Arsenic-induced Health Hazards

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Abdulrahman Alsayegh	--	2801	2022-05-31 22:19:53	\|
2	format change	Peter Tang	Meta information modification	2801	2022-06-01 03:02:19	\|

This entry is adapted from the peer-reviewed paper 10.3390/nu14102136

Arsenic (As) is a naturally found crystalline metalloid with ubiquitous distribution throughout the earth’s crust. As exposure to the human food chain ecosystem comprises air, water, food, and soil. Daily diet contamination depends on the inorganic or organic forms, oxidation state, water solubility, and food matrix. The differentiation and categorization of different foods as sources of inorganic and organic As contamination in daily life is an important issue.

arsenic health hazards water

1. Introduction

As is a naturally found crystalline metalloid with ubiquitous distribution throughout the earth’s crust. As exposure to the human food chain ecosystem comprises air, water, food, and soil. Daily diet contamination depends on the inorganic or organic forms, oxidation state, water solubility, and food matrix. The differentiation and categorization of different foods as sources of inorganic and organic As contamination in daily life is an important issue. Industrialization, urbanization, and anthropogenic activities such as glassware, industrial chemicals, lead alloys, and pharmaceuticals manufacturing processes are prime causes of arsenic exposure in the environment. Heavy metal concentrations in all-natural water reservoirs exceed the cut-off of WHO’s safe limits for human health ^[1]^[2].

It is found that both organic and inorganic forms have no taste, odor, or color. Pentavalent arsenic (As (V) or arsenate) and trivalent arsenic (As (III) or arsenite), both in inorganic and organic forms, are present in natural ecosystems ^[3]^[4]^[5]. Inorganic arsenic (As (III) and As (V) or a combination of both) in ground water and biological activity transformation converts into arsenobetaine and different arsenosugars. Moreover, lipid-soluble arsenic forms, namely arsenolipids, have also been detected in fish and algae. Different As species can be seen in Table 1.

Table 1. Different species of arsenic and their distribution in various foods with toxicities.

Different Species of Arsenic	Abbreviation	Distribution	References
Arsenocholine	AC	Arsenic species generally found in seafood and oxidized to arsenobetaine in a biological system.	^[6]
In organic arsenic	iAs	Found in most foods and its presence in water is in low amounts.	^[7]
Arsenite	As (III)	It is highly toxic in nature but present in lesser amounts in most foods.	^[7]
Arsenate	As (V)	It is highly toxic in nature but present in lesser amounts in most foods and water.	^[8]^[9]
Dimethylarsinate	DMA	Found in seafood and terrestrial foods and is a urine metabolite of iAs arsenosugars.	^[10]
Dimethylarsinite	DMA (III)	It cannot be detected in food samples. It is a metabolite of iAs and can be seen in human urine samples but is highly toxic in nature.	^[11]
Methylarsonate	MA	Found in seafood and terrestrial foods in very low amounts and is a metabolite of iAs that can be seen in urine.	^[12]
Methylarsonite	MA (III)	It cannot be detected in food samples. It is a metabolite of iAs that can be seen in human urine samples but it is a toxic metabolite.	^[13]
Arsenobetaine Arsenosugar	AB	It is a major arsenic species and commonly found in seafood but is non-toxic in nature.	^[7]
Trimethylarsonio propionate	TMAP	Present in most foods. It is one of the major arsenic species.	^[14]
Trimethylarsine oxide	TMAO	It is generally found in seafood and distributed in small amounts.	^[11]

2. Arsenic Cellular Metabolism

iAs present in the human body is generally excreted through urine and bile ^[15]. Urinary arsenic measurements (iAs%, MMA%, and DMA%) act as indicators of arsenic metabolism and methylation capacity ^[16]^[17]. Trans-cellular and paracellular pathways are major modes of iAs transportation ^[18]. Cellular metabolism includes methylation in four forms, namely monomethylarsonic acid (MMA^V), monomethylarsonous acid (MMA^III), dimethylarsinic acid (DMA^V), and dimethylarsinous acid (DMA^III). Among the different forms, MMA^III is reported as the most cytotoxic ^[19]. MMA^III species can inhibit mitochondrial I and III processes by electron escape through the electron transport chain, leading to the production of reactive oxygen species (ROS) and reactive nitrogen (RNS). Free radical production leads to DNA damage and impaired gene expression ^[20]. Enzymatic methylation occurs by way of the primary enzyme involved in As metabolism, called arsenic (3+) methyltransferase (AS3MT), and endogenous reducing agents such as thioredoxin (Trx) and glutathione (GSH) ^[21]^[22].

Arsenic has an affinity with thiol groups, inhibiting the catalytic activity of an enzyme by binding with thiol-containing active sites. GSH plays an important role in transforming arsenate (AsV) to arsenite (AsIII); the arsenite form has a shorter half-life in comparison to arsenate. Antioxidants act as electron donors during the reduction of pentavalent to trivalent arsenic due to their high affinity to GSH ^[23]. Arsenic–thiol interaction consequences include MMA^III inhibiting GSH reductase and thioredoxin reductase ^[24]. Arsenate produces glucose-6-arsenate and 6-arsenogluconate by the substitution of phosphate in glucose and gluconate and forms glucose-6-arsenate and 6-arsenogluconate, analogous to glucose-6-phosphate and 6-phospho-gluconate, respectively. Glucose-6-arsenate binds to glucose-6-phosphate dehydrogenase and a high concentration of arsenate inhibits hexokinase activity through negative feedback mechanisms during glycolysis. Arsenic inhibits the conversion of pyruvate to acetyl coenzyme A (acetyl-coA), which leads to diminished cellular glucose uptake, gluconeogenesis, the oxidation of fatty acid, and further acetyl-CoA production. Mitochondria is an important cellular target by arsenite and free radical production, lipid peroxidation, H₂O₂ production, and mitochondrial swelling. Arsenic induces the formation of superoxide anion radicals such as singlet oxygen, the peroxyl radical, hydroxyl radicals, NO, H₂O₂, dimethyl-arsinic-peroxyl radicals, and dimethylarsinic radicals in a dose-dependent manner and consequently leads to health complications ^[25].

3. Arsenic-induced Health Hazards

3.1. Major Organ Damage and Chronic Disease Development

Human body organs are typically distressed by As poisoning. Major organs susceptible to As toxicity are the kidneys, lungs, liver, and skin. Severe As toxicity leads to coma and death. Target organ damage (TOD) depends on the ingested arsenite (As⁺³) content in the body. Firstly, an initial sign of skin changes involves its binding with keratin and accumulation in hair and nails. The appearance of keratosis is a common early sign of arsenic exposure. Recently, squamous cell carcinoma (SQCC), melanosis, and keratosis to Bowen’s disease have been reported in Asian countries, especially in India, Nepal, and Bangladesh ^[26]^[27]. Increased monomethylarsonate (MMA)% and decreased dimethylarsinate (DMA)% of arsenic species are directly proportional to a higher risk of bladder, pulmonary, and skin cancers. Carcinogenic and chromatin alteration have been exhibited due to transcription initiation and gene sequencing. The cellular genomic modification of deoxyribonucleic acid (DNA) methylation and the post-transcriptional modification (PTMs) of histone proteins lead to tumors and benign dysplasia. Arsenic induces miRNA gene expression that affects polymerase elongation and the recruitment of splicing regulatory factors and leads to carcinogenicity ^[8]^[28].

Drinking water iAs is nearly 80–90% absorbed by the intestine and protein transporters of arsenic such as aquaporin-10, GLUT-5, and organic anion-transporting polypeptides (OATPB) in the gut epithelium ^[29]. As exposure can lead to developing a risk of nonalcoholic fatty liver diseases among adolescents ^[30]. As is a promoter of inflammation, oxidative stress, and endothelial dysfunction by different mechanisms including the activation of transcription factors such as protein-1 and nuclear factor κβ ^[31]^[32]. The mechanisms of carcinogenesis take place through multiple pathways, including the perturbation of gut microbiota, genotoxicity, and epigenetic dysregulation ^[33]^[34]^[35]. The conjugation of arsenic with glutathione forms arsenic triglutathione, and the methylation of arsenic produces dimethylarsenic glutathione and enters bile and the bloodstream. This unstable species changes into the volatile compound dimethylarsine. As is transported via RBCs and is stored as protein-bound trivalent dimethyl arsenicals in different organs of the body ^[7]. As exhibits carcinogenic effects in the liver and produces hepatocellular carcinoma through DNA repair inhibition and the development of micronuclei and epigenetic dysregulation ^[33]^[36]. Different As species-linked health effects have been mentioned in Table 2.

Table 2. Various arsenic species and associated health hazards.

Arsenic Chemical Forms	Health Effects	References
Inorganic arsenic (As^III and As^V)	Cancer	^[37]
	Chronic diseases	^[38]^[39]
	Mutation	^[40]
	DNA damage	^[41]
	Mitochondrial dysfunction	^[42]
	Reduces bone mineralization	^[43]
	Hyperglycemia	^[44]
	Lipid disorders	^[45]
	Coronary heart disease	^[46]
	Liver toxicity	^[47]
	Hypertension	^[48]
	Genotoxicity	^[49]
Arsenite (As^III)	Cancer	^[50]
	Fatty liver	^[51]
	Hepatotoxicity	^[52]
Arsenic trioxide	Breast cancer	^[53]

Chronic exposure to As produces harmful effects on the immune system. Immune responses depend on the proliferation of T and B cells as well as macrophages. Chronic exposure to As may cause immunosuppression by affecting cellular and humoral immunity ^[39]^[54]. It has been found that immunosuppression due to decreased T-cell proliferation is linked with low cytokine secretion, tumor necrosis factor (TNF)-α, interferon-γ, IL-2, IL-10, IL-5, and IL-4. A similar study states that chronic exposure leads to high serum immunoglobulin IgA, IgG, and IgE, which may lead to the development of respiratory complications such as pneumonia, allergic bronchitis, and chronic obstructive pulmonary disease ^[55]. Chronic exposure to As leads also to several other clinical manifestations such as hypercalciuria, glomerulonephritis, acute tubular necrosis, albuminuria, nephrocalcinosis, and renal papillae necrosis ^[18]. The development of incipient nephropathy and the incidence of chronic kidney disease (CKD) have been reported due to As-induced injury of the nephron ^[56]. As nephritis and renal damage occur due to direct podocyte injury and endothelial dysfunction and increase the expression of the vascular cell adhesion molecule 1 (VCAM-1) ^[57]^[58]. The direct effects of arsenic species and metabolites on chronic diseases with their respective mechanisms are listed in Table 3.

Table 3. Direct effects of arsenic species and their metabolites with respective mechanisms in different chronic diseases.

Arsenic Species	Direct Toxic Effect and Target Organ Damage (TOD)	Molecular Mechanisms	References
Inorganic arsenic in drinking water and rice	Skin cancer	Differentiation and generation of cancer stem cells	^[59]^[60]
	Coronary artery disease and cardiac muscle damage	Cardiac tissue hypoxia and inflammation	^[61]
	Diabetes and insulin resistance	Inhibition of glycolysis, Krebs’s cycle, and ATP synthesis	^[62]^[63]
	Acute Kidney Injury (AKI)	Kidney injury molecule-1 (KIM1)	^[64]
	Chronic kidney disease (CKD)	Decreased glomerular filtration rate	^[65]
Arsenite (As^III)	Insulin resistance and metabolic syndrome	Diminished translocation of GLUT4	^[66]
MMA (Monomethylarsonic acid)	Breast cancer	Endocrine disruptor	^[67]
	Lung cancer	DNA damage	^[41]^[68]
	Kidney cancer	DNA damage	^[68]

As affects the gluconeogenesis in muscle cells by inhibiting glucose transporters and suppressing glucose metabolism regulatory genes. Hence, the glycolytic pathway and mitochondrial energy production are altered ^[69]^[70]. In experimental studies of mice, it has been reported that As decreases the functional capacity of muscle and destroys muscle progenitor cells ^[71]. Muscle damage occurs by inhibiting muscle repair and increasing the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), along with inflammation signaling, a long healing time, and fibrosis. Consequently, As exposure contributes to sarcopenia progression ^[72].

As acute toxicity generates oxidative stress and pro-inflammatory reactions in the epithelial cells of the intestine in in vivo studies ^[73]^[74]. Therefore, reactive oxygen species (ROS) damage the cytoskeleton and cause the loss of tight junction proteins such as claudin-5 and occludin in the blood–brain barrier ^[75]. iAs species might be liable to increase paracellular transport at tight junctions ^[76]. The high permeability of intestinal junctions is related to intestinal abnormalities such as dysbiosis, colitis, Crohn’s disease, ulcerative colitis, and other gastrointestinal complications ^[77]. High As levels increase colonies of pathogenic bacteria in dysbiosis, whereas low levels directly increase intestinal commensal bacteria. Therefore, gut microbiome health depends on a variety of species of probiotic bacteria ^[78]. A study conducted on children exposed to high As shows plenty of proteobacteria in stool samples ^[79]. A recent study on the Bangladeshi population demonstrated the toxic effect of high As on the species and flora of gut bacteria and the high number of pathogens ^[80]. Furthermore, it has also been seen that different forms of As species cross the blood–brain barrier, reducing neurotransmitters, including mono-amines and those associated with the cholinergic, dopaminergic, and glutamatergic systems, leading to damaged synaptic transmission ^[81]. Glutamate receptor expression inhibition may cause changes in synaptic plasticity, for instance, the long-term potentiation of learning and memory linked with enhancing extracellular glutamate levels ^[82]. Various diseases linked with As toxicity are depicted in Figure 1.

Figure 1. Arsenic exposure leads to acute to chronic complications such as chronic kidney disease, cardiovascular disease, schizophrenia, fatty liver, cirrhosis, dysbiosis, and different types of cancer.

3.2. Effects on Maternal Health

A recent study of As exposure and gestational diabetes mellitus (GDM) showed their strong positive links to each other ^[83]. Sung et al. reported a negative metabolic effect of As toxicity in GDM ^[63]. iAs changes glucose homeostasis by switching phosphates in adenosine triphosphate (ATP) synthesis and impairing ATP-dependent insulin. Furthermore, arsenate conjugates with the disulfide bridges of insulin, insulin receptors, glucose transporters (GLUTs), and glucose metabolism enzymes. Peroxisome proliferator-activated receptor γ (PPARγ) plays a significant role in the expression of insulin activation. As free radical damage interferes with the signal transduction and gene expression of β-cells, leading to the development of diabetes. As activates superoxide and binds with uncoupling protein 2 (UCP2), consequently decreasing insulin secretion ^[84]. UCP2 acts as a negative regulator for the secretion of insulin and also mediates proton leakage across the inner mitochondrial membrane ^[85].

In a research study on high exposure to As in Bangladeshi women, it was concluded that As exposure is the cause of cervical cancer (squamous cell carcinoma) ^[86]. Further, in another study of Bangladeshi women, it was found that As is also responsible for anemia. A prevalence of anemia has been found in the reproductive female age group and was linked to arsenicosis skin lesions ^[87]. High exposure to As also leads to early menopause of two years compared to low- or normal-limit exposed females’ menopausal stages ^[88]. In vivo and in vitro research of iAs exposure has revealed that As can attach to human and animal hemoglobin and can alter morphology, cell shape, levels of hemoglobin, and heme metabolism. Absorbed arsenic is transported through portal circulation via RBCs and WBCs. In another study, a 2–3-fold higher prevalence of anemia has been reported with a low dose of As-exposed drinking water compared to normal potable water, and pregnant women were more susceptible than non-pregnant women ^[89]^[90].

Ahmed et al. reported the effect on cellular innate immunity and immunosuppression of prenatal As exposure in Bangladeshi women ^[91]. The immune-suppressive effect on T and B cells as well as macrophages is due to the reduced expression of major histocompatibility complex (MHC) class II molecules, CD69, interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α). Inflammatory cascades of cytokine release low lymphocyte proliferation and IL-2 secretion, leading to inflammation, macrophage adhesion, phagocytosis, the increased apoptosis of peripheral blood mononuclear cells (PBMC), reduced ROS stimulus by PBMC, and stop the progress of the immunogenic response in hosts ^[39]. The disruption of estrogen receptors and the suppression of the signaling pathway of estrogen is linked to breast cancer, and As is a potential metallo-estrogen and acts as a medium to promote breast cancer ^[92]^[93]^[94]. Marciniak et al. (2020) reported in a Poland study that high-dose arsenic exposure increases the risk of breast cancer by 13 times compared to normal women ^[95].

3.3. Effects on Fetal and Neonatal Health

As exposure’s adverse effects have been reported also in neonatal health. It has been observed that arsenic exposure during the last trimester of pregnancy directly affects newborn telomere length (TL). Telomeres are DNA–protein structures; they are present at the end of each strand of DNA and defend the genome from nucleolytic degradation, interchromosomal fusion, and unnecessary recombination. Thus, telomeres exhibit a significant role to preserve information within the genome. Prenatal arsenic toxicity is the cause of newborn telomerase elongation and may suggest a new approach to neonatal health hazards ^[96]. Exposure to arsenic has harmful genotoxicity in newborns, DNA strand breaks, and increased MN frequency in cord blood. Increased arsenic maternal biomarkers are associated with genetic defects in newborns. Milton et al. (2017) reported the effect of As on spontaneous abortion and stillbirth, which are increased by up to 2–3-fold, and the risk of complications is 6-fold higher than in unexposed women. The ingestion of high arsenic content in food and water reduces methylation, which leads to folate deficiency and high homocysteine in urine, significantly contributing to congenital malformations and placental abruption ^[97]^[98]^[99].

Neural tube defects (NTDs) and insufficient neuron growth, as well as self-regulation in newborns, have been reported due to maternal As exposure ^[100]^[101]. Similar effects on newborns with high arsenic exposure were also reported in a Turkish study ^[102]. Deficits in memory, attention, and IQ from early life exposures are also noted with exposure to As ^[103]. Quansah et al. (2015) analyzed prospective birth cohort study results that indicate increased risks of spontaneous abortion, stillbirth, and neonatal and infant mortality among populations highly exposed to arsenic in drinking water. Chronic iAs exposure leads to placental insufficiency complications including preterm delivery and intrauterine growth retardation (IUGR) ^[91]. During pregnancy, As inorganic forms and their methylated metabolites cross the placenta and enter cord blood, leading to altered immune cell and gene expression in the cord blood of a highly exposed mother ^[104]^[105]^[106]^[107]. Moreover, other fetal complications also reported include slow fetal growth, low birth weight, and the effect of neuronal development in early life ^[26]^[108]. Many case-control and observation studies on As exposure have shown that it delays cognitive function and causes low intelligence quotients ^[109]^[110]. Children up to five years of age are more susceptible to arsenic exposure due to the high consumption of baby foods and more demand for energy and carbohydrate-rich diets. As-associated maternal and fetal complications can be seen in Figure 2.

Figure 2. Arsenic-induced maternal health complications such as anemia, early menopause, cervical and breast cancer, and child health complications including neural tube defects, DNA fragmentation, intrauterine growth retardation, and autism.

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