Abstract
Arsenic, one of the most prevalent naturally occurring elements is referred to as the King of Poisons and is frequently present in diet and drinking water. It is primarily found in an inorganic form. The most common and toxic forms of arsenic are the trivalent form called arsenite which has an oxidation state of + 3, and the pentavalent form called arsenate or As(V). Common organic arsenic compounds are arsanilic acid, monomethylarsonic acid (MMAV), dimethylarsonic acid (DMAV, also called cacodylic acid), trimethylarsonic acid (TMA) and arsenobetaine. Cancer in the lungs, skin, kidney, liver, bladder, and prostate is associated with arsenic toxicity in drinking water. Other sources of arsenic are soil, air, cosmetics, pesticides, chemotherapeutic agent, and the by-product of metal ore smelters. It serves benefits as pesticides, semiconductors, glassware, alloys, and preservatives. In addition, it can be used to treat many ailments like ulcers, syphilis, leukemia, trypanosomiasis, cancers, etc. The negative effects of arsenic are caused by several interdependent modes of action. One of the first proposed MOAs for arsenic, suggested by Binz and Schulz in 1879, was the interference of cellular oxidation from the cycling of oxygen during the interconversion of arsenate and arsenite. As a result, arsenolysis occurs that reduces ATP in the body due to the formation of anhydrides during glycolysis and oxidative phosphorylation. Additionally, the formation of reactive oxygen and nitrogen species also contributes to arsenic toxicity. Formed ROS are involved in genotoxicity, signalling, cell proliferation, and inhibition of DNA repair. Arsenic carcinogenicity includes inhibition of DNA repair under conditions of oxidative stress, inflammation, and proliferative signalling. There are many neurobehavioral disorders and nervous system disorders. Polyneuropathy, and electroencephalographic (EEG) abnormalities are some disorders caused due to arsenic exposure. Arsenic exposure to a mother during her pregnancy causes oxidative stress and slashes ATP production, causing improper development of the brain and altering normal neurobehavior. Arsenic exposure also interferes with cognitive function, particularly learning and remembering during childhood, and causes impaired learning and increased anxiety-like behaviour. Adults are more prone to peripheral and sensory neuropathy whereas children are more prone to neurodevelopmental syndromes such as attention-deficit hyperactivity disorder, intellectual disabilities, learning disorder, and autism.
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1 Arsenic: An Overview
Arsenic is one of the prevalent naturally occurring elements. It (As) is a metalloid possessing properties of both metals and non-metals and has atomic no. 33 and an atomic weight of 74.92. It is a trace element as it is present in less than 1% (< 1%) of most rocks, coals, and soils (Alam et al. 2002). It is characterized as a white, yellow, grey metallic, or black solid that is odorless. It is highly toxic in nature. For centuries arsenic and its compounds have been in produced and utilized for commercial purposes like in pharmaceutical industry, agricultural industry, and semiconductor industry. Agricultural and industrial processes like mining and smelting contributes to high arsenic levels in the environment. Several areas of Japan, Mexico, Thailand, Brazil, Australia, and the USA have high arsenic levels in local water sources, due to mining, smelting, and other industrial activities (IARC 2004). However, Minerals and geogenic sources are primary sources of arsenic contamination with anthropogenic activities also contributing to it via extensive soil and water contamination throughout the world (Smith et al. 1998). Arsenic comes in three major forms: inorganic, organic and arsine gas (− 3 oxidative state), as well as three major valence states arsenic element (0), arsenite (trivalent + 3), and arsenate (pentavalent + 5) among which arsenite (+ 3) and arsenate (+ 5) are the most common toxic inorganic forms (Yousef et al. 2008). In general, trivalent arsenic compounds; inorganic (arsenite) and organic (monomethyl arsenic) are considered more toxic than pentavalent compounds. Arsenic, “when combined with carbon and hydrogen (in plants and animals) forms organic arsenic compounds whereas when combine with oxygen, sulfur, and chlorine in environment form inorganic arsenic compounds” (Martinez et al. 2011). Inorganic arsenic compounds are more prevalent in the environment and contribute more to toxicity. Arsanilic acid, monomethylarsonic acid (MMAV), dimethylarsonic acid (DMAV, also called cacodylic acid), trimethylarsonic acid (TMA) and arsenobetaine are some common organic arsenic compounds. Until the 1970s arsenic was used for medicinal purposes. For the treatment of leukemia, psoriasis, and chronic bronchial asthma, inorganic arsenic was used and for the treatment of spirochetal and protozoal disease organic arsenic was used in antibiotics (ATSDR 2007). It was considered that the father of medicine, Hippocrates used arsenic as a paste for the treatment of ulcers and abscesses. The arsenic paste appears to be beneficial for chemotherapeutic purposes as suggested by the pharmacology texts from the 1880s (Antman 2001). Arsenic organic compounds are used in the agricultural industry as well in the form of pesticides, herbicides, defoliants, and as soil sterilizing agents but in 2009 the US issued an order to remove organic arsenic-containing pesticides from agricultural practices by 2013 (EPA 2009) as the large area of agricultural land gets contaminated due to repeated use of arsenic-containing pesticides. Arsenic and its compounds are also used for a variety of industrial purposes like in the semiconductor and electronics industry, in the manufacturing of alloys, and also in the making of an anti-fungal wood preservative (Tchounwou et al. 1999).
Before the advent of penicillin, some organic arsenicals such as arsphenamine, salvarsan and their derivatives were used as anti-syphilitic agents (Globus and Ginsburg 1933; Osterberg and Kernohan 1934; Russell 1937). Some arsenic compounds are used to treat trypanosomiasis (Harrison et al. 1997) and acute promyelocytic leukemia (Look 1998).
2 Exposure to Arsenic
Based on known toxicity, arsenic is the most toxicant that poses substantial harm to human health and therefore ranked first among the toxicants (Hughes et al. 2011). Arsenic was used throughout history to kill the emperors for their wealth and empire because of many reasons like multiple ways of administration, its potency, and availability, and therefore called as “King of Poisons.” Nonetheless, arsenic is ubiquitous in the environment, the majority of organic and inorganic arsenic uptake by an individual comes from the diet. An average adult in the United States has an intake of 3.2 μg/day as per Schoof et al. (1999) and similar results were found for children as well (Yost et al. 2004) but the European Food Safety Authority (EFSA) estimated a higher intake level 9.1–39.2 μg/day for a 70 kg adult as estimates include the ratio of inorganic arsenic to total arsenic in food i.e., 0.13–0.56 μg/kg/day for an average consumer (EFSA 2009). The diet of an individual has both organic as well as inorganic forms of arsenic compounds and 25% of daily dietary arsenic intake comes from inorganic sources. It is considered that organic forms of arsenic are less toxic than the inorganic forms. Arsenic is found in highest concentration in seafood. Monomethylarsonic acid, DMAsV, arsenobetaine, arsenocholine, arsenosugars, and arsenolipids are arsenic compounds that are organic in nature and majorly found in food.
2.1 Exposure in Water
Inorganic forms of arsenic predominantly exist in water which stabilizes as (trivalent, + 3) arsenite and (pentavalent, + 5) arsenate (Saxe et al. 2006). Arsenic in drinking water at levels over the WHO recommended threshold of 10 ppb (parts per billion) was estimated to have contaminated approximately 140 million people in 2009 (Ravenscroft 2009). Over 1.5 million people in India have been estimated to be exposed to arsenic levels higher than the WHO threshold of 10 ppb leading to more than 200,000 cases of arsenicosis (de Castro et al. 2009). Arsenic ingestion via drinking water was found to be associated with increased cases of cancer and with some non-cancer effects like skin lesions, and neurological effects (NRC 2001).
2.2 Exposure in Soil
Globally, arsenic levels present naturally in soil ranges from 0.01 to over 600 mg/kg with a mean of 2–20 mg/kg. Mostly, inorganic forms of arsenic (trivalent and pentavalent) are present in the soil. Due to the oxidation of trivalent arsenicals, pentavalent arsenic compounds are found predominately in soil (Gong et al. 2001). There are numerous ways to be exposed to arsenic in the soil. Dermal absorption and inhalation of soil particles carried by the wind are some potential exposure routes but incidental ingestion is the most common pathway for the intake of arsenic in soil (Yan-Chu 1994). Numerous studies have revealed that less than 50% of arsenic in soil that is taken by mouth can be absorbed and used by the body (Roberts et al. 2002).
2.3 Exposure in Air
Arsenic exposure from the air is quite minimal compared to that of food and water. The contribution of air in arsenic exposure is less than 1% as per the data collected by European Commission (2000). Arsenic trioxide is an inorganic compound primarily involved in contaminating the air with arsenic. Cosmetic Products also contain arsenic in some amount and act as a source for direct arsenic exposure (Chung et al. 2014). Increasing exposure to arsenic via drinking water and contaminated food to a large population is a matter of great concern due to many toxic effects associated with arsenic (Chatterjee et al. 2010; Rahman et al. 2009).
3 Mode of Action of Toxicity by Arsenic
It is challenging to determine the method of action using the epidemiological literature since long-term exposures to arsenic are probably amplified by exposures to pollution. The harmful effects of arsenic are presumably the result of several pathways; in fact, these mechanisms may be interrelated. Trivalent arsenic compounds (arsenite) have more toxicity as compared to pentavalent arsenic compounds (arsenate) due to higher solubility and slower excretion rate.
Binz and Schulz suggested the arsenic’s initial proposed route of action in 1879 (Parascandola 1977). It suggested that both arsenicals are equally potent by describing how cellular oxidation is interfered with by oxygen cycling during the interconversion of arsenate and arsenite, but as it soon became clear that arsenite is more potent than arsenate, this hypothesis was quickly abandoned.
Phosphate and arsenate have similar properties (after protonation) due to their comparable structure, making arsenate capable of substituting phosphate in different metabolic reactions. Arsenate also forms a less stable ester bond with a higher bond length between As–O in comparison to the P–O bond formed between phosphate and its hydroxyl groups (Dixon 1996). In a process known as arsenolysis, arsenate decouples the production of adenosine 5-triphosphate (ATP) in vitro. This process occurs in the presence of arsenate during glycolysis and oxidative phosphorylation (OXPHOS). Both reactions result in the formation of unstable arsenate anhydrides that are simple to hydrolyse like 3-phosphoglyceroyl arsenate in case of the glycolytic pathway. The end outcome is a reduction in the production of ATP (Gresser 1981).
One of the most extensively researched mode of action (MOA) for arsenic toxicity currently is the production of reactive oxygen and nitrogen species by arsenic (Hughes and Kitchin 2006). There are number of the hypothesised mode of actions for arsenic, such as genotoxicity, cell proliferation, and suppression of DNA repair, that include reactive oxygen species generated by arsenic. Reactive oxygen species (ROS) can be formed by arsenic in a variety of reactions such as during the conversion of arsenite to arsenate (Del Razo et al. 2001), during the metabolism of arsenic resulting in the formation of arsine (Yamanaka and Okada 1994).
“Deletion mutations, oxidative DNA damage, breaks in DNA strand, sister chromatid exchanges, chromosomal abnormalities, aneuploidy, and micronuclei are some of the impacts of arsenic’s genotoxicity” (Basu et al. 2001; Hei et al. 1998; Rossman 2003). Studies on human cell nuclear extracts revealed that arsenic’s indirect effect of inhibiting DNA repair was brought on by the generation of ROS or by altered cell signalling that altered gene expression (Hu et al. 1998). Arsenic also affects the working of enzymes involved in repair mechanisms such as nucleotide and base excision repair (Hartwig et al. 2003). Arsenic trivalent compounds interact with the zinc finger motifs of proteins and disrupt the function of proteins by moving zinc from its binding site causing inhibition of base excision repair (BER) and nucleotide excision repair (NER) activity (Ding et al. 2009; Pia̧tek et al. 2008).
Gentry et al. (2009) examined in vitro cellular and in vivo gene expression alterations after exposure to inorganic arsenic and concluded that arsenic inhibits DNA repair as a method of action for its carcinogenic effect. The findings suggested that DNA repair inhibition under the influence of oxidative stress, inflammation, and proliferative signalling is one of the important processes in arsenic’s carcinogenicity. Such circumstances could result in mitosis progressing without preserving the integrity of the cellular DNA.
Arsenic by altering the signal transduction pathways can regulate the expression of transcription factors and proteins (Bode and Dong 2002; Druwe and Vaillancourt 2010; Huang et al. 2004; Kumagai and Sumi 2007; Leonard et al. 2004; Platanias 2009). In vitro, arsenite activated the protein p38, a component of the mitogen-activated protein kinase (MAPK) cascade (Rouse et al. 1994). Arsenic also activates the c-Jun N-terminal kinases (JNKs) and extracellular-regulated protein kinases (ERKs), two other components of the MAPK pathway (Bode and Dong 2002; Yang and Frenkel 2002). Arsenic also affects the transcription factors nuclear factor-κβ (NF-κβ) and (Nrf2) nuclear factor erythroid-2-related factor 2 (Kumagai and Sumi 2007). By altering a reactive thiol in Iκβ kinase, arsenite seems to prevent activation of tumor necrosis factor-α induced NF-κβ (Roussel and Barchowsky 2000; Shumilla et al. 1998). With the help of generating ROS, arsenic also found to activate NF-κβ (Felix et al. 2005; Wijeweera et al. 2001).
Inorganic arsenic compounds expresses the growth factors to such an extent that it results in a condition called hyperkeratosis which is an indication of arsenic toxicity in humans (Germolec et al. 1997).
Arsenic alters the methylation in DNA, according to investigations done by Zhao et al. (1997). It is unclear what the mechanism is for this. However, dietary factors, DNA methyltransferase inhibition, or shunting of the methyl donor, S-adenosylmethionine for the methylation of both DNA and arsenic are some of the reasons for hypomethylation (Chanda et al. 2006).
Arsenite and arsenate can be transported by human RBCs using anion exchange proteins (Zhang et al. 2000). The necessary sulfhydryl groups of proteins and enzymes are blocked by arsenite due to its interactions with thiol groups present in them. As a result, it disrupt the activity of enzymes involved in the metabolism of carbohydrates such as pyruvate dehydrogenase (Aposhian 1989). Arsenite causes cytoskeletal components to become disorganized once it enters the cell (Li and Chou 1992; Ramirez et al. 1997).
4 Effect of Arsenic on Neurological Function in Human
An unidentified mechanism allows arsenic to reach the brain. It builds up in the choroid plexus, preventing arsenic from entering the brain (Zheng et al. 1991). It induces changes in neurotransmitter levels and cause alterations in functions (Rodríguez et al. 2001). Neural health and behaviour of an individual get affected by the accumulation of arsenic during the childhood stage (Tsai et al. 2003). Arsenic-induced neuritis is a well-known side effect of arsenic toxicity and is known to impair the sensory capabilities of the peripheral nerves. Several other neurological conditions, such as polyneuropathy and aberrant electroencephalographic (EEG) are also induced by arsenic exposure (Rodríguez et al. 2003). Additionally, it has the ability to activate the p38 MAPK and JNK3 genes, which may result in Alzheimer’s disease (Gharibzadeh and Hoseini 2008).
According to the studies, arsenic exposure via drinking water is linked to neurodegeneration, including oxidative stress, damaged protein degradation, intracellular accumulation and autophagy, mitochondrial dysfunction, and more (Escudero-Lourdes 2016). Arsenic exposure via dust and drinking water can also cause damage to the peripheral nerves (Gerr et al. 2000; Mazumder et al. 2010). Arsenic exposure during pregnancy causes oxidative stress and decreased ATP generation, endangering the structural and functional maturity of nerve cells and impairing brain development as well as associated behaviours (Gandhi and Kumar 2013). Arsenic exposure to copper smelters causes them to exhibit a lower rate of conduction of nerve signals and damage to peripheral nerves (Lagerkvist and Zetterlund 1994). Additionally, they may have muscle tiredness, irritability, headaches, severe muscle spasms in their extremities, and lethargy or lack of sleep (Sinczuk-Walczak et al. 2010). Rising urine arsenic levels negatively affect processing speed and fine motor function (Carroll et al. 2017). Arsenic exposure at workplace can lead to neurological and electromyographic abnormalities (Blom et al. 1985). Exposure in mines can be harmful and causes sensory neuropathy and hearing impairment (Ishii et al. 2018).
5 Effect of Arsenic on Cognitive Function in Human
Numerous epidemiological studies have indicated that arsenic exposure can affect how well people think and learn, especially in young children. Children’s intellectual development may be harmed more by chronic moderate exposure to arsenic than by severe acute exposure. Children exposed to arsenic had an IQ drop of 0.4, which can have collective effects in later stage of life (Rodríguez-Barranco et al. 2013). In youngsters between the ages of 6 and 8 years old, a 2007 study discovered a strong correlation between urine arsenic concentrations above 50 g/L and poor performance on tests of remembrance, cognitive, visual and spatial reasoning, linguistic development (Rosado et al. 2007). These children also exhibited symptoms of Attention Deficit Hyperactive Disorder (Roy et al. 2011). Additionally, several studies suggested that arsenic hinders young females’ growth and development more than males, which may have an impact on cognitive function (Gardner et al. 2013). The likelihood of intellectual disability in children rises as the concentration of arsenic and lead increases in the soil, and the prevalence of mental retardation is significantly connected with the presence of soil metals like arsenic, copper, lead, manganese, etc. (Aelion et al. 2008; McDermott et al. 2011). Exposure to arsenic during the gestation and lactation period can cause nitric oxide dysfunction in brain (Zarazúa et al. 2006). “The research showed that prolonged exposure can impair pattern memory and attention switching” (Tsai et al. 2003). Low-level prenatal arsenic exposure and early children’s neurobehavioral performance have been found to have an inverse relationship. Prenatal arsenic exposure can impact newborn infant neurobehavioral development (Wang et al. 2018). In addition, postnatal exposure exhibited impaired learning and increased anxiety-like behaviors (Zhou et al. 2018). Flawed Memory, sleep dysfunction, and visual disruption are among the signs of temporal and occipital lobe exposure to DPAA that are brought on by water consumption (Ishi and Tamaoka 2015). Inorganic arsenic exposure during pregnancy, according to Ramos-Chávez et al. (2015), affected the development of cysteine/glutamate transporters in the cortex and hippocampus and also caused an unfavourable regulation of the NMDA receptor (NMDAR) NR2B subunit in the hippocampus. When exposed to arsenic, there is also a decrease in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) levels as well as a drop in motor coordination (Sharma et al. 2018). Children are more likely to have neurodevelopmental syndromes such as autism spectrum disorders, cognitive impairments, intellectual disabilities, and attention deficit hyperactivity disorder (Schug et al. 2015).
6 Conclusion
A common metalloid, arsenic can be found in food, water, and items manufactured by humans. Numerous epidemiological investigations have produced evidence pointing to a substantial link between exposure to arsenic and neurological and cognitive impairment in both children and adults. Multiple systems and particular pathways involved in various elements of learning, memory, mobility, decision-making, and mood are all impacted by arsenic exposure. Most people are exposed to arsenic through their diet and water consumption. Other sources of exposure include using arsenic as a pesticide, a by-product of smelting metal ore, a chemotherapeutic agent, or coming into contact with arsenic-contaminated soil. Chronic exposure to arsenic damages the peripheral nervous system by causing peripheral neuropathy, whereas acute and occupational exposure to arsenic compounds has been linked to encephalopathy and the impairment of higher neurological processes in patients. Arsenic exposure has been linked to skin, lung, and bladder cancers, according to research. Arsenic exposure results in a large number of health-related problems around the world, and it should be considered a serious threat to humans. Treatment of the afflicted areas should have broader consequences for issues with public health. Arsenic exposure needs to be reduced or eliminated. Arsenic levels in drinking water need to be constantly tracked and checked. Affected areas by arsenic should also have access to clean drinking water. When using cosmetics and when eating a diet, precautions should be made. Arsenic levels in drinking water need to be constantly tracked and checked. Affected areas by arsenic should also have access to clean drinking water. When using cosmetics and when eating a diet, precautions should be made. Arsenic-related health risks to people can be lessened by carefully examining potential sources of exposure.
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Arya, I., Bhardwaj, A., Karn, S.K. (2023). The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human. In: Kumar, N., Kumar, S. (eds) Arsenic Toxicity Remediation: Biotechnological Approaches . Environmental Science and Engineering. Springer, Cham. https://doi.org/10.1007/978-3-031-37561-3_7
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