Exploring the Interplay between Arsenic and Cutaneous Physiology, Pathology, and Regeneration

Abstract

Arsenic poisoning and groundwater exposure are not regional hazards; we can call them a “silent global hazard.” The victims are not always aware of arsenic-exposed daily life and the use of contaminated groundwater. The World Health Organization (WHO) reported that several countries, including Bangladesh, India, Argentina, Chile, Viet Nam, Cambodia, Pakistan, China, the United States of America (USA), and Mexico, have inorganic arsenic naturally present at high levels in the groundwater. Many of these countries exceeded the typical toxic risk index of arsenic level of the WHO standard of 10 μg L⁻¹. The skin is the primary barrier of the body, and compromising the function of the skin is the beginning of psychosocial and physiological discomfort in humans. Hair loss, skin pigmentation, and skin irritation are the leading psychosocial and physiological facts induced by exposure to arsenic contamination. Like hair, nails are susceptible to external harm from arsenic because they may absorb and accumulate arsenic in vitro. The normal architecture of the skin changes to form epithelial hyperplasia, epidermal erosion, hyperkeratosis, degeneration of skin glands, and gradual replacement of hair shaft to keratinized substance. The extreme condition of arsenic exposure ultimately result in various skin carcinomas and alopecia.

1. Introduction

Arsenic is an element abundantly distributed in the earth’s crust. That way, arsenic was exposed to humans and other lives, causing a hazard in strongly occurring regions. Long known to be harmful to human health, arsenic is a common element in the earth’s crust and is frequently found in small amounts in food, water, and air [1]. The use of lead arsenate and sodium arsenite as pesticides has since been phased out in the United States of America (USA), but monomethyl arsenate is still used in agriculture in significant quantities. High exposure to them once occurred from drugs such as Fowler’s solution and chemical pesticides such as sodium arsenite and lead arsenate. Arsenic exposure can result from mining operations where workers breathe ore dust, smelting fumes, or those people who come into contact with the leaching from tailings into waterbodies. Creating glass, using high-arsenic coal to dry food, disposing of a lot of wood that has been chromated with copper arsenate, and using poultry litter that has been given organic arsenical antibiotics can all lead to high exposures. There are three different types of arsenic compounds: first, pentavalent, As⁺⁵ organic or arsenate compounds (such as alkyl arsenates); second, trivalent, As⁺³ inorganic or arsenate compounds (such as sodium arsenate, arsenic trioxide); and third, arsine gas, AsH3, an inert gas produced by the reaction of acids with arsenic. Compared to pentavalent As (As⁵⁺), trivalent As (As³⁺) is more soluble and mobile. Some microbes, such as some types of Bacillus and Pseudomonas, have the ability to oxidize or reduce arsenic [2]. The deadly and extremely volatile arsenes can be produced by Penicillin brevicaule, also known as the arsenic fungi. Fungi, yeasts, and bacteria can methylate arsenic to produce monomethyl arsonate, dimethylarginine, and gaseous variants of arsine, which are found in large quantities in soils [3]. According to [4], two rod-shaped gram-positive bacteria were to be able to eliminate about 50% of arsenite and arsenate from culture media containing arsenic that had been isolated from the Purbasthali block of West Bengal, India. It has been proven beyond a shadow of a doubt that one of the main contributors of arsenic in polluted groundwater throughout much of the world is the microbial mobilization of arsenic in the aqueous phase [5]. Understanding the processes used by purely cultured bacteria that were isolated from arsenic-polluted groundwater will deepen our understanding of the role of microbes in the biogeochemical cycle of arsenic. It may also make it easier to create effective management methods for groundwater resources that will provide affected populations with clean drinking water [6].

As a result of arsenic bacterial metabolisms shaping the lithosphere, arsenic biogeochemistry is inextricably linked to the evolution of microbes on Earth [7]. While extensive research has been done in recent years on the microbial communities that live in arsenic-affected Holocene and Pleistocene aquifers in Asia, little is known about the microbial communities responsible for the arsenic dissolution in polluted groundwater in Northern Italy [8].

2. Sources of arsenic exposure

Arsenic reaches out into the environment via various natural sources like volcanic eruptions. A broad, natural spreading occurs as a result of weathering and sedimentation. Arsenic is unintentionally released into the environment by fossil fuel combustion and non-ferrous metal smelting, typically as arsenic trioxide. In conjunction with sulfur, as in the majority of coals, arsenic builds up on fly ash particles during combustion together with other trace elements. Despite being present in very small amounts in coal, fly ash has a large amount of arsenic [9].

Arsenic enters the body in three ways: through the respiratory tract, through the gastrointestinal tract, and through the skin. The size and chemical makeup of the arsenic particles determine how far arsenic will penetrate into the lungs [10]. The amount of absorption in the gastrointestinal tract depends on the solubility of arsenic molecules [11]. Arsenic has demonstrated the capacity to disrupt the population of gut microbes, producing adverse responses in mice and people [12]. Around 95% of the dose consumed by soluble trivalent compounds of arsenic is absorbed from the gastrointestinal tract [13]. Acute gastrointestinal symptoms are more frequently observed following intake of arsenic than after inhalation or cutaneous absorption. The stomach and intestine can experience severe inflammation, necrosis, and perforation of the mucosa and submucosa. Bloody diarrhea may emerge as a symptom of hemorrhagic gastroenteritis [14]. Arsenic absorbed through the skin is poorly studied, and evidence suggests that arsenic trichloride and arsenic acid are absorbed via skin. The arsenic acid-induced dermal injury will promote absorption [10]. Arsenic exposure may occur while handling conserved wood items that contain it through direct skin contact. However, just barely is known about the chemical form, absorption circumstances, kinetics, or other details necessary to conclude skin absorption in certain populations [15]. Arsenic trichloride splashes on a worker’s skin have been reported to have toxic consequences in the occupational literature [16].

Arsenic pollution is not a regional hazard because of the stratification of the compound naturally found throughout our environment. The World Health Organization (WHO) identified the world’s major arsenic-exposed regions, including Bangladesh, India, Argentina, Chile, Viet Nam, Cambodia, Pakistan, China, the United States of America, and Mexico. The sample water from the most affected regions of Argentina has an approximately 88% of 86 groundwater sources exceeding the arsenic concentration according to the WHO guideline value [17] in 2007. The risk of arsenic poisoning from drinking water from tainted tube wells has been estimated to affect 50 million people in Bangladesh [18]. Arsenic groundwater pollution has been discovered in Cambodia, where around 100,000 family-based wells provide drinking water. A previous study of an extensive groundwater survey and seasonal fluctuations in the Mekong River floodplain comprised 3700 km² (131 samples, 30 parameters). The 1.2 million residents of this region face a health risk due to the arsenic levels, which range from 1 to 1340 gL⁻¹, with an average of 163 g L⁻¹, and 48% exceeding 10 g L⁻¹. The potential exposure of 350 people km⁻² to chronic arsenic poisoning is comparable to Bangladesh’s 200 km⁻² magnitude [19]. The investigation of the long-term dangers of arsenic-caused cancer has numerous significant advantages due to an unusual arsenic exposure situation in northern Chile. River water from the nearby Andes Mountains that contained significant levels of naturally occurring arsenic was diverted to the area’s major city (Antofagasta) for drinking in the late 1950s [20]. As a result, the city’s water supply had an average arsenic concentration of 860 g/L for 13 years (1958 to 1970) [18, 21]. According to the West Bengal study’s conclusions, arsenic-induced disease manifestation in humans may be caused by deficiencies in DNA repair ability, disruptions in the methylation of the p53 and p16 gene promoter regions, and changes in genomic methylation. Arsenic-induced keratosis has been found to be more common and associated with P53 polymorphism [22].

3. Impact of arsenic exposure: a global scenario

In the previous two to three centuries of the last completed millennium, the Bengal region faces the first incidence of arsenic detection in groundwater in India. The Ganga-Brahmaputra River delta, which creates the Bengal Basin, is where most of the arsenic in drinking water is found. This has been explained by the significant amounts of sediments rich in arsenic that these rivers carried downstream during the Pleistocene and Holocene epochs [23]. The detection of arsenic has been reported in the Indian states of Uttar Pradesh, Bihar, Assam, Chhattisgarh, Jharkhand, and Karnataka. Most of it is found in alluvial soil in Bihar, West Bengal, and Uttar Pradesh, whereas in Chhattisgarh, it is predominantly found in volcanic rocks. Now that populations in Bangladesh and India numbering in the tens of millions who are at risk make well water drawn from geological formations with high-arsenic levels a serious health problem, this issue is brought up [24]. In India, groundwater arsenic contamination and its health effects were documented for over 28 years (1988–2016) in the states of Jharkhand, West Bengal, Uttar Pradesh, and Bihar in the Ganga River floodplain and the states of Assam and Manipur in the Brahmaputra and Imphal river flood plains. Although Rajnandgaon village in Chhattisgarh state is not on a flood plain, the groundwater there is still contaminated with arsenic. After being analyzed, more than 170,000 samples of tube well water from the impacted states contained arsenic, with a maximum concentration of 3700 g/L in half of the samples [25].

Due to water contamination, several communities are at risk of a high prevalence of skin cancer, especially Chileans as well as some Taiwanese. Elderly people who exhibit indications of persistent arsenic poisoning are more likely to develop cancer. Animals generally have a much lower incidence of As-induced cancer [26]. Research conducted in the past on residents of southwest Taiwan revealed a connection between high-arsenic exposure and altered skin pigmentation, Blackfoot disease, hyperkeratosis of the palms and soles, which is brought on by poor circulation and endothelial cell damage, and skin cancer and several other organs such as the liver and lung bladder. Skin hyperpigmentation and keratosis occur at drinking water concentrations of around 50 parts per billion (ppb), the previous US drinking water norm, according to more recent concentration-dependent- tests conducted in Bangladesh [27]. India and Bangladesh have been claimed to be the most severely affected nations, with over 100 million people potentially at risk due to excessive levels of arsenic in groundwater [25].

It has been found that natural sources are the primary causes of this contamination. But only in a few zones have the precise mechanisms that release these toxic substances into groundwater been identified [28]. In many areas of Pakistan, arsenic is a significant problem, and contaminated groundwater causes substantial health risks. Lahore’s rural areas have reported on early research on groundwater and the health dangers of arsenic poisoning, but no such studies have been carried out in the nation’s major cities [29]. Aquifers in different parts of Mexico have been found to contain concentrations of arsenic and fluoride that are higher than those of Mexican drinking water standards.

Arsenic may travel long distances and adhere to tiny airborne particles, remaining in the atmosphere for several days. Mild exposure to arsenic may occur of its beneficial uses. Arsenic is frequently used as a pesticide, herbicide, or wood preservative due to its germicidal properties and the ability to withstand rot and decay [30]. Since many common compounds containing arsenic can dissolve in water, they can contaminate lakes, rivers, or underground water when they are exposed to rain, snow, or abandoned waste from industries. Because of this, arsenic pollution of groundwater poses a severe risk to human health globally.

4. Routes of arsenic exposure and its consecutive health hazards

Detrimental health consequences, such as hyperpigmentation, keratosis, different types of cancer, and vascular illnesses, have also been connected to long-term arsenic exposure from ingesting contaminated food or water or breathing contaminated air in a number of different nations [31, 32]. According to a recent article by the US Agency for Toxic Substances and Disease Registry, occupational workers are more likely to be exposed to arsenic through inhalation and the dermal layer than the general population.

There are no reliable studies to quantify the rate of arsenic absorption via healthy human skin. The skin may be a potential route of absorption in humans, according to occupational incidents where significant interaction of the skin with aqueous solutions of inorganic arsenic compounds resulted in systemic poisoning and increased urine arsenic excretion by the employees involved in their manufacture [33]. On the other hand, the spectrophotometric study reveals that mean arsenic levels in hair represent systemic absorption. When hair grows, it is absorbed into the matrix and only lost again when lost or removed [34, 35]. Arsenic is difficult to detect because it is found in hair in trace amounts, despite providing strong evidence in numerous investigations. The scalp is primarily affected by arsenic from food, work, and water [36].

Oral exposure to arsenic is the main way people get exposed to it. Thus, most diets are the main way people are exposed to arsenic. Routine activities may expose young children to small amounts of arsenic orally, which may be a significant exposure route. A pathologic sign of chronic exposure is patchy hyperpigmentation, which can occur anywhere on the body. And it occurs predominantly on the axillae, groin, neck, eyelids, temples, and nipples. “Raindrops on a dusty road” frequently describes the dark brown patches with scattered lighter specks. In extreme cases, the pigmentation covers a large portion of the chest, back, and belly. Pigment alterations have been seen in populations regularly consuming water with an arsenic content of 400 parts per billion (ppb) or more [14]. The palms and soles are the most common sites for arsenical hyperkeratosis. Topical application of arsenic for medical purposes will only contribute to total body load via direct dermal uptake of arsenic.

5. The fate of arsenic: a comprehensive overview of its biochemical aspect

After absorption, arsenic compounds typically undergo metabolic processing in the liver, where they are transformed into a variety of inorganic and organic species such as arsenite, dimethylarsinate, arsenate, and monomethylarsonate. Arsenic, both organic and inorganic, is quickly absorbed into the bloodstream and is circulated to the human digestive system. Since they are not well absorbed by tissues, organic arsenic forms are typically regarded as harmless [37]. Nevertheless, inorganic arsenic species are highly reactive and impact several intracellular processes [38]. Along with the significant role that methylated trivalent arsenic compounds play in the development of cancer, the ability of arsenic compounds to cause cancer in humans in the skin, lung, liver, and bladder appears to be best explained by the oxidative stress theory [24].

Arsenic exposure can come out of the environment via natural as well as man-made sources. Skin absorption is among the several ways through which arsenic enters the body [39, 40]. International Agency for Research on Cancer (IARC) has acknowledged arsenic as a class 1 carcinogen. Its effects were mediated through abnormal DNA repair and other cellular mechanisms [41, 42]. Arsenic has an impact on all organ systems in our body. Skin, the interface between the external and internal environments, is the most vulnerable organ in our body. Dermal impacts are the most sensitive and are considered the endpoint of arsenic exposure. Often, arsenic toxicity is manifested through the skin [43]. Often it takes about more than 20 years for its manifestation [44]. The time between exposure and the development of skin cancer can last up to 30 years. Long-term exposure to arsenic will lead to skin darkening and hyperkeratosis [45]. Dermal effects, such as melanosis, leukomelanosis, keratosis, Bowen’s disease, and cancer, will result from chronic exposure to arsenic [46]. Pigment alterations and palmoplantar hyperkeratosis also characterize chronic arsenic exposure. Arsenical keratoses may develop into cancer. Mees lines in the nails may be a sign of the delayed consequences of acute or chronic exposure. Mees lines are horizontal ridges found in digit nails [14].

However, due to the local absorption of proteins containing sulfhydryl groups, the skin is a crucial organ for arsenic toxicity independent of the route of exposure. Despite the fact that arsenic poisoning’s effects on the skin are characterized by multifocal lesions all over the body, chronic arsenic build-up increases the skin’s vulnerability to ultraviolet (UV) radiation and is linked to an increased risk of tumors of exposed skin [47, 48]. Because of the high quantities of keratin in hair and skin, autoradiographic investigations on the concentrations of arsenic in animals reveal that these tissues have the highest levels of long-term retention [49]. Desquamation and hair loss are important methods of excreting arsenic due to its attraction for sulfhydryl groups, which causes build-up and persistent retention in keratin-rich tissues like hair, skin, and nails [50].

Liver damage, dermatological lesions, respiratory disorders, peripheral neuropathy, ocular inflammation, and irritations, make up the majority of the common health outcomes in humans to date. Recently, in vitro research using human cancer cell lines has revealed these harmful mechanisms linked to liver, neuronal, lungs, bladder, and dermatological health outcomes [51, 52]. With human cancer cell lines, studies on arsenic over the previous 10 years have demonstrated that arsenic alters the pattern of gene expression within the cell as well as epigenomic profile, telomere length, cell cycle, etc. [53, 54].

Hutchinson published the first account of arsenic-induced skin cancer and its connection to hyperkeratosis in patients exposed to medicinal arsenic in 1887 [55]. The human elementary canal is where arsenite chemical is mostly absorbed and deposits heavily in all kinds of bodily cells. As a result, it has an impact on the cell’s enzyme function, and eventually the damaged cells progressively decompose [56].

The distinctive skin lesions included keratoses on the palms and soles and pigmentation changes, mostly on the upper chest, arms, and legs. Skin cancers, raindrop guttate hypopigmentation, excessive arsenical keratosis (scaly skin formation), excessive scaly skin formation on the palms and feet, and exfoliative acne are some of the other signs caused by arsenic (particularly Bowen’s disease) [57]. The most prevalent skin alteration associated with chronic arsenic toxicity is hyperpigmentation [58].

People having age over 40 years had the highest prevalence of arsenical dermatosis. The prevalence did not differ by gender. A 60-year-old man from Murshidabad, West Bengal, showed several raised lesions on his palms and soles that had been present for 4 years and were painless and asymptomatic. Both palms displayed numerous hyperkeratotic papules upon cutaneous examination. The ulceroproliferative lesion’s histopathological analysis suggested that it was a moderately differentiated squamous cell carcinoma. Hair and nail samples had substantial amounts of arsenic. He was diagnosed with arsenical keratoses and squamous cell carcinoma and underwent surgery and chemotherapy for his condition [59].

To comprehend the mechanism of toxicity and evaluate the health effects, biomarkers of inorganic arsenic exposure are required. The four biological substrates that are most frequently used in epidemiological studies are blood, urine, hair, and nails [60]. In addition to the key function that methylated trivalent arsenic compounds carry in cancer development, the oxidative stress theory appears to be the mechanism of action that best accounts for the ability of arsenic compounds to trigger cancer in humans in the skin, lung, bladder, and liver [24]. The presence of arsenic in these biological samples suggests that it was absorbed systemically after exposure. In addition, they can bind to hair and nails, which can serve as biomarkers of arsenic toxicity caused due to external exposure [61]. Despite the fact that human fingernails naturally contain arsenic, a study explored the possibility of using arsenic levels as a biological indicator of occupational exposure to this substance [62]. Arsenic uptake through drinking water ingestion is related to the concentration of arsenic in fingernails, a biomarker for human exposure.

In addition to the 40 healthy participants from the arsenic-affected rural areas of Iran, 49 fingernail samples were also collected from people who lived in areas where drinking water sources had not been reported to be contaminated with arsenic. It was found that the fingernail arsenic contents in 50 and 4.08% of the samples taken from arsenic-contaminated and reference villages were higher than the typical arsenic values of nails (0.43–1.08 g/g) [63]. The measurement of total arsenic in nails can be performed using the inductively coupled plasma-mass spectrometry (ICP-MS) technique [64].

It can be challenging to select an appropriate biomarker to study arsenic exposure. A biomarker of arsenic exposure from drinking water is the total arsenic concentration in blood or urine [65]. Contact with water and particles containing arsenic can contaminate nails, hair, and skin, but chemical hair therapies can change the rate at which arsenic accumulates in the body [66].

6. Long-term arsenic exposure: chronic health impacts

Drinking water contaminated with arsenic can have long-lasting negative effects on the condition of one’s physical well-being. The prevalence of skin lesions and arsenic concentration in drinking water have a dose-response relationship, according to sizable population research conducted in West Bengal, India [67].

Consumption of water containing arsenic can lead to adverse health effects such as cutaneous abnormalities and lesions. Keratosis and pigment disorders, including hyperpigmentation and hypopigmentation, are the diagnoses. According to a particular study, compared to the exposed group, the incidence of hyperkeratosis, including Palmar hyperkeratosis, was 34 times higher than in the control group [68]. The most recent estimate of the population exposed to arsenic concentrations over the WHO safety threshold (10 g/L) for drinking water showed that about 140 million people in atleast 70 countries have been affected. These findings imply that, despite the most recent recommendations for the maximum allowable limit of arsenic in drinking water, the population that has been chronically exposed to arsenic for a long time may still be in danger.

The majority of earlier studies on arsenic toxicity focused on population-based epidemiological outcomes, analyses of particular disease risks, chemical-based and physiologic aspects of arsenic metabolic processes, and research on related gene expression profiles, DNA damage, and cancer; all of which were linked to the process of toxicity and subsequent consequence or manifestation of disease. To explain differences in susceptibility to arsenic exposure, research is currently shifting toward the study of epigenetic modifications (DNA methylation, microRNA (miRNA), and histone modification) [69].

6.1 Exploring the link between arsenic exposure and skin lesions

One of the most prevalent signs of chronic arsenic poisoning is skin lesions. A rise in the frequency of skin lesions was found even at a mild exposure range of 0.005–0.01 mg/l of arsenic in drinking water [70].

Arsenical skin lesions were recognized when at least one of the following criteria was met: changes in the body’s covered surfaces’ pigmentation and/or keratosis, especially on the palms and toes. Anywhere on the body, melanosis can appear, and its typical symptoms include raindrop-like pigmentation or extensive dark brown dappling in non-exposed areas of the body. The distribution of leukomelanosis is the same and it can exist even when there is no melanosis. Keratosis is characterized by small, nodular elevations resembling corns, typically 0.4–1 cm in diameter. It can be seen on the lateral edges of the palms, soles, fingers, heels, and toes. On the soles and palms, diffuse keratosis can also be seen. Melanosis and keratosis are the most obvious skin lesions linked to arsenic toxicity, which can eventually turn into skin cancers. There were 675 subjects with keratosis and 1135 subjects with melanosis overall in the survey that was conducted in Bangladesh, with a sex ratio of 1.5:1 (men:women) [71].

In addition to accumulating other trace elements, toes can also accumulate arsenic. This suggests that there are frequent exposure sources and metabolic pathways [72]. Toenail arsenic is also linked to cadmium, manganese, and lead concentrations [73]. According to research, the total arsenic concentrations in toenails can serve as a biomarker for prolonged exposure. They are being studied because they can accumulate arsenic, have a slow growth rate, and may be less susceptible to external contamination than samples from fingernails and hair [74]. Arsenic content in toenails and several cancers is correlated, including squamous cell skin cancer, which has been found [75]. Higher toenail arsenic concentrations were linked to an increased risk of keratosis in Bangladesh and India [76]. Due to arsenic’s high affinity for keratin, hair contains more of it than other tissues. In an examination of samples taken from Chilean villagers, inorganic arsenic, commonly known as inorganic arsenic, was the most common kind of arsenic found in human hair [77].

6.2 The cause and devastating impact of arsenic-induced skin cancer

Skin cancer and other internal cancers are known to be caused by the known cancer-causing agent—arsenic. Cancer is slowly developed after decades (approximately 20 years) after exposure to contact with the carcinogen [78]. The abnormal epidermal keratinocyte growth, differentiation, dysplasia, and dermal inflammatory infiltrates that are the hallmark of arsenical skin cancer may be due to mitochondrial control of cell proliferation, energy production, reactive oxygen species (ROS) production, DNA damage and mutations, and immune control [41].

These dermatological lesions and the risk of skin cancer are significantly correlated. Basal cell carcinoma (BCC), Bowen’s disease, and squamous cell carcinoma (SCC) are the three skin cancers most frequently triggered once exposed to arsenic [45]. Strong evidence suggests that only highly exposed populations exhibit a linear dose-response relationship between the concentration of arsenic and cancer risks. The dose-response curve may be influenced by several factors, including gender, ionizing radiation, smoking, diet, and genetic susceptibility, which may act synergistically or as confounders [24].

In the region of Taiwan where persistent arsenic breakouts take place, a study was conducted on the prevalence of skin cancer. The majority of the population had Blackfoot disease, which showed up as keratosis and hyperpigmentation on the palms and soles. According to a survey on chronic arsenicism conducted on 40,421 people in 37 villages, 360 had Blackfoot disease, 428 had skin cancer, 7418 had hyperpigmentation, and 2868 had keratosis. In these circumstances, they commonly coexisted with one another. The most prevalent types of skin cancer, epidermoid or basal cell carcinomas, typically appear on exposed parts including the head, face, and extremities [79].

6.3 Arsenic’s societal impact: a growing cause for concern

The socioeconomic and demographic circumstances of the population exposed to arsenic dangers worsen its effects on human health [80]. Typically, underprivileged people suffer the most and are most at risk when arsenic levels in food and drinking water are high [81]. Children are the most susceptible age group and are at risk for the build-up of heavy metals since they require more energy and water per body weight than adults [82]. Arsenic at greater concentrations can result in various acute arsenic poisoning symptoms, including vomiting, abdominal discomfort, and diarrhea. The following symptoms are sensations of numbness and tingling in the extremities, cramping muscles, and in severe cases, death [83].

Numerous studies have examined the association between long-term exposure to arsenic and multiple medical conditions, including Blackfoot disease, cardiovascular and cerebrovascular diseases, chromosomal abnormalities, diabetes, hypertension, and peripheral vascular disease [68]. Arsenic readily crosses the blood-brain barrier and can build up in the striatum and hippocampus, among other brain regions. This increases arsenic toxicity and tissue damage [84]. Numerous neurological disorders are known to be brought on by arsenic exposure through various molecular mechanisms, including cytotoxicity, cellular DNA damage, chromosomal abnormalities, and a rise in the production of reactive oxygen species [85]. Capillary damage and dilatation also occur, causing fluid to transude, which in turn reduces blood volume and results in circulatory collapse. Blackfoot is a prevalent disease in Taiwan that is brought on by arsenic (As) and is characterized by the loss of blood flow to the extremities, which causes gangrene [26]. Arsenic-induced capillary alterations bring on kidney tubular degeneration.

6.4 What role does arsenic play in signaling pathways and stem cell functioning?

Signaling pathways can be impacted by arsenic. For instance, exposure to arsenic can result in neuronal cell death via activation of the nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) pathways [86, 87]. Arsenite (3 μM) exposure activates the serine-threonine liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) signaling pathway and can suppress neuronal expansion [88]. It has the ability to modulate the protein kinase B (AKT) pathway to prevent myocyte differentiation and muscle regeneration [89]. Low amounts of arsenic seem to have the ability to inhibit stem cell development in stem cells via the Wnt/β-catenin pathway. The viral skin pathogen can interact with the effect of arsenic on skin. Arsenic exposures reduce the immunological response, at least in part, by reducing dendritic cell immune surveillance and cluster of differentiation 4 (CD4) cell activation [90]. Arsenic weakens the immune system’s ability to fight off infections. Arsenic exposure has been shown to have this effect for influenza A, which raises viral titers and morbidity [91]. Similar to arsenicosis, human papillomavirus (HPV), a pathogen that only affects humans, shares several clinical traits with it, and may be a factor in arsenical skin disease. By avoiding recognition by Langerhans cells, cutaneous HPV develops infection. Therefore, it makes sense that arsenic’s immune suppression could expose preexisting illnesses or weaken the immune system’s response to fresh exposures [92]. In addition to its impact on the functioning of the immune system, arsenic may facilitate the process of HPV-mediated neoplasia, which involves the incorporation of HPV DNA into the keratinocyte genome. The expression of genes that encourage keratinocyte proliferation and hinder differentiation is brought on by damage to the episomal HPV DNA, such as that forced on by oxidative stress [93]. Interleukin-1 (IL-1) production in the murine keratinocyte cell line HEL30, which is linked to skin cancer, has been greatly attributed to arsenic [94]. There have been studies on arsenic-induced myocardial aberrations. When applied to rats, arsenic decreased cardiomyocyte viability, increased ROS production, and caused apoptotic cell death by activating caspase-3 and cleaving poly-ADP ribose polymerase (PARP). This increased IkB kinases (IKK) and NF-kB (p65) phosphorylation via an oxidative-mediated pathway, and ultimately caused cardiac apoptosis [95]. A transfected thyroid hormone receptor-mediated gene response element-luciferase construct and the endogenous thyroid receptor-regulated type I deiodinase (DIO1) gene were both significantly altered by treatment of human embryonic NT2 with low concentrations of arsenite (0.01–5 μM sodium arsenite) [96].

6.5 Aging

The epigenome may play a role in the health effects of arsenic and act as a biomarker for exposure. Numerous epigenetic biomarkers have been developed to measure various aspects of aging, including chronological age, morbidity, and mortality, in particular tissue types. Ongoing research on the health effects of aging as in Bangladesh revealed that middle-aged men had the highest incidence of as-induced skin lesions [97]. Organ pathophysiology is directly correlated with age, and oxidative stress negatively impacts the body and worsens with age [98]. There is a correlation between epigenetic age acceleration and prenatal and early-life arsenic exposure [99]. The balance between adipogenic and osteogenic differentiation may be impacted by arsenic exposure’s promoting senescence in human mesenchymal stem cells. In a study conducted comparing women without arsenic skin lesions, those with arsenic skin lesions were 1.5 years younger at the time of menopause [100].

6.6 Strategies for the management of arsenicosis

Arsenicosis has no known treatment, so the best course of action is to stop drinking water that has been contaminated with arsenic [101]. The availability, effectiveness, and development potential of nearby alternative water sources will determine the region’s choice of water source. In most areas with rainfall, safe surface water for drinking, cooking, or collecting rainwater has good potential. It can be used in conjunction with technology found in the average home if sufficient storage tanks are provided. This approach is especially helpful where there are few sources of surface water in sufficient quantities and of high quality. For the Treatment of arsenic-contaminated water, various options are available depending on technologies, cost, and acceptability and range from filter units for domestic use, through filter units for communitylevel use to piped supply of arsenic-treated water. Arsenic-contaminated water can be treated using a range of methods. Filter units for domestic use, community use, and piped supplies of water treated for arsenic are all options, depending on technologies, cost, and acceptability. Studies have shown that medications, various types of herbal remedies, vitamin C supplements, and other dietary supplements may reduce the effects of arsenic toxicity [102].

• Avoiding drinking water and other sources that may have high levels of arsenic.

• Setting up a mechanism to monitor drinking water quality and developing intersectoral connections to ensure a steady supply of arsenic-free drinking water are both essential.

• Treatment is the use of nutrition and medicines to hasten recovery and prevent further sickness.

• Arsenic in urine, hair, and nails can be tested for by establishing ties to existing diagnostic centers.

• The administration of all-encompassing palliative care in an effort to resolve specific problems or alleviate bodily symptoms.

• Medical observation is a secondary method for avoiding undesired outcomes.

• Offering sufficient therapy, education, and rehabilitation to deal with the psychological fallout of the disease.

7. Conclusion

Arsenic is present in small amounts in food, water, and the air in the earth’s crust. By burning fossil fuels and smelting non-ferrous metals, arsenic is unintentionally released into the environment, usually as arsenic trioxide. Arsenic enters the body in three different ways: through the skin, through the gastrointestinal tract, and through the respiratory tract.

Arsenic compounds are usually metabolically processed in the liver following absorption, where they are converted into various inorganic and organic species such as arsenite, dimethylarsinate, arsenate, and monomethylarsonate. The major areas of the world exposed to arsenic include Bangladesh, India, Argentina, Chile, Viet Nam, Cambodia, Pakistan, China, the United States of America (USA), and Mexico, according to the World Health Organization (WHO). Fifty million people may be at risk of arsenic poisoning after consuming water from contaminated tube wells. Skin lesions are one of the most common symptoms of chronic arsenic poisoning. In several nations, long-term arsenic exposure from consuming contaminated food or water or breathing contaminated air has also been linked to detrimental health effects such as hyperpigmentation, keratosis, various types of cancer, and vascular illnesses.

Indicators of arsenic toxicity brought on by external exposure include hair and nails. Many epigenetic biomarkers have been developed to measure different aspects of aging, such as chronological age, morbidity, and mortality, in specific tissue types. To prevent the effects of arsenic toxicity, it is best to stop drinking water that has been contaminated with arsenic and start taking dietary supplements.