Mechanisms Associated with Cognitive and Behavioral Impairment Induced by Arsenic Exposure.

Arsenic (As) is a metalloid naturally present in the environment, in food, water, soil, and air; however, its chronic exposure, even with low doses, represents a public health concern. For a long time, As was used as a pigment, pesticide, wood preservative, and for medical applications; its industrial use has recently decreased or has been discontinued due to its toxicity. Due to its versatile applications and distribution, there is a wide spectrum of human As exposure sources, mainly contaminated drinking water. The fact that As is present in drinking water implies chronic human exposure to this metalloid; it has become a worldwide health problem, since over 200 million people live where As levels exceed safe ranges. Many health problems have been associated with As chronic exposure including cancer, cardiovascular diseases, gastrointestinal disturbances, and brain dysfunctions. Because As can cross the blood-brain barrier (BBB), the brain represents a target organ where this metalloid can exert its long-term toxic effects. Many mechanisms of As neurotoxicity have been described: oxidative stress, inflammation, DNA damage, and mitochondrial dysfunction; all of them can converge, thus leading to impaired cellular functions, cell death, and in consequence, long-term detrimental effects. Here, we provide a current overview of As toxicity and integrated the global mechanisms involved in cognitive and behavioral impairment induced by As exposure show experimental strategies against its neurotoxicity.

Arsenic causing gallbladder cancer disease in Bihar.

In recent times Gallbladder cancer (GBC) incidences increased many folds in India and are being reported from arsenic hotspots identified in Bihar. The study aims to establish association between arsenic exposure and gallbladder carcinogenesis. In the present study, n = 200 were control volunteers and n = 152 confirmed gallbladder cancer cases. The studied GBC patient's biological samples-gallbladder tissue, gallbladder stone, bile, blood and hair samples were collected for arsenic estimation. Moreover, n = 512 gallbladder cancer patients blood samples were also evaluated for the presence of arsenic to understand exposure level in the population. A significantly high arsenic concentration (p < 0.05) was detected in the blood samples with maximum concentration 389 µg/L in GBC cases in comparison to control. Similarly, in the gallbladder cancer patients, there was significantly high arsenic concentration observed in gallbladder tissue with highest concentration of 2166 µg/kg, in gallbladder stones 635 µg/kg, in bile samples 483 µg/L and in hair samples 6980 µg/kg respectively. Moreover, the n = 512 gallbladder cancer patient's blood samples study revealed very significant arsenic concentration in the population of Bihar with maximum arsenic concentration as 746 µg/L. The raised arsenic concentration in the gallbladder cancer patients' biological samples-gallbladder tissue, gallbladder stone, bile, blood, and hair samples was significantly very high in the arsenic exposed area. The study denotes that the gallbladder disease burden is very high in the arsenic exposed area of Bihar. The findings do provide a strong link between arsenic contamination and increased gallbladder carcinogenesis.

Arsenic: a Culpable Element and a Possible Menace for HIV/AIDS Patients.

Arsenic contamination has long been recognized as one of the most harmful environmental pollutants resulting from anthropogenic activity. Apart from being an environmental toxicant or pollutant, this culpable heavy metal also has detrimental effects on human health. People throughout the world are exposed to arsenic (As) mostly through polluted drinking water. Acute inorganic arsenic (iAs) poisoning causes nausea, vomiting, stomach discomfort, and severe diarrhea. As on long-term exposure is a potent carcinogen, characterized by IARC (International Agency for Research on Cancer). As levels are high mainly in Gangetic regions due to which the people living around are suffering the consequences. The carcinogenicity of As is well established but the immunotoxicity caused by it is still unknown. Some animal model supports the toxicity of As in the immune system as well, but in humans, mainly suffering from human immunodeficiency virus (HIV), it is not well established. iAs suppresses the immune system by acting on different targets and exacerbating infections. Although animal studies have demonstrated that arsenic trioxide (As2O3) reduces viral rebound and restores CD4 + count in vivo when coupled with antiretroviral medications, elemental AS may have devastating effects on the immune system of HIV patients, making them more prone to opportunistic infections (OIs). It is well known that in later stages of HIV infection, neurological problems also complicate the conditions such as cognitive impairment and AIDS dementia complex (ADC). Along with immunotoxicity, As has the potential to damage HIV patients' brains. This article addresses the immunotoxicity of arsenic and exacerbations caused by it, along with the neurotoxicity, particularly in HIV patients residing near the Gangetic belt.

Chemopreventive Role of Black Tea Extract in Swiss Albino Mice Exposed to Inorganic Arsenic.

OBJECTIVE: Chronic exposure to inorganic arsenic (iAs) may cause a number of health problems including skin cancer. Present study is aimed to look into the potential of black tea extract (BTE) to prevent the development of skin carcinoma in Swiss albino mice. METHODS: The study was done on Swiss albino mice, chronically exposed to inorganic arsenic. 150 mice were housed in different cages, 5 in each cage. The control mice did not receive any treatment. Mice were sacrificed at 30, 90, 180, 270 and 330 days. Development of carcinogenesis was assessed by histological studies. Generation of Reactive Oxygen Species (ROS) and Reactive Oxygen Species (RNS) were estimated using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Greiss reagent respectively, and their consequences on DNA (by Micronuclei and Comet assay), protein (by protein carbonyl assay kit) and lipid (by lipid peroxidation) were estimated. Activity of antioxidant enzymes, along with total antioxidant capacity were measured by respective kits. Repair percentage was obtained by Comet assay. Western blotting was employed to study the expression of repair enzymes and expression of cytokines. Sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique was employed to study the activity of various cytokines. RESULTS: At 330 days, invasive squamous cell carcinoma of the skin developed. With increasing time generation of ROS and RNS increased, causing damage to DNA, protein and lipid. Antioxidant defence system gets repressed with time. Capacity to repair the DNA damage is inhibited by iAs, due to alteration in repair enzymes - XRCC I, DNA Ligase I, PARP I, ERCC1, ERCC2, XPA, DNA Ligase IV, DNA PKc and Ku-70. Another consequence of iAs exposure is chronic inflammation due to disrupted cytokine level. Intervention with BTE reverses these deleterious effects, preventing development of skin carcinogenesis.

Assessing the potential value and mechanism of Ginkgo biloba L. On coal-fired arsenic-induced skin damage: In vitro and human evidence.

Exposure through arsenic-contaminated air and food caused by the burning of coal is a major environmental public health concern in Guizhou Province of China. Previous studies have shown that immunological dysfunction is involved in the pathogenesis and carcinogenesis of arsenic; however, knowledge regarding effective prevention measures have not been fully examined. The effect of Ginkgo biloba extract (EGb761) on arsenic-induced skin damage of human immortalized keratinocyte cells (HaCaT) was first evaluated in this study. The results showed that 200 µg/mL EGb761 can reduce the expression of miR-155-5p, and the indicators reflecting arsenic-induced skin damage (Krt1, Krt6c and Krt10) in arsenic-exposed cells (P < 0.05), the expression levels of NF-AT1; the indicators reflecting arsenic-induced immunological dysfunction (IL-2, IFN-γ) in cells; and the levels of secreted IL-2 and IFN-γ in cell supernatants were significantly increased (P < 0.05). Further randomized controlled double-blind experiments showed that compared to the placebo control group, the expression level of miR-155-5p in the plasma of the Ginkgo biloba intervention group, the indicators in the serum reflecting arsenic-induced skin damage (Krt1, Krt6c, and Krt10) and the epithelial-mesenchymal transformation (EMT) vimentin were significantly reduced (P < 0.05), but the levels of NF-AT1 and the indicators reflecting arsenic-induced immunological dysfunction (IL-2, IFN-γ) and EMT (E-cadherin) in serum were significantly increased (P < 0.05). Our study provides some limited evidence that Ginkgo biloba L. can increase the expression of NF-AT1 by downregulating the level of miR-155-5p, alleviating immunological dysfunction, and decreasing the expression of EMT biomarkers, thus indirectly improving arsenic-induced skin damage.

Increased prevalence of Parkinson's disease in soils with high arsenic levels.

INTRODUCTION: Exposure to arsenic (As)-containing pesticides was associated with an increased risk for Parkinson's disease (PD). Arsenic also induced in murine brains α-synuclein aggregates, a pathognomic feature of PD. OBJECTIVES: People living on farms irrigated with high As water in Taiwan are likely exposed to increased As. We addressed whether increased farm soil As levels correlate with an increased PD risk. METHODS: We used the information from several national surveys (1983-1986) on soil metal contents to study the relationships between soil metal contents and PD prevalence in Taiwan. PD prevalence (2009-2013) was calculated with a database from Taiwan's compulsory national health insurance. A patient is defined by a PD diagnosis and prescriptions of Levodopa in three or more office visits in twelve months. We used regression models to study the correlation between PD prevalence and soil metal contents. RESULTS: The PD prevalence ranged from 83 to 213 per one hundred thousand persons in different regions of Taiwan. Among the studied heavy metals, we found only As was significantly associated with the PD prevalence. The top three regions (Yunlin, Chiayi, Tainan) in the PD prevalence list correspond exactly with the top three in soil As levels. Soil As levels and PD prevalence had a strong correlation (r = 0.75). CONCLUSION: PD prevalence is statistically correlated with farm soil As levels in Taiwan.

Arsenic exposure in Indo Gangetic plains of Bihar causing increased cancer risk.

Reportedly, 300 million people worldwide are affected by the consumption of arsenic contaminated groundwater. India prominently figures amongst them and the state of Bihar has shown an upsurge in cases affected by arsenic poisoning. Escalated arsenic content in blood, leaves 1 in every 100 human being highly vulnerable to being affected by the disease. Uncontrolled intake may lead to skin, kidney, liver, bladder, or lung related cancer but even indirect forms of cancer are showing up on a regular basis with abnormal arsenic levels as the probable cause. But despite the apparent relation, the etiology has not been understood clearly. Blood samples of 2000 confirmed cancer patients were collected from pathology department of our institute. For cross-sectional design, 200 blood samples of subjects free from cancer from arsenic free pockets of Patna urban agglomeration, were collected. Blood arsenic levels in carcinoma patients as compared to sarcomas, lymphomas and leukemia were found to be higher. The geospatial map correlates the blood arsenic with cancer types and the demographic area of Gangetic plains. Most of the cancer patients with high blood arsenic concentration were from the districts near the river Ganges. The raised blood arsenic concentration in the 2000 cancer patients strongly correlates the relationship of arsenic with cancer especially the carcinoma type which is more vulnerable. The average arsenic concentration in blood of the cancer patients in the Gangetic plains denotes the significant role of arsenic which is present in endemic proportions. Thus, the study significantly correlates and advocates a strong relation of the deleterious element with the disease. It also underlines the need to address the problem by deciphering the root cause of the elevated cancer incidences in the Gangetic basin of Bihar and its association with arsenic poisoning.

Association of arsenic exposure and cognitive impairment: A population-based cross-sectional study in China.

BACKGROUND: The influence of chronic arsenic exposure on cognitive impairment has been explored broadly by previous studies. However, most of them focused mainly on children rather than adults. In addition, in China, studies in this field are not sufficient. To illustrate how long-term arsenic exposure affects cognitive function, we designed a cross-sectional study involving 1556 adults. METHODS: All of them came from three locations around the Realgar Plant. The cognitive function of the participants was evaluated using a Chinese version of the Mini-mental state Examination (MMSE). The participants' internal arsenic exposure status (hair arsenic concentrations) and the external arsenic exposure status (the distance between the participants' location of residence and the Realgar Plant) were measured. RESULTS: Our research revealed that both of hair arsenic concentrations and the prevalence of arsenicosis, two important indexes, were significantly higher in the cognitive-impaired (CI) group than in the cognitive-normal (CN) group (P < 0.05). In addition, distance from the Realgar Plant was positively correlated with the MMSE scores and was negatively correlated with the prevalence of cognitive impairment. Moreover, our results demonstrated that there was a negative correlation between hair arsenic concentrations and MMSE scores. We conducted a two-level Logistic regression analysis and further confirmed that even after adjusting for potential confounding variables, arsenicosis retained a risk factor for cognitive impairment (odds ratio (OR) = 1.84, P < 0.05). CONCLUSIONS: Our results indicated that chronic arsenic exposure could impair adults' cognitive function in a dose-dependent manner. Additionally, arsenicosis could be an independent risk factor for cognitive impairment.

Did poisoning play a role in Napoleon's death? A systematic review.

INTRODUCTION: On 5 May 2021 we celebrate the bicentenary of Napoleon's death. Despite autopsy findings of a "gastric cancer" and, more importantly, gastric perforated ulcer complicated with bleeding, the questions about the illness that tormented Napoleon at St. Helena and whether the death was a consequence of a poisoning, maintain an unbroken fascination. PubMed/MEDLINE lists hundreds of articles. We also consulted Index-Cat library for articles dating back to the eighteenth century. The present paper presents for the first time a systematic review on this topic. METHODS: The authors divided the selected articles according to the methodology of the papers: (a) illness and autopsy evidence revised by current pathological knowledge; (b) toxicological tests on Napoleon's hair performed by modern analytical techniques. RESULTS: None of the articles denied the toxicological evidence from Napoleon's hair, although analytical papers did not offer homogeneous results due to several biases. Few of them refuted the hypothesis of death due to primary toxic substances. Most considered gastric bleeding is the primary cause of Napoleon's death due to solely or nearly completely gastric cancer or to medications containing antimony, mercury, or arsenic. CONCLUSIONS: Upon review of the contemporary and modern evidence, we classify Napoleon's 1821 death as "unnatural" with massive gastric bleeding due to primary involvement of toxic substances that may have precipitated or exacerbated an underlying "natural" pathological condition or a disease as likely could be a stomach carcinoma; it does not imply criminal intent.

Association of arsenic with recurrence of urinary bladder cancer.

Arsenic is known to be an important aetiological factor for the development of urinary bladder cancer. It is known to be found excessively in ground water in certain geographical areas, including West Bengal. We have studied patients with recurrent bladder cancer from different areas of this Indian state and correlated arsenic as a causative aetiological factor for development and aggressiveness of the biological behaviour of urinary cancer. We included 31 patients from various parts of West Bengal state with recurrent bladder cancer who were operated in our institute. Their clinical and residential data and their arsenic content of tumour tissue were measured. Statistical analysis was performed to test the association of tissue arsenic with clinicopathological features of recurrent disease. We found very high levels of arsenic in tumour tissue in all residents of the districts with high prevalence of arsenic in the drinking water. We also observed more aggressive clinicopathological progression and early recurrence in patients with high arsenic content. We conclude that arsenic is a causal factor in the clinicopathological progression of recurrent urinary bladder cancer. Measures to decrease the level of arsenic in drinking water should be taken as this may both improve clinicopathological outcomes in the recurrence of urinary bladder carcinoma, as well as reducing its overall incidence.

Clinicopathological Correlates: Chronic Arsenic Toxicity Causing Bilateral Symmetric Progressive Optic Neuropathy.

A 70 year-old man presented with insidiously progressing central visual acuity loss in both eyes over several years. Objectively the only abnormality identified on the exam was questionable granularity in the fovea in each eye. Extensive work up which included neuro-imaging, screening blood work for toxic and nutritional causes of optic neuropathy as well as electroretinogram and fluorescein angiography to rule out subtle maculopathy was all unrevealing. When vision continued to deteriorate over the next several years investigations were repeated and again did not yield any positive results. Levels of heavy metals were then obtained after further progression of visual loss, revealing very high levels of arsenic. Subsequent investigations revealed that patient has been spending almost every weekend for the past 28 years alone at a remote country cottage where the sole supply of water was from the local well. He also recalled that 1.5 months after purchasing the cottage he developed hemorrhagic colitis requiring partial colectomy. The specimen from colectomy was located and total reflection x-ray fluorescence testing performed in a specialized lab revealed greatly increased level of arsenic particle in the colonic biopsy from 28 years ago. This case is a reminder that heavy metal toxicity should be considered in a differential diagnosis of patients with bilateral symmetric optic neuropathy.

The association of tryptophan and phenylalanine are associated with arsenic-induced skin lesions in a Chinese population chronically exposed to arsenic via drinking water: a case-control study.

OBJECTIVES: We investigated the association of specific serum amino acids (AAs) with the odds of arsenic-induced skin lesions (AISL) and their ability to distinguish patients with AISL from people chronically exposed to arsenic. DESIGN: Case-control study. SETTING: Three arsenic-exposed villages in Wuyuan County, Hetao Plain, Inner Mongolia, China were evaluated. PARTICIPANTS: Among the 450 residents aged 18-79 years, who were chronically exposed to arsenic via drinking water, 56 were diagnosed as having AISL (defined as cases). Another 56 participants without AISL, matched by gender and age (±1 year) from the same population, were examined as controls. MAIN OUTCOME MEASURES AND METHODS: AA levels were determined by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics analysis. Potential confounding variables were identified via a standardised questionnaire and clinical examination. Multivariable conditional logistic regression model and receiver operating characteristic curve analyses were performed to investigate the relationship between specific AAs and AISL. RESULTS: Tryptophan and phenylalanine levels were negatively associated with AISL (p<0.05). Compared with that in the first quartile, the adjusted OR of AISL in the second, third and fourth quartiles were decreased by 44%, 88% and 79% for tryptophan and 30%, 80% and 80% for phenylalanine, respectively. The combination of these two higher-level AAs showed the lowest OR for AISL (OR=0.08; 95% CI 0.02 to 0.25; p<0.001). Furthermore, both AAs showed a moderate ability to distinguish patients with AISL from the control, with the area under the curve (AUC; 95% CI) as 0.67 (0.57 to 0.77) for tryptophan and 0.70 (0.60 to 0.80) for phenylalanine (p<0.05). The combined pattern with AUC (95% CI) was 0.72 (0.62 to 0.81), showing a sensitivity of 76.79% and specificity of 58.93% (p<0.001). CONCLUSIONS: Specific AAs may be linked to AISL and play important roles in early AISL identification. TRIAL REGISTRATION NUMBER: NCT02235948.

Treatment of lead and arsenic poisoning in anuric patients - a case report and narrative review of the literature.

BACKGROUND: Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical practice in this area is rather scattered. CASE PRESENTATION: We present a case of symptomatic lead and arsenic poisoning from use of Ayurvedic medicine in a 28-year-old man with end-stage kidney disease on chronic hemodialysis. We describe his treatment course with chelating agents and extracorporeal blood purification, and review the relevant literature to provide general guidance. CONCLUSION: Cumulative clinical experience assists in identifying preferred chelators and modalities of extracorporeal blood purification when managing such patients. However, a larger body of real-world or clinical trial evidence is necessary to inform evidence-based guidelines for the management of heavy metal poisoning in anuric patients.

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.

The life-threatening rash of poisoning.

Dermatology is frequently viewed by physician and surgical colleagues as a specialty with few emergencies. Although the majority of dermatology practice is in the office setting, cutaneous emergencies do occur through referrals from primary care and as ward consults. Even though cutaneous signs of poisoning would be an uncommon emergency consultation, it is important for dermatologists to be aware of the clinical presentations so as to be able instigate appropriate time critical treatments.

Acquired disorders with hypopigmentation: A clinical approach to diagnosis and treatment.

Acquired hypopigmented skin changes are commonly encountered by dermatologists. Although hypopigmentation is often asymptomatic and benign, occasional serious and disabling conditions present with cutaneous hypopigmentation. A thorough history and physical examination, centered on disease distribution and morphologic findings, can aid in delineating the causes of acquired hypopigmented disorders. The second article in this 2-part continuing medical education series focuses on conditions with a hypopigmented phenotype. Early diagnosis and appropriate management of these disorders can improve a patient's quality of life, halt disease progression, and prevent irreversible disability.

Is There Any Role of Arsenic Toxicity in HPV Related Oral Squamous Cell Carcinoma?

Arsenic is a potent human carcinogen affecting the rate of cancer deaths worldwide. In India, West Bengal is the worst affected state by arsenic. To our best knowledge, this is the first study relating arsenic toxicity with oral carcinoma, along with HPV infection, the latter being well established in western countries. To find out a possible correlation between arsenic toxicity and oral carcinoma in the population of West Bengal, in or without any association with human papilloma virus infection. Ethical clearance of this study was obtained from the institutional committee. One hundred and four malignant and 103 premalignant cases were selected for this study along with 200 healthy age and sex-matched individuals selected as control (100 each for malignant and premalignant) (2013-2017). On proper consent, their buccal swab and hair samples were assessed for the presence of HPV DNA by DNA extraction, followed by PCR and arsenic estimation by flow injection hydride generation atomic absorption spectrometry respectively. A very highly significant correlation has been observed between arsenic toxicity, HPV infection and the occurrence of oral carcinoma (p value = 2.18e-06; p value = 0.00100 respectively). A correlation has also been observed between these two factors simultaneously, contributing to this malignancy (phi coefficient = 0.2194839). A statistically significant correlation observed between this metal toxicity and viral infection in the occurrence of oral carcinoma in this population indicates a possible symbiotic role between these two factors in this malignancy.