Detailed Analysis of Neurological Symptoms and Sensory Disturbances Due to Chronic Arsenic Exposure in Toroku, Japan

As a result of population growth and the development of tube wells, humans’ exposure to arsenic has increased over the past few decades. The natural course of organ damage secondary to arsenic exposure is not yet well understood. In Toroku, Japan, an arsenic mine was intermittently operated from 1920 to 1962, and residents were exposed to high concentrations of arsenic. In this paper, we analyzed 190 consecutive residents for whom detailed records of neurological symptoms and findings were obtained from 1974 to 2005. All participants were interviewed regarding the presence of general, skin, hearing, respiratory, and neurological symptoms. Neurological symptoms were classified into extremity numbness or pain, constipation, dyshidrosis, sensory loss, and muscle atrophy. Superficial and vibratory sensation was also evaluated. More than 80% of participants experienced extremity numbness, and numbness was the most common neurological symptom. Numbness was associated with superficial sensory disturbance, and was correlated with the subsequent development of other neurological symptoms, including autonomic and motor symptoms. No previous studies have investigated the natural course of chronic arsenic intoxication; thus, these data serve as a guide for detecting early symptoms due to arsenic exposure.

Dietary Selenium Deficiency Partially Mimics the Metabolic Effects of Arsenic

Chronic arsenic exposure via drinking water is associated with diabetes in human pop-ulations throughout the world. Arsenic is believed to exert its diabetogenic effects via multiple mechanisms, including alterations to insulin secretion and insulin sensitivity. In the past, acute arsenicosis has been thought to be partially treatable with selenium supplementation, though a potential interaction between selenium and arsenic had not been evaluated under longer-term exposure models. The purpose of the present study was to explore whether selenium status may augment arsenic’s effects during chronic arsenic exposure. To test this possibility, mice were exposed to arsenic in their drinking water and provided ad libitum access to either a diet replete with selenium (Control) or deficient in selenium (SelD). Arsenic significantly improved glucose tolerance and decreased insulin secretion and β-cell function in vivo. Dietary selenium deficiency resulted in similar effects on glucose tolerance and insulin secretion, with significant interactions between arsenic and dietary conditions in select insulin-related parameters. The findings of this study highlight the complexity of arsenic’s metabolic effects and suggest that selenium deficiency may interact with arsenic exposure on β-cell-related physiological parameters.

Dynamic alteration in miRNA and mRNA expression profiles at different stages of chronic arsenic exposure-induced carcinogenesis in a human cell culture model of skin cancer

Chronic arsenic exposure causes skin cancer, although the underlying molecular mechanisms are not well defined. Altered microRNA and mRNA expression likely play a pivotal role in carcinogenesis. Changes in genome-wide differential expression of miRNA and mRNA at 3 strategic time points upon chronic sodium arsenite (As3+) exposure were investigated in a well-validated HaCaT cell line model of arsenic-induced cutaneous squamous cell carcinoma (cSCC). Quadruplicate independent HaCaT cell cultures were exposed to 0 or 100 nM As3+ for up to 28-weeks (wk). Cell growth was monitored throughout the course of exposure and epithelial-mesenchymal transition (EMT) was examined employing immunoblot. Differentially expressed miRNA and mRNA profiles were generated at 7, 19, and 28-wk by RNA-seq, followed by identification of differentially expressed mRNA targets of differentially expressed miRNAs through expression pairing at each time point. Pathway analyses were performed for total differentially expressed mRNAs and for the miRNA targeted mRNAs at each time point. RNA-seq predictions were validated by immunoblot of selected target proteins. While the As3+-exposed cells grew slower initially, growth was equal to that of unexposed cells by 19-wk (transformation initiation), and exposed cells subsequently grew faster than passage-matched unexposed cells. As3+-exposed cells had undergone EMT at 28-wk. Pathway analyses demonstrate dysregulation of carcinogenesis-related pathways and networks in a complex coordinated manner at each time point. Immunoblot data largely corroborate RNA-seq predictions in the endoplasmic reticulum stress (ER stress) pathway. This study provides a detailed molecular picture of changes occurring during the arsenic-induced transformation of human keratinocytes.

Transgenerational effects in DNA methylation, genotoxicity and reproductive phenotype by chronic arsenic exposure

An emerging concern is the influences of early life exposure to environmental toxicants on offspring characteristics in later life. Since recent evidence suggests a transgenerational transference of aberrant phenotypes from exposed-parents to non-exposed offspring related to adult-onset diseases including reproductive phenotype. The transgenerational potential of arsenic a well know genotoxic and epigenetic modifier agent has not been assessed in mammals until now. In this experimental study, we evaluated the transgenerational effects of arsenic in a rat model with chronic exposure to arsenic. Rats chronically exposed to arsenic in drinking water (1 mg As2O3/mL) (F0) were mated to produce the arsenic lineage (F1, F2, and F3). The arsenic toxic effects on were evaluated over the four generations by analyzing the DNA methylation percentage, genotoxicity in WBC and physical and reproductive parameters, including sperm quality parameters and histopathological evaluation of the gonads. Chronic exposure to arsenic caused genotoxic damage (F0–F3) different methylation patterns, alterations in physical and reproductive parameters, aberrant morphology in the ovaries (F0 and F1) and testicles (F1–F3), and a decrease in the quality of sperm (F0–F3, except F2). Parental chronic arsenic exposure causes transgenerational genotoxicity and changes in global DNA methylation which might be associated with reproductive defects in rats. Combined with recent studies reveal that disturbances in the early life of an individual can affect the health of later generations.

Arsenic Induced Vascular Endothelial Dysfunction Prevented by Antioxidants in Fetal kidneys of Albino Mice

Background &Objectives: Cardiovascular diseases and hypertension has a significant correlation with chronic arsenic exposure through drinking water. This study was designed to investigate the prevention of sodium arsenate induced vascular disorders by Vitamins C& E in fetal renal blood vessels of albino mice. Materials & Methods: Gravid albino mice of BALB/c strain (twenty four) were randomly divided into 4 groups having 6 animals each. Control group A was inoculated with 0.1ml/kg/day distilled water I/P for 18 days. Animals of groups B, C & D were given a single I/P injection of sodium arsenate 35mg/kg on 8th GD, whereas groups C and D were also injected with Vitamin C, 9 mg/kg/day and vitamin E 15 mg/kg/day by I/P route, beginning from 8th GD and continued for the entire pregnancy period. On 18th day of gestation fetal kidneys were extracted. Histological examination of renal blood vessels was performed for any discernable congestion, endothelial disruption and hyalinization and frequency of changes were expressed as percentages. Results: In group (B) sodium arsenate induction resulted in congestion of blood vessels, hemorrhages in glomerular capillaries and thickening of endothelial walls. The addition of Vitamins C and E in groups C & D respectively had reduced the congestion and endothelial thickening. Mean score of histological changes was statistically significant. Conclusions: The results showed the antioxidant prospective of Vitamins C and E in combating against the vascular lesions induced by sodium arsenate.