscopy. Hypertension was defined as a systolic blood pressure (SBP) value of ≥140 and a diastolic (DBP) value of ≥90 mmHg. Serum NO levels reflected by total serum nitrite concentrations were measured by immunoassay. A formal causal mediation analysis was used to assess NO as a mediator of the association between arsenic level and hypertension. RESULTS: Increasing concentrations of arsenic measured in drinking water, hair, and nails were associated with the increasing levels of SBP and DBP. The odds of hypertension were dose-dependently increased by arsenic even in participants exposed to relatively low to moderate levels (10-50µg/L) of water arsenic [odds ratios (ORs) and 95% confidence intervals (CIs): 2.87 (95% CI: 1.28, 6.44), 2.67 (95% CI: 1.27, 5.60), and 5.04 (95% CI: 2.71, 9.35) for the 10-50µg/L, 50.01-150µg/L, and >150µg/L groups, respectively]. Causal mediation analysis showed a significant mediating effect of NO on arsenic-related SBP, DBP, and hypertension. CONCLUSION: Increasing exposure to arsenic was associated with increasing odds of hypertension. The association was mediated through the reduction of vascular NO bioavailability, suggesting that impaired NO bioavailability was a plausible underlying mechanism of arsenic-induced hypertension in this Bangladeshi population. https://doi.org/10.1289/EHP13018.

Association between serum periostin levels and the severity of arsenic-induced skin lesions.

Arsenic is a potent environmental toxicant and human carcinogen. Skin lesions are the most common manifestations of chronic exposure to arsenic. Advanced-stage skin lesions, particularly hyperkeratosis have been recognized as precancerous diseases. However, the underlying mechanism of arsenic-induced skin lesions remains unknown. Periostin, a matricellular protein, is implicated in the pathogenesis of many forms of skin lesions. The objective of this study was to examine whether periostin is associated with arsenic-induced skin lesions. A total of 442 individuals from low- (n = 123) and high-arsenic exposure areas (n = 319) in rural Bangladesh were evaluated for the presence of arsenic-induced skin lesions (Yes/No). Participants with skin lesions were further categorized into two groups: early-stage skin lesions (melanosis and keratosis) and advanced-stage skin lesions (hyperkeratosis). Drinking water, hair, and nail arsenic concentrations were considered as the participants' exposure levels. The higher levels of arsenic and serum periostin were significantly associated with skin lesions. Causal mediation analysis revealed the significant effect of arsenic on skin lesions through the mediator, periostin, suggesting that periostin contributes to the development of skin lesions. When skin lesion was used as a three-category outcome (none, early-stage, and advanced-stage skin lesions), higher serum periostin levels were significantly associated with both early-stage and advanced-stage skin lesions. Median (IQR) periostin levels were progressively increased with the increasing severity of skin lesions. Furthermore, there were general trends in increasing serum type 2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and immunoglobulin E (IgE) levels with the progression of the disease. The median (IQR) of IL-4, IL-5, IL-13, eotaxin, and IgE levels were significantly higher in the early-and advanced-stage skin lesions compared to the group of participants without skin lesions. The results of this study suggest that periostin is implicated in the pathogenesis and progression of arsenic-induced skin lesions through the dysregulation of type 2 immune response.

Elevated serum periostin levels among arsenic-exposed individuals and their associations with the features of asthma.

Chronic exposure to arsenic via drinking water is a serious public health issue in many countries. Arsenic causes not only cancers but also non-malignant diseases, including asthma. We have previously reported that arsenic exposure increases the risk of Th2-mediated allergic asthma. The serum level of periostin, an extracellular matrix protein activated by Th2 cytokines, is recognized as a biomarker for Th2-mediated eosinophilic asthma and contributes to enhanced airway inflammation and remodeling. However, the role of periostin in arsenic-related asthma is unknown. Therefore, this study was designed to explore the associations of serum periostin levels with arsenic exposure and the features of asthma in 442 individuals in Bangladesh who participated in our previous study. Exposure levels of the participants were determined by measuring the arsenic concentrations in drinking water, hair, and nails through inductively coupled plasma mass spectroscopy. Periostin levels in serum were assessed by immunoassay. In this study, we found that serum periostin levels of the participants were increased with increasing exposure to arsenic. Notably, even the participants with 10.1-50 µg/L arsenic in drinking water had significantly higher levels of periostin than participants with <10 µg/L of water arsenic. Elevated serum periostin levels were positively associated with serum levels of Th2 mediators, such as interleukin (IL)-4, IL-5, IL-13, and eotaxin. Each log increase in periostin levels was associated with approximately eight- and three-fold increases in the odds ratios (ORs) for reversible airway obstruction (RAO) and asthma symptoms, respectively. Additionally, causal mediation analyses revealed that arsenic exposure metrics had both direct and indirect (periostin-mediated) effects on the risk of RAO and asthma symptoms. Thus, the results suggested that periostin may be involved in the arsenic-related pathogenesis of Th2-mediated asthma. The elevated serum periostin levels may predict the greater risk of asthma among the people living in arsenic-endemic areas.

Parental Lead Exposure Promotes Neurobehavioral Disorders and Hepatic Dysfunction in Mouse Offspring.

Lead (Pb) induces neurotoxicity in both children and adults. Children are more vulnerable to Pb toxicity than adults. Little is known about the effects of Pb on the mental health of the children who are prenatally exposed. Therefore, we designed an animal experiment to compare the adverse effects of Pb on neurobehavioral and hepatic functions between Pb-exposed (Pb mice) and parental Pb-exposed (P-Pb mice) group mice. Mice were treated with Pb-acetate (10 mg/kg bodyweight/day) via drinking water. Male mice from unexposed parents treated with Pb for 90 days were defined as Pb mice, whereas male mice from Pb-exposed parents treated with Pb for further 90 days were defined as P-Pb mice. Anxiety-like behavior and spatial memory and learning were assessed by elevated plus maze and Morris water maze. Serum hepatic enzyme activities and butyrylcholinesterase activity were measured by an analyzer. P-Pb mice displayed increased anxiety-like behavior and memory and learning impairments compared to Pb mice. BChE activity was significantly decreased in P-Pb mice compared to Pb mice. Pb levels in the brains of P-Pb mice were significantly higher than those of Pb mice. The activities of serum hepatic enzymes of P-Pb mice were also higher than those of Pb mice. Additionally, histopathology data revealed that hepatic tissue injury was more pronounced in P-Pb mice than in Pb mice. Thus, the results suggest that persistent exposure to Pb from fetus to adult causes more severe neurobehavioral changes and hepatic toxicities than adult exposure only.

Arsenic Secondary Methylation Capacity Is Inversely Associated with Arsenic Exposure-Related Muscle Mass Reduction.

Skeletal muscle mass reduction has been implicated in insulin resistance (IR) that promotes cardiometabolic diseases. We have previously reported that arsenic exposure increases IR concomitantly with the reduction of skeletal muscle mass among individuals exposed to arsenic. The arsenic methylation capacity is linked to the susceptibility to some arsenic exposure-related diseases. However, it remains unknown whether the arsenic methylation capacity affects the arsenic-induced reduction of muscle mass and elevation of IR. Therefore, this study examined the associations between the arsenic methylation status and skeletal muscle mass measures with regard to IR by recruiting 437 participants from low- and high-arsenic exposure areas in Bangladesh. The subjects' skeletal muscle mass was estimated by their lean body mass (LBM) and serum creatinine levels. Subjects' drinking water arsenic concentrations were positively associated with total urinary arsenic concentrations and the percentages of MMA, as well as inversely associated with the percentages of DMA and the secondary methylation index (SMI). Subjects' LBM and serum creatinine levels were positively associated with the percentage of DMA and SMI, as well as inversely associated with the percentage of MMA. HOMA-IR showed an inverse association with SMI, with a confounding effect of sex. Our results suggest that reduced secondary methylation capacity is involved in the arsenic-induced skeletal muscle loss that may be implicated in arsenic-induced IR and cardiometabolic diseases.

T helper 2-driven immune dysfunction in chronic arsenic-exposed individuals and its link to the features of allergic asthma.

Limited information is available regarding the effects of arsenic exposure on immune function. We have recently reported that chronic exposure to As was associated asthma, as determined by spirometry and respiratory symptoms. Because T helper 2 (Th2)-driven immune responses are implicated in the pathogenesis of allergic diseases, including asthma, we studied the associations of serum Th1 and Th2 mediators with the As exposure markers and the features of asthma among individuals exposed to As. A total of 553 blood samples were selected from the same study subjects recruited in our previous asthma study. Serum levels of Th1 and Th2 cytokines were analyzed by immunoassay. Subjects' arsenic exposure levels (drinking water, hair and nail arsenic concentrations) were determined by inductively coupled plasma mass spectroscopy. Arsenic exposure levels of the subjects showed significant positive associations with serum Th2-mediators- interleukin (IL)-4, IL-5, IL-13, and eotaxin without any significant changes in Th1 mediators- interferon-γ and tumor necrosis factor-α. The ratios of Th2 to Th1 mediators were significantly increased with increasing exposure to As. Notably, most of the Th2 mediators were positively associated with serum levels of total immunoglobulin E and eotaxin. The serum levels of Th2 mediators were significantly higher in the subjects with asthma than those without asthma. The results of our study suggest that the exacerbated Th2-driven immune responses are involved in the increased susceptibility to allergic asthma among individuals chronically exposed to As.

Arsenic exposure-related hyperglycemia is linked to insulin resistance with concomitant reduction of skeletal muscle mass.

BACKGROUND: Alargebodyof evidence has shown a link between arsenic exposure and diabetes, but the underlying mechanisms have not yet been clarified. OBJECTIVE: We explored the association between arsenic exposure and the reduction of skeletal muscle mass as a potential mechanism of insulin resistance for developing arsenic-related hyperglycemia. METHODS: A total of 581 subjects were recruited from arsenic-endemic and non-endemic areas in Bangladesh and their fasting blood glucose (FBG), serum insulin, and serum creatinine levels were determined. Subjects' arsenic exposure levels were assessed by arsenic concentrations in water, hair, and nails. HOMA-IR and HOMA-ß were used to calculate insulin resistance and ß-cell dysfunction, respectively. Serum creatinine levels and lean body mass (LBM) were used as muscle mass indicators. RESULTS: Water, hair and nail arsenic concentrations showed significant positive associations with FBG, serum insulin and HOMA-IR and inverse associations with serum creatinine and LBM in a dose-dependent manner both in males and females. Water, hair and nail arsenic showed significant inverse associations with HOMA-ß in females but not in males. FBG and HOMA-IR were increased with the decreasing levels of serum creatinine and LBM. Odds ratios (ORs)of hyperglycemia were significantly increased with the increasing concentrations of arsenic in water, hair and nails and with the decreasing levels of serum creatinine and LBM. Females' HOMA-IR showed greater susceptibility to the reduction of serum creatinine and LBM, possibly causing the greater risk of hyperglycemia in females than males. Path analysis revealed the mediating effect of serum creatinine level on the relationship of arsenic exposure with HOMA-IR and hyperglycemia. CONCLUSION: Arsenic exposure elevates FBG levels and the risk of hyperglycemia through increasing insulin resistance with greater susceptibility in females than males. Additionally, arsenic exposure-related reduction of skeletal muscle mass may be a mechanism underlying the development of insulin resistance and hyperglycemia.

Association between chronic arsenic exposure and the characteristic features of asthma.

Widespread contamination of arsenic (As) has become a global public health concern. Exposure to As causes respiratory complications. Asthma, a major respiratory complication, is increasing worldwide. However, the effect of chronic As exposure on the risk of asthma remains to be clarified. This study aims to examine the associations between As exposure (water, hair and nail As) and the risk of asthma among 842 individuals exposed to a wide range of As concentrations through drinking water in Bangladesh. Subjects' As exposure levels were measured with ICP-MS. Lung function was examined by a handheld spirometer. Characteristic features of asthma were evaluated by bronchodilator-mediated reversibility in airway obstruction and asthma-like symptoms through a structured questionnaire. Total serum immunoglobulin E (sIgE) levels were measured by immunoassay. As exposure metrics showed inverse associations with lung function measures (FEV1, FEV6, and FEV1/FEV6 ratio) and positive associations with the risks of airway obstruction (AO), reversible airway obstruction (RAO), and asthma-like symptoms. The majority of AO patients (70 of 97) were RAO with one or more characteristic symptoms of asthma. Intriguingly, subjects' As exposure levels showed positive associations with total sIgE levels. Total sIgE in RAO patients was significantly (p < 0.001) higher than that in the control group. Thus the results revealed that chronic As exposure was associated with the risk of the characteristic features of asthma. Additionally the association between As exposure and subjects' total sIgE levels and an elevated level of total sIgE in RAO group suggested that As exposure-related asthma might be allergic in nature.

In vivo evaluation of arsenic-associated behavioral and biochemical alterations in F0 and F1 mice.

Groundwater contaminated with arsenic (As) is the biggest threat to public health in Bangladesh. The children of As-exposure parents are also exposing to As through drinking water. The effects of As on the children's health of As-exposure parents are poorly understood. An animal study was taken to evaluate the effects of As on behavioral and biochemical changes in F1 mice. Swiss albino mice were separated into three groups: a) control, b) As-treated F0 and c) As-treated F1. Elevated plus maze and Morris water maze tests were used for evaluating anxiety, spatial memory and learning, respectively. We found that the effect of As on anxiety like behavior, spatial memory and learning impairment in As-treated F1 mice was significantly higher than that of As-treated F0 mice and control group. Additionally, we also evaluated the effects of As on biochemical parameters by measuring ALT, AST, ALP, BChE, SOD activities and the level of creatinine in As-induced mice, where we found that all of the blood parameters were significantly changed in F1 generation. A significant portion of As accumulated in the brain, liver and kidney of F1 mice than F0 mice. Histological analysis revealed a significant change in tissue damage related to hepatic and renal dysfunctions that might be associated with As-induced biochemical alterations. In conclusion, arsenic plays an important role for the development of As-associated neurological disorders, hepatic toxicities, and renal dysfunctions in both F0 and F1 generations. Notably F1 mice were much more vulnerable to As-exposure than F0 mice.

Manganese attenuates the effects of arsenic on neurobehavioral and biochemical changes in mice co-exposed to arsenic and manganese.

An unsafe level of manganese (Mn) was detected in the drinking water in some arsenic (As)-contaminated areas in Bangladesh. Mn is an essential trace element; however, the intake of a higher level of Mn through the drinking water is associated with the development of toxicity in humans. This study was designed to evaluate the effects of As and Mn co-exposure on neurobehavioral and biochemical alterations in a mouse model. Sodium arsenite (10 mg/kg body weight) and manganese chloride tetrahydrate (10 mg/kg body weight) were given to mice individually and in combination with drinking water for 90 days. Results showed that individual As and Mn exposure as well as co-exposure of As and Mn significantly (p < 0.05) reduced the percent of time spent in the open arms when compared with that of control mice. In addition, percent of time spent in open arms significantly (p < 0.05) increased in co-exposed mice compared with As exposure in elevated plus maze (42.05 ± 1.10 versus 38.94 ± 0.66). In the Morris water maze test, the mean time latency to find the platform was longer in metal-treated mice in comparison to that of control mice (p < 0.05). Importantly, the co-exposed group had shorter time when compared with the As-exposed group during the training periods (p < 0.05). Moreover, co-exposed mice stayed significantly (p < 0.05) more time in the target quadrant in the probe trial in comparison with that of As-exposed mice (27.25 ± 1.21 versus 23.83 ± 0.87 s) but less time than control mice (27.25 ± 1.21 versus 43.17 ± 1.49 s). In addition, a significant (p < 0.05) alteration of biochemical parameters such as ALT, AST, ALP, BChE, and SOD as well as urea and creatinine levels were noted in the As-exposed group compared with the control group and Mn significantly (p < 0.05) attenuated the effects of As in co-exposed mice. Therefore, the results of this study suggest that As and Mn may have some antagonistic effect and Mn could attenuate the As-induced neurobehavioral and biochemical alterations in co-exposed mice.

Dose-dependent relationships between chronic arsenic exposure and cognitive impairment and serum brain-derived neurotrophic factor.

BACKGROUND: Arsenic poisoning is a public health problem worldwide. A few studies have reported the effects of arsenic exposure on adult cognitive function, but with limitations in the subject selection and exposure markers. Moreover, information regarding the association between arsenic exposure and biomarker of cognitive impairment is scarce. OBJECTIVES: We examined the associations between arsenic exposure and adult cognitive impairment using the Mini-Mental State Examination (MMSE) and the serum levels of brain-derived neurotrophic factor (BDNF), a potential biomarker of cognitive health status. METHODS: We designed a cross-sectional study that recruited 693 adult (18-60 years old) subjects from the areas of low- and high­arsenic exposure in rural Bangladesh. The subjects' arsenic exposure levels (drinking water, hair, and nail arsenic concentrations) were measured by inductively coupled plasma-mass spectroscopy. The Bangla version of the MMSE was used as a cognitive assessment tool. Serum BDNF (sBDNF) levels were assessed by immunoassay. RESULTS: In this study, we found that average MMSE score and sBDNF level of the subjects in arsenic-endemic areas were significantly (p < 0.001 for both) lower than those of the subjects in non-endemic area. Our analyses revealed that both MMSE scores and sBDNF levels were decreased with the increasing concentrations of arsenic in drinking water, hair, and nails in a dose-dependent fashion. In regression analyses, significant associations of arsenic exposure metrics with MMSE scores and sBDNF levels were observed even after adjustment for several variables. Intriguingly, MMSE scores showed a significantly positive correlation with sBDNF levels. CONCLUSION: Our findings demonstrate that chronic exposure to arsenic dose-dependently decreases cognitive function in adults, with a concomitant reduction of sBDNF levels. A decreased BDNF level may be part of the biochemical basis of chronic arsenic exposure-related cognitive impairment.

Higher risk of hyperglycemia with greater susceptibility in females in chronic arsenic-exposed individuals in Bangladesh.

Arsenic (As) toxicity and diabetes mellitus (DM) are emerging public health concerns worldwide. Although exposure to high levels of As has been associated with DM, whether there is also an association between low and moderate As exposure and DM remains unclear. We explored the dose-dependent association between As exposure levels and hyperglycemia, with special consideration of the impact of demographic variables, in 641 subjects from rural Bangladesh. The total study participants were divided into three groups depending on their levels of exposure to As in drinking water (low, moderate and high exposure groups). Prevalence of hyperglycemia, including impaired glucose tolerance (IGT) and DM was significantly associated with the subjects' drinking water arsenic levels. Almost all exposure metrics (As levels in the subjects' drinking water, hair and nails) showed dose-dependent associations with the risk of hyperglycemia, IGT and DM. Among the variables considered, sex, age, and BMI were found to be associated with higher risk of hyperglycemia, IGT and DM. In sex-stratified analyses, As exposure showed a clearer pattern of dose-dependent risk for hyperglycemia in females than males. Finally, drinking water containing low-to-moderate levels of As (50.01-150 µg/L) was found to confer a greater risk of hyperglycemia than safe drinking water (As ≤10 µg/L). Thus the results suggested that As exposure was dose-dependently associated with hyperglycemia, especially in females.

Butyrylcholinesterase-a potential plasma biomarker in manganese-induced neurobehavioral changes.

Groundwater particularly drinking water contamination with metals has created an environmental disaster in Bangladesh. Manganese (Mn), an essential trace element, plays a key role in the development and function of the brain. Excess Mn exposure is reported to be associated with complex neurological disorders. Here, we have found a notably large extent of Mn above the permissive limit in the tube-well water of Rajshahi and Naogaon districts in Bangladesh. Higher levels of Mn in hair and nail samples, and a decreasing level of butyrylcholinesterase (BChE) activity were detected in plasma samples of the human subjects recruited from Naogaon district. Mn concentrations in water, hair, and nails were negatively correlated with the plasma BChE levels in Mn-exposed populations. To compare and validate these human studies, an animal model was used to determine the in vivo effects of Mn on neurobehavioral changes and blood BChE levels. In elevated plus maze, the time spent was significantly reduced in open arms and increased in closed arms of Mn-exposed mice compared to control group. The mean latency time to find the platform was declined significantly in control mice compared to Mn-treated group during 7 days in Morris water maze test, and Mn-exposed group also spent significantly less time in the desired quadrant as compared to the control group in probe trial. BChE activity was significantly reduced in Mn-exposed mice compared to control mice. Taken together, these results suggest that plasma BChE levels may serve as reliable biomarker of Mn-induced neurotoxicity related to behavioral changes.