Accepted Manuscript

Title: Arsenic and human health effects: A Review

Author: Khaja Shameem Mohammed Abdul Sudheera

Sammanthi Jayasinghe Ediriweera P.S. Chandana Channa
Jayasumana P. Mangala C.S. De Silva

PII: S1382-6689(15)30094-6
DOI: http://dx.doi.org/doi:10.1016/j.etap.2015.09.016
Reference: ENVTOX 2362

To appear in: Environmental Toxicology and Pharmacology

Received date: 16-4-2015

Revised date: 22-9-2015
Accepted date: 26-9-2015

Please cite this article as: Abdul, K.S.M., Jayasinghe, S.S., Chandana,
E.P.S., Jayasumana, C., Silva, P.M.C.S.D.,Arsenic and human health
effects: A Review, Environmental Toxicology and Pharmacology (2015),
http://dx.doi.org/10.1016/j.etap.2015.09.016

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*Manuscript

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4 Arsenic and human health effects: A Review.
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7 Khaja Shameem Mohammed Abdula,*, Sudheera Sammanthi Jayasingheb, Ediriweera P. S.
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9 Chandanaa, Channa Jayasumanac and P. Mangala C.S. De Silvaa.
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12 Department of Zoology, Faculty of Science, University of Ruhuna, Matara, 81000, Sri Lanka.

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14 Department of Pharmacology, Faculty of Medicine, University of Ruhuna, Galle, Sri Lanka.
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Department of Pharmacology, Faculty of Medicine, Rajarata University, Anuradhapura, 50008,

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Corresponding author at Department of Zoology, Faculty of Science, University of Ruhuna,
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Corresponding author address:
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31 Khaja Shameem Mohammed Abdul,
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34 Department of Zoology,
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41 Matara,
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43 81000,
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46 Sri Lanka.
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48 Telephone: +94412222681(4702); Fax: +94412222701.
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51 Email address: khajashameem@zoo.ruh.ac.lk (K.S. Mohammed Abdul)
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4 Abstract:
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7 Arsenic (As) is ubiquitous in nature and humans being exposed to arsenic via atmospheric air,
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9 ground water and food sources are certain. Major sources of arsenic contamination could be
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12 either through geological or via anthropogenic activities. In physiological individuals, organ

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14 system is described as group of organs that transact collectively and associate with other systems
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for conventional body functions. Arsenic has been associated with persuading a variety of

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19 complications in body organ systems: Integumentary, nervous, respiratory, cardiovascular,

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21 hematopoietic, immune, endocrine, hepatic, renal, reproductive system and development. In this
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24 review, we outline the effects of arsenic on the human body with a main focus on assorted organ

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26 systems with respective disease conditions. Additionally, underlying mechanisms of disease
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development in each organ system due to arsenic have also been explored. Strikingly, Arsenic
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31 has been able to induce epigenetic changes (in utero) and genetic mutations (a leading cause of
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34 cancer) in the body. Occurrence of various arsenic induced health effects involving emerging
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36 areas such as epigenetics and cancer along with their respective mechanisms are also briefly
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discussed.
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43 Key Words:
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46 Arsenic; Environmental Exposure; Toxicity; Organs at risk; Epigenesis; Neoplasms.

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4 Abbreviations:
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7 iAs, inorganic arsenic; JNK3, c-Jun N-terminal kinase-3; p38MAPK, p38 mitogen activated
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9 protein kinase; ROS, reactive oxygen species; CC16, clara cell protein; CVD, cardiovascular
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12 diseases; BFD, endemic black foot disease; PVD, peripheral vascular disease; GSTP1,

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14 glutathione S-transferase P1; IHD, ischemic heart disease; ECG, electro cardiography; HERG,
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cardiac potassium channel human ether-a-go-go-related gene; UPR, unfolded protein response;

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19 T3, tri-iodothyronine; T4, thyroxine; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes

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21 mellitus; SNP, single nucleotide polymorphism; CAPN-10, clapain-10 gene; NGal, Neutrophil
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24 gelatinase-assoicated lipocalin; ROS, reactive oxygen species; NF-κB, nuclear factor-κB; TNFα,

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26 tumor necrosis factor α; IL-6, interleukin-6; PPARγ, peroxisome proliferator activated receptor
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γ; JNK, C-Jun N-terminal kinase; CKDu, chronic kidney disease of unknown etiology; ATF-2,
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31 activation transcription factor-2; AP-1, activator protein-1; ELK-1, ETS domain containing
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34 protein ELK-1; C-Src, proto-oncogene tyrosine-protein kinase Src; JAK, janus kinase; STAT,
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36 signal transducer and activator of transcription; MAPK, mitogen-activated protein kinases;

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EGFR, epidermal growth factor receptor; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase;
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41 AKT, protein kinase B; PTEN, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase; VEGF,
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43 vascular endothelial growth factor; NOTCH2, neurogenic locus notch homolog protein 2;
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46 ADAMTS9, A disintegrin and metalloproteinase with thrombospondin motifs 9; NRF2, nuclear

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48 factor (erythroid-derived 2)-like 2; KEAP1, kelch-like ECH-associated protein-1; CUL3, cullin-
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51 3; DAPK, death-associated protein kinase; RHBDF1, rhomboid family member 1; Alu,
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53 Arthrobacter luteus; LINE-1, long interspersed element-1; DNA, deoxyribonucleic acid; HCY,
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hydrofolatehomocysteine; SAM, S-adenosylmethionine; IARC; international agency for research
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58 on cancer; ATP, adenosine triphosphate; UV, ultraviolet; NMSC, non-melanoma skin cancer;
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4 BCC, basal cell carcinoma; SCC, squamous cell carcinoma; SMI, arsenic methylation index;
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7 CAE, cumulative arsenic exposure.
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4 1. Introduction:
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7 Arsenic is a metalloid, ubiquitously available in the earth’s environment and considered to be a
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9 global health risk factor. Essentially, arsenic concentrates in earth’s crust, bedrocks and leaches
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12 gradually into the drinking water (Vahter, 2008). One of the most stable forms of arsenic is 75As

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14 isotope and -3, 0, +3 and +5 are some of the common valence states of arsenic. Being a
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metalloid, arsenic exists in various allotropic forms such as elemental, sulfide and carbonate

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19 form (Henke 2009). Exposure to inorganic arsenic through consumption of contaminated food,

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21 water, air and occupational exposure but not organic arsenic (majorly seafood such as fish,
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24 oysters, prawns, mussels etc.,) leads to serious effects on human health. Low doses and long term

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26 exposures of arsenic leads to a range of medical complications termed as “Arsenicosis”
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(McCarty et al 2011).
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31 Arsenic exposure is a consequence of natural or anthropogenic sources. Ingestion, inhalation and
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34 skin absorption are some of the crucial routes for arsenic entering human body. Both pentavalent
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36 and trivalent arsenic compounds are rapidly and extensively absorbed from the gastrointestinal
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tract. Moreover, sodium arsenate absorption is higher and inorganic tetravalent arsenic is poorly
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41 absorbed. However, arsenic trisulfide and lead arsenate are some of the arsenic compounds with
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43 lowest rate of oral absorption (Ueki et al., 2004). Arsenic exposure by inhalation entirely
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46 depends on its molecular size. The rate of absorption through inhalation for sodium arsenite,
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48 sodium arsenate and arsenic trioxide were rated higher than arsenic sulfide and lead arsenate.
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51 Trivalent compounds are more water soluble than pentavalent arsenic compounds and therefore
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53 are more toxic in nature. Reduced (trivalent As (III)) and oxidized (pentavalent As(V)) forms of
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arsenic, maybe absorbed and accumulated in tissues and body fluids (Ueki et al., 2004).
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58 Distribution of arsenic in the body is fairly constant but widely distributed in organs such as skin,
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4 lungs, liver and kidneys (Hong et al., 2014). In liver, the metabolism of arsenic involves
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7 enzymatic and non-enzymatic methylation. Inorganic arsenic is reduced from pentoxide to
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9 trioxide via enzymatic or non-enzymatic (glutathione) processes (Thompson 1993). About 70%
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12 Arsenic (both organic and inorganic types) excreted through renal system via urine. Inorganic

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14 arsenic (iAs) retains in the body longer than organic arsenic and excretion process of iAs is
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longer (Goyer and Clarkson, 1996).

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19 Low to moderate levels of arsenic exposure (10−300µg/L) through drinking water has adverse

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21 effects such as skin lesions, circulatory disorders, neurological complications, diabetes,
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24 respiratory complications, hepatic and renal dysfunction including mortality due to chronic

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26 diseases (Chen et al., 2009). An estimation of about 100 million population all around the world
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are exposed to arsenic levels more than 50µg/L (Moon et al., 2012) via drinking water but also
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31 through industrial processes (Vahter, 2008). Certain countries such as India, Taiwan, China and
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34 Bangladesh are facing serious issues eliminating contamination of arsenic from drinking water
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36 sources (IARC, 2004). Depending on the type of arsenic exposure (i.e. acute or chronic)
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development of clinical symptoms varies. However, symptoms of acute exposure develops much
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41 quicker, whereas clinical symptoms of chronic arsenic exposure develops over a prolonged
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43 period of exposure. In acute arsenic toxicity organ damage could occur and may lead to death.
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46 On the other hand, disfiguration of extremities due to chronic arsenic exposure may lead to the
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48 development of malignant tumors.
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51 Various complications involving dermatological effects, cardiovascular effects, pulmonary
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53 disorders, reproductive effects, neurological effects have been reported in adults and children due
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to arsenic exposure specifically via drinking water (Ahsan et al., 2006; Argos et al., 2010; Chen
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4 Vahter et al., 2006; Wasserman et al., 2004) (Figure 1). Moreover, iAs ingestion may lead to
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7 tumorigenesis in various body parts such as skin, bladder, kidneys, lungs and liver along with
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9 other circulatory and neurological complications (Mandal et al., 2001). Effects of arsenic
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12 exposure are distinctly divided into four stages. They are preclinical, clinical, internal

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manifestations is explicitly elucidated in (Figure 2).

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19 2. Effects of arsenic on various organ systems of human body ensuing potential molecular

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mechanisms:
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24 2.1. Effects of arsenic on Integumentary system:

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26 Skin along with its appendages such as hairs and nails forms Integumentary system. It is
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commonly described as the largest organ of the body. Skin is considered to be more susceptible
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31 and highlight initial manifestations of arsenicosis (Rahman et al., 2009). Skin abnormalities
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34 holds the hallmark of chronic arsenic exposure in adults. Moreover, men are likely to develop
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36 arsenic induced skin disorders compared to women (Lindberg et al., 2008). Some of the key
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characteristic features of arsenic exposure induced skin lesions are melanosis, keratosis and
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41 pigmentation (Rahman et al., 2009). These features are often used while diagnosing chronic
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46 (Mazumder et al., 1998). Skin pigmentation along with thickening palm and sole were reported
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48 in 66% patients out of 156 patients encountered with arsenic exposure through drinking water
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51 sources (As concentration= 0.05-3.2mg/L) in West Bengal, India (Mazumder et al., 1998). The
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53 study population in Inner Mangolia, China was exposed to severe levels of arsenic (50-
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1860µg/L) through drinking water. About 22% of study population showed dermal lesions along
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4 study population in Inner Mangolia, China. (Guo et al., 2007). It is evident that skin lesions are
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7 commonly observed in patients exposed to acute arsenic exposure (Uede and Furukawa, 2003).
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12 through burning arsenic containing coal. About 17% of the residents developed dermal lesions

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conducted in Bangladesh reported a strong association between arsenic exposure and skin lesions

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19 development. It depicted the occurrence of melanosis and keratosis in residents (36 out of 167

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21 patients) exposed to rather low arsenic levels (≤10µg/L). Moreover, 3 fold increase in skin
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24 lesions were also observed in the subjects with highest levels of urinary arsenic (Ahsan et al.,

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26 2000). In a recent study, abnormal skin manifestations were observed including
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hyperpigmentation of 54.4% palms and 39% soles with relatively low keratosis in 23.2% palms
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31 and 17.6% soles with high urinary arsenic levels in 125 patients affected by chronic kidney
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34 disease in Sri Lanka (Jayasumana et al., 2013). Apart from skin, arsenic deposition in other
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distinct white lines (Mee’s lines) in the nails of fingers and toes (Ratnaike, 2003). In particular to
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41 hairs, alopecia is a common clinical manifestation of chronic arsenic exposure (Amster et al.,
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43 2007). Major dermatological signs and symptoms has been illustrated in Figures 3 (Saha et al.,
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46 1999).
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48 2.2. Effects of arsenic on Nervous System:
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51 Brain is a key target organ of arsenic toxicity affecting learning and concentration due to its
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53 ability of crossing blood brain barrier easily (Mundey et al., 2013). Arsenic species are
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distributed in all parts of the brain. However, highest accumulation was observed in hypophysis
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4 acute and chronic exposure of arsenic is rather quick and usually reported as symmetrical
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7 sensorimotor neuropathy. Sensory nerves are more sensitive to arsenic than motor nerves and
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9 neurons with long axons are affected more than neurons with short axon. Some of the very
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Species (ROS) and glutathione production (Aoyama et al., 2008). Oxidative stress considered to

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19 be one of the major cause of arsenic induced neurotoxicity (Figure 4) (Mundey et al., 2013). In

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21 severe conditions, inactivation of crucial enzymes that governs the cell function may be
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26 the disorganisation of cytoskeletal framework either by altering protein composition of
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cytoskeleton and/or hyper-phosphorylation of proteins (Figure 4). Further, arsenic is also
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34 (JNK3) mitogen-activated protein kinases (Figure 4) (Namgung and Xia, 2001).

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36 Neuropsychological studies confirm severe impairment of memory and verbal learning skills
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upon arsenic exposure (Vahidnia et al., 2007). Development of neurobehavioral disorders and
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41 cognitive dysfunction due to suppression of N-methyl-D-aspartate receptors in hippocampus
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46 of neurotransmitters (dopamine, norepinephrine, acetylcholine, glutamate, gamma-aminobutyric

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48 acid and 5-hydroxytryptamine) following arsenic exposure (Kannan et al., 2001; Rodrıguez et
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51 al., 2002). Arsenic induces both central and peripheral neuropathies (Rodriguez et al., 2003).
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53 Yet, typical feature of arsenic induced neurotoxicity is peripheral neuropathy occurring due to
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damage of peripheral nerves (Mathew et al., 2010). Moreover, acute arsenic exposure lead to
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58 encephalopathy with gradual loss of brain function and activity over time. Some of the common
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4 symptoms include headache, hallucinations, seizures and coma (Bartolome et al., 1999). In a
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7 recent study, peripheral neuropathy was the predominant neurological complication in patients
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9 exposed to consumption of arsenic contaminated ground water in West Bengal, India (Mukherjee
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2.3. Effects of Arsenic on Respiratory System:

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19 Arsenic exposure by either drinking water or occupational source may lead to respiratory

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21 complications over time. Arsenic exposure from drinking water exhibited association with high
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24 mortality rate in Bangladesh population (Argos et al., 2010). On the other hand, correlation of

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26 arsenic exposure related lung dysfunction and increased morality rate due to respiratory diseases
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has been overwhelming (Parvez et al., 2011). Arsenic dust or fume inhalation during mining or
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31 milling of ores often produces respiratory complications such as chronic cough, laryngitis,
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36 observed in a cohort study includes chronic cough, chest sounds, shortness of breath, blood in
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sputum and other breathing problems (Parvez et al., 2010).
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41 In a cross sectional study, positive association between urinary arsenic levels and serum Clara
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46 biomarker for respiratory illness. Moreover, urinary arsenic levels showed inverse relationship
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48 with lung function (Parvez et al., 2008). Recent prospective cohort studies found, low to
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51 moderate levels of arsenic exposure in Bangladesh population resulted in impaired lung function
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53 and tuberculosis (Parvez et al., 2013; Parvez et al., 2012). Dauphiné and colleagues found that in
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utero and childhood exposure of arsenic through drinking water was linked with long term lung
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4 vital capacity and a restrictive spirometric pattern were observed in lungs of children exposed to
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7 high levels of drinking water arsenic (Mean: 152.13µg/L) during in utero and early life stages
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19 other affecting in a dose dependent manner (Chang et al., 2004; Chen et al., 2011; Wang et al.,

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22 2007a). Smelters are typically at risk of CVD due to arsenic exposure (Axelson et al., 1978;
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cardiovascular system including heart and blood vessels (Lewtas, 2007). Certain epidemiological
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36 negative impacts on cardiovascular system (Rahman et al., 2009). Cohort studies has shown
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increased risk of CVD and mortality due to high levels of arsenic exposure through drinking
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41 water in South Western Taiwan (Tseng et al., 2003), Utah, United States (Chen and Karagas,
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2013, Lewis et al., 1999), and Bangladesh (Chen et al., 2011). Recently, CVD mortality due to
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46 high arsenic concentrations (from >100µg/L to >300µg/L) has also been reported (Chen et al.,
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48 2011). However, low to moderate levels of arsenic exposure through drinking water increased
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51 mortality due to chronic diseases including CVD (Chen et al., 2009). Low to moderate arsenic
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53 exposure via municipal drinking water (<1−118μg/L) was associated with rise in death rate due
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56 to CVD in Spain population (Medrano et al., 2010). Effects of arsenic on vascular system are
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58 well documented (Chen et al., 2007). Low arsenic exposure has shown nonlinear effects on
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4 blood pressure. High pulse pressure (pulse pressure ≥ 55 mmHg) was observed in Bangladesh
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7 population, upon low to moderate levels of arsenic exposure via drinking water (Chen et al.,
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9 2007). Exposure of iAs through drinking water on a long term basis increased the prevalence of
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12 cerebrovascular disease (Chiou et al., 1997). Arsenic exposure has shown a direct relationship

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14 with certain critical cardiac complications such as myocardial injury, cardiac arrhythmias and
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cardiomyopathy (Benowitz, 1992; Goldsmith and From, 1980; Manna et al., 2008). Long term

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19 iAs exposure also has a significant role in occurrence of endemic black foot disease (BFD)

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21 which is a specific type of peripheral vascular disease (PVD) occurring in limited locations of
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24 Southwestern Taiwan (Tseng et al., 2005). In the early 20th century BFD was reported in

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26 Southwestern coast of Taiwan with typical clinical symptoms such as severe arteriosclerosis,
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progressive arterial occlusions and subsequent gangrene of lower extremities. Epidemiological
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31 studies confirmed that high arsenic exposure through drinking water and lower capacity to
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34 methylate iAs were the major reasons behind the development of PVD and BFD (Tseng, 2002;
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36 Tseng et al., 2005). Moreover, a dose response pattern was observed in arsenic ingestion and
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prevalence of peripheral vascular disease in BFD endemic village population (Tseng et al.,
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41 1996). Arsenic exposure and atherosclerosis has a strong correlation causing mortality and it
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43 demonstrates the role of arsenic in atherogencity. Arsenic induces a range of pathophysiological
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46 events that potentially leads to the development of atherosclerosis (Figure 5) (Simeonova and
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48 Luster, 2004). In (Figure 6), major mechanisms involved in atherogenesis and other
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51 cardiovascular complications (i.e. hypertension, arrhythmias and ischemic heart diseases) due to
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53 arsenic has been depicted (Simeonova and Luster, 2004). A recent animal study reported that
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arsenic exposure induces gene expression of mediators influencing inflammation (Figure 6)
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58 including interleukin-8 but do not modulate other cellular mechanisms such as endothelial cell-
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4 mediated lipid oxidation or smooth muscle cell proliferation to induce atherogenesis (Simeonova
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7 et al., 2003). iAs ingestion may lead to development of carotid atherosclerosis. A study
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9 conducted in arseniasis endemic population of Taiwan has established a significant biological
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12 gradient between iAs ingestion and carotid atherosclerosis (Wang et al., 2002). Furthermore,

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14 genetic polymorphism of glutathione S-transferase P1 (GSTP1) and tumor protein p53 has
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shown joint effects on susceptibility of carotid atherosclerosis upon arsenic exposure (>50 μg/L)

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19 (Wang et al., 2007b). Long term arsenic exposure may also induce ischemic heart disease (IHD)

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21 (Figure 6). A study conducted in arseniasis-hyperendemic villages in Taiwan has shown
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24 association between IHD development and long term arsenic exposure. However, prevalence of

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26 IHD was highest in age group >60years (24.1%) and lowest in age group 30-39 years (5.2%)
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(Tseng et al., 2003).
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31 Exposure to high arsenic concentrations has shown firm association with prolonged QT interval
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34 (Mordukhovich et al., 2009; Mumford et al., 2007). QT-interval on the ECG represents the
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36 depolarization and repolarization of ventricles. It is measured from onset of QRS complex until
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T wave ends (Goldenberg et al., 2006; Straus et al., 2006). Changes in duration of QT-interval
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41 either short or prolonged have shown association with increased sudden cardiac death due to the
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43 development of malignant ventricular arrhythmias (Zhang et al., 2011). Many recent studies have
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46 shown strong association between arsenic exposure via drinking water and QT prolongation
47
48 (Chen et al., 2013; Mordukhovich et al., 2009; Mumford et al., 2007; Wang et al., 2009a) and
49
50
51 dose dependent chronic arsenic exposure increased QT/QTc depression linking to atherosclerotic
52
53 diseases (Wang et al., 2010). Crucially, low arsenic levels have shown a positive tendency to
54
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alter QT interval duration (Mordukhovich et al., 2009). In women, subsequent QT prolongation
57
58 was observed at long term exposure to arsenic concentrations ranging from 0.1 to 790µg/L
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4 through drinking water (Chen et al., 2013). In vitro experiments have shown mechanisms
5
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7 involved in arsenic induced QT prolongation. Indirect increase in cardiac calcium currents and
8
9 inhibition of cardiac potassium channel Human ether-a-go-go-related gene (HERG) trafficking
10
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12 to the plasma membrane potentially causing QT prolongation and torsade de pointes (Ficker et

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14 al., 2004). Moreover, prolonged action potential duration, calcium overload and lipid
15
16
peroxidation are some of critical electrophysiological abnormalities induced by arsenic trioxide

cr
17
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19 (Yamazaki et al., 2006).

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21 Long term arsenic exposure may induce hypertension in humans and the relationship is well
22
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24 established (Chen et al., 1995; Li et al., 2013; Rahman et al., 1999; Yang et al., 2007). Decreased

an
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26 ability to methylate arsenic increases hypertension risk (Huang et al., 2007). Arsenic exposure
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28
mediated hypertension was observed in various countries such as Bangladesh (Huda et al., 2014),
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31 Iran (Dastgiri et al., 2010), Taiwan (Wang et al., 2011), India (West Bengal) (Guha Mazumder et
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34 al., 2012) and China (Li et al., 2013; Zhang et al., 2013a). However, based on the Meta-analysis,
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36 connection between arsenic exposure and hypertension still remains controversial and
37
38
inconclusive due to limited evidence (Abir et al., 2012). In a cross sectional study, no risk of
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39
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41 hypertension was associated with arsenic exposure (>50 µg/L). However, a relationship was
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43 noticed between arsenic exposure/duration and pulse pressure (Islam et al., 2012a). Most
44
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46 importantly, exposure to low to moderate arsenic levels, specifically in US population has shown
47
48 no association with hypertension and systolic/diastolic blood pressure (Jones et al., 2011).
49
50
51 Arsenic exposure may increase calcium sensitization, phosphorylation of myosin light chain,
52
53 oxidative stress resulting in decreased antioxidant mechanisms causing hyper contraction in
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blood vessels (Lee et al., 2005).
57
58 2.5. Effects of Arsenic on Hematopoietic System:
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4 Arsenic exposure affects hematopoietic system including bone marrow, spleen and erythrocytes.
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7 Highest rates of arsenic accumulation was observed in spleen with 2 to 3 folds higher
8
9 accumulation compared to other organs such as heart, liver and kidney (Zhang et al., 2014). Due
10
11
12 to arsenic accumulation, epigenetic modifications were observed in spleen via 5-

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14 hydroxymethylcytosine and it is considered to be a possible explanation for the organ specific
15
16
arsenic induced toxicity (Zhang et al., 2014).

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19 Immediately after exposure, arsenic enters into systemic circulation. Majority of the arsenic

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21 primarily binds to hemoglobin and accumulates in the erythrocytes inducing hemolysis (Lu et al.,
22
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24 2004). Likewise, curtailing longevity of erythrocytes leads to reduced number of healthy

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26 erythrocytes and cause development of anemia. Anemia is one of the most common symptoms in
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28
arsenic exposed population. However, significantly negative association was observed between
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31 arsenic exposure during pregnancy and occurrence of anemia (Heck et al., 2008; Vigeh et al.,
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34 2014). Intravascular hemolysis, leukopenia, and thrombocytopenia are some of the distinct signs
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36 of and chronic arsenic induced hematological effects (Hall, 2002; Pakulska and Czerczak, 2006).
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38
Moreover, bone marrow depression is also a well-known manifestation but megaloblastic
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41 erythropoiesis occurs occasionally due to arsenic intoxication (Feussner et al., 1979; Szymanska-
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43 Chabowska et al., 2002). Based on the erythrocyte morphological changes induced by arsenic
44
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46 exposure, a classic discocyte-echinocyte transformation was observed which later on advanced to

47
48 become spheroechinocytes in a concentration dependent manner (Winski and Carter, 1998).
49
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51 Morphological changes in erythrocytes could affect microcirculation and capable of developing
52
53 circulatory disorders (Biswas et al., 2008). Figure 7, extensively elucidates various mechanisms
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involved in chronic arsenic induced erythrophagocytosis and hemolysis.
57
58 2.6. Effects of Arsenic on Immune system:
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4 Recently, role of arsenic inducing detrimental effects on the immune system of the exposed
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6
7 organism (Selgrade, 2007; Vahter, 2008). Both experimental animals and humans have shown
8
9 distinct disruptive signs of innate immunity due to iAs exposure (Srivastava et al., 2013).
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12 Moreover, arsenic exposure demonstrated a quantitative association with immune suppression

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14 (Selgrade, 2007). Arsenic can either produce inhibition or induce proliferation of immune cells
15
16
in a dose dependent manner (Soto-Peña and Vega, 2008). Human macrophages are the major

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19 targets of iAs contributing immunotoxicity. Arsenic exposure on macrophages induce rapid cell

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21 rounding and subsequently losing its adhesion capabilities. Further, macrophagic surface markers
22
23
24 expression also gets affected altering endocytosis and phagocytosis (Lemarie et al., 2006).

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26 Human peripheral blood monocytes are the precursors of mature macrophages of immune
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28
system. Monocytes are also capable of becoming macrophages (a key player in developing
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31 immune response in the body against microorganisms). However, arsenic sensitively inhibited
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34 colony stimulating factor induced maturation of monocytes into macrophages and thereby
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36 increased susceptibility towards infections (Sakurai et al., 2006). The key underlying mechanism
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38
behind impaired functions of macrophage is due to malfunction in unfolded protein response
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39
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41 (UPR) signaling pathway upon arsenic exposure (Srivastava et al., 2013).
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43 Arsenic is capable of inducing a range of auto-immune diseases including diabetes,
44
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46 atherosclerosis and non-melanoma skin cancers (Banerjee et al., 2009). Apart from macrophages,
47
48 iAs also impairs the development, activation, proliferation and function of lymphocytes
49
50
51 (Banerjee et al., 2009; Martin-Chouly et al., 2011; Ostrosky-Wegman et al., 1991). Arsenic
52
53 exposure affects human lymphocytes following a variety of mechanisms such as increasing free
54
55
56
radicals within the cells, oxidative damage, apoptosis, DNA strand damage, modification of
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58 DNA bases, crosslinking proteins, lipid peroxidation (Singh et al., 2013). It is evident that
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4 arsenic promotes inflammation in vivo (Srivastava et al., 2009) and prolonged exposure to
5
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7 arsenic may increase the expression of inflammatory molecules in the body (Wu et al., 2003).
8
9 Certain distinct clinical manifestations such as hypertrophy of liver and/or spleen (Sakurai et al.,
10
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12 2006) and atherosclerotic lesions (Srivastava et al., 2009) were observed in humans experiencing

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14 chronic inflammation due to arsenic exposure.
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In utero arsenic exposure affects immune mediated cells and thymus development. In fact

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19 arsenic exposure during pregnancy impaired thymic development of the baby via

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21 immunosuppression (Moore et al., 2009; Raqib et al., 2009). Arsenic exposure during pregnancy
22
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24 significantly reduced placental CD+3 T cells as well as decreased the size and function of

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26 thymus (Ahmed et al., 2014). A study based on pre-school children in Bangladesh has reported
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28
reduced cell mediated immunity following abated levels of Th1 cytokines in the body due to
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31 persistent arsenic exposure. However, no changes were observed in Th2 cytokines (Ahmed et al.,
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34 2014). While, in vitro studies confirm that arsenic directly impairs the physiology of human T
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36 cells and stimulate skin cancer development via modulating the activity of immune system
37
38
(Martin-Chouly et al., 2011). Some of the vital mechanisms involved in arsenic induced
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41 immunosuppression are depicted in (Figure 8).
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43 2.7. Effects of Arsenic on endocrine system:
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46 Arsenic is a well-known disruptor of endocrine system (Davey et al., 2007; Davey et al., 2008)
47
48 including thyroid, thyroid hormone (Ciarrocca et al., 2012; Naujokas et al., 2013), pancreas (Lu
49
50
51 et al., 2011), gonads (Davila-Esqueda et al., 2012; Shen et al., 2013) and disrupts hypothalamic-
52
53 pituitary-adrenal axis (Goggin et al., 2012). Impaired thymic functions were evident with
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prenatal exposure possibly via arsenic induced oxidative stress and apoptosis (Ahmed et al.,
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58
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4 2012). However, information about the specific effects of arsenic on adrenal gland and pituitary
5
6
7 gland are rather limited (Davey et al., 2008).
8
9 Thyroid plays a critical role in regulating metabolism in human body and responsible for
10
11
12 production of tri-iodothyronine (T3) and thyroxine (T4) hormones (Ciarrocca et al., 2012).

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14 Interactions between arsenic and thyroid are not well established, however, a recent study
15
16
reported a positive relationship between occupational exposure to arsenic in outdoor workers and

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19 its effects on thyroid hormones and thyroid gland (Ciarrocca et al., 2012). Exposure to low levels

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21 of arsenic through ground water (2−22µg/L) was associated with hypothyroidism among
22
23
24 population living in rural West Texas counties (Gong et al., 2015). Figure 9 overviewed the

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26 mechanisms behind heavy metals induced endocrine toxicity (i.e. adrenal gland, pituitary gland,
27
28
thyroid gland and pancreas) (Davey et al., 2008).
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31 It is clearly evident that arsenic accumulates in pancreas and decreases the secretion of insulin as
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34 well as viability of the cells (Lu et al., 2011). Pancreas produces insulin, glucagon and regulates
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36 blood glucose levels in our body. High blood glucose levels due to insufficient insulin
37
38
production by pancreatic β-cells is considered to be one the distinct complication of the
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39
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41 heterogeneous disorder causing Diabetes. Diabetes is majorly classified further into two types.
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43 Type 1 Diabetes Mellitus (T1DM) is a type of autoimmune disease, develops upon destruction of
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46 pancreatic β-cells by the host immune system, whereas Type 2 Diabetes Mellitus T2DM is
47
48 characterized by development of insulin resistance in the body. Over time insulin
49
50
51 secretion/handling diminishes and develops T2DM complications. Approximately 12% adult US
52
53 population and 336 million people worldwide are effected by T2DM (Ashcroft and Rorsman,
54
55
56
2012). Based on experimental and epidemiological evidence, high iAs exposure and T2DM
57
58 reportedly shares a strong association with each other (Navas-Acien et al., 2006). Moreover,
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4 apart from high concentrations, long term exposure to iAs may also increase the risk of T2DM
5
6
7 (Wang et al., 2014b). Risk of T2DM development has been associated with exposure to high
8
9 arsenic concentrations in various countries such as Cyprus (Makris et al., 2012), Bangladesh
10
11
12 (Islam et al., 2012b; Rahman et al., 1998), Mexico (Coronado-Gonzalez et al., 2007; Del Razo et

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14 al., 2011), Sweden (Rahman and Axelson, 1995; Rahman et al., 1996), Taiwan (Jiang et al.,
15
16
2012; Tseng et al., 2000a; Tseng et al., 2000b) and United States (Gribble et al., 2012; Kim et al.,

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19 2013; Navas-Acien et al., 2008). Low to moderate levels of arsenic exposure and occurrence of

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21 T2DM was unknown. But in 2008, an US study hypothesized a threefold increase in T2DM over
22
23
24 low concentrations of urinary arsenic (Navas-Acien et al., 2008; Steinmaus et al., 2009). In 2012

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26 and 2013, further convincing evidences of arsenic associated diabetes in US population have
27
28
been reported (Gribble et al., 2012; Kim et al., 2013). Moreover, a recent study in Bangladesh
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31 has also confirmed the increased risk of T2DM with modest levels of arsenic exposure (Pan et
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34 al., 2013b). However, in 2009, a study found no evidence of T2DM occurrence at low arsenic
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36 exposure in US population (Steinmaus et al., 2009). Furthermore, a cross-sectional study

37
38
conducted in Bangladesh and China has also confirmed no profound association between arsenic
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41 exposure and increased risk of T2DM (Chen et al., 2010; Li et al., 2013). Recent gene expression
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43 study found genetic variations in ‘neurogenic locus notch homolog protein 2’ (NOTCH2) gene,
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46 ‘a disintegrin and metalloproteinase with thrombospondin motifs 9’ (ADAMTS9) gene may

47
48 increase the susceptibility towards T2DM (Pan et al., 2013a). Additionally, single nucleotide
49
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51 polymorphism (SNP-43) in calpain-10 gene (CAPN-10) independently associated with T2DM
52
53 occurrence upon arsenic exposure through drinking water (Diaz-Villasenor et al., 2013).
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Common mechanisms involved in arsenic induced diabetes are insulin resistance and pancreatic
57
58 β-cell dysfunction. These complex mechanisms are initiated by activating reactive oxygen
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4 species (ROS), nuclear factor−κB (NF−κB), cytokines [tumor necrosis factor α (TNFα) and
5
6
7 interleukin-6 (IL-6)], and inhibition of peroxisome proliferator activated receptor γ (PPARγ)
8
9 (Tseng, 2004) (Figure 10). Additionally, apoptotic death/damage of pancreatic β-cell due to
10
11
12 increased levels of ROS and oxidative stress is also considered to be a common mechanism in

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14 increasing the risks of diabetes due to iAs exposure (Lu et al., 2011) (Figure 10).
15
16
Gastrointestinal symptoms such as nausea, vomiting and diarrhea are commonly associated with

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19 arsenic exposure. Initial clinical signs of acute or sub-acute arsenic induced gastrointestinal

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21 disturbances including excessive salivation, nausea, thirst, burning lips, swallowing problems,
22
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24 gastrointestinal cramps, abdominal pain, dehydration and severe diarrhea were reported

an
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26 (Ratnaike, 2003; Uede and Furukawa, 2003; Vantroyen et al., 2004). Typical symptoms of
27
28
dyspepsia were reported in 60 people (38.4%) while screening a group of arsenic (0.05-3.2mg/L)
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31 exposed individuals (n=156) in West Bengal, India (Mazumder et al., 1998). Gastro intestinal
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34 problems were also observed in the study population (43.9%) affected by drinking water
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36 contaminated by arsenic (50-1860µg/L) in Inner Mongolia, China (Guo et al., 2007). Deaths due
37
38
to arsenic induced gastrointestinal complications could be due to massive fluid loss, dehydration,
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41 esophagitis and gastritis (Ratnaike, 2003).
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43 2.8. Effects of Arsenic on Hepatic System:
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46 Accumulation of arsenic in liver following repeated exposures is relatively higher and prone to
47
48 increased hepatic toxicity (Ratnaike, 2003). Metabolism of iAs takes place in liver to detoxify
49
50
51 and later excreted out through urine (Watanabe and Hirano, 2013). Some of the early clinical
52
53 symptoms followed by liver disease due to arsenic exposure includes bleeding from esophageal
54
55
56
varices, ascites, jaundice, or enlargement of liver (Kapaj et al., 2006). Blood analysis may also
57
58 indicate increased levels of liver enzymes (Jomova et al., 2011; Kapaj et al., 2006). In later
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4 stages of severe toxicity, hepatic lesions may appear along with other complications such as
5
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7 hepatic fibrosis, non-cirrhotic portal fibrosis, cirrhosis with likely chances of liver failure (Kapaj
8
9 et al., 2006). In certain cases, liver enlargement was observed with elevated levels of globulin,
10
11
12 alkaline phosphatase, alanine amino transferase and aspartate amino transferase in population

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14 exposed to arsenic (0.05-3.2mg/L) in West Bengal, India (Mazumder et al., 1998). Moreover,
15
16
elevated levels of globulin (6.8%) was also observed in a study population affected by drinking

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19 arsenic contaminated water (50-1860µg/L) in Inner Mongolia, China (Guo et al., 2007).

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21 Residents exposed to high arsenic levels in Guizhou, China had hepatomegaly and liver damage.
22
23
24 Furthermore, cirrhosis, ascites, and liver cancer were some of the common manifestations

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26 developed over time with arsenic exposure (Liu et al., 2002). On the other hand, lethal doses of
27
28
arsenic could impair liver function (Vantroyen et al., 2004). Increased levels of bilirubin, alanine
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31 transaminase, aspartate transaminase, alkaline phosphatase in serum could validate liver function
32
33
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34 upon chronic arsenic exposure (Das et al., 2012). Due to increased oxidative stress and ROS
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36 activity following chronic arsenic exposure leads to the activation of key kinase signaling
37
38
molecules such as C-Jun N-Terminal Kinases (JNK), p38 Mitogen Activated Protein Kinase
p

39
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41 (p38 MAPK) (Suzuki and Tsukamoto, 2006) and Cytochrome-P450 (Bashir et al., 2006) that are
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43 responsible inducing hepatocyte apoptosis/cell injury (see Figure 11). On the other hand,
44
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46 increased activity of ROS following arsenic exposure may also induce lipid peroxidation and
47
48 further causing hepatic cell damage and hepatic toxicity (Bashir et al., 2006; Kokilavani et al.,
49
50
51 2005) (Figure 11).
52
53 2.9. Effects of Arsenic on Renal System:
54
55
56
During the process of arsenic elimination through renal system, accumulation of arsenic in
57
58 kidneys leads to cytotoxicity in renal tissue (Madden and Fowler, 2000). Hypourea, elevated
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4 levels of serum creatinine, blood urea nitrogen and proteinuria are some of the clinical
5
6
7 manifestations followed by renal injury (acute tubular necrosis) due to arsenic toxicity (Sasaki et
8
9 al., 2007). Further, a positive association between arsenic exposure and occurrence of
10
11
12 albuminuria and proteinuria has been reported (Zheng et al., 2014). Malfunction of proximal

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14 convoluted tubules is warranted in heavy metal induced nephrotoxicity (Madden and Fowler,
15
16
2000). In addition, arsenic may cause damage to capillaries and glomeruli of kidney (Rahman et

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19 al., 2009). Distinct relationship between arsenic exposure and kidney dysfunction was reported

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21 in a study population living in arsenic endemic areas of Xinjiang, China (Wang et al., 2009b).
22
23
24 Epidemiological studies also revealed a casual association between arsenic exposure and kidney

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25
26 diseases. Furthermore, chronic kidney disease has shown a gradual growth in the recent past as a
27
28
notable outcome in arsenic induced disease complications (Zheng et al., 2014). Exposure to high
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31 arsenic levels increased the mortality rate due to kidney disease in various countries such as US
32
33
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34 (Lewis et al., 1999; Meliker et al., 2007), Taiwan (Tsai et al., 1999), Chile (Smith et al., 2012a)
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36 and Bangladesh (Lokuge et al., 2004). Research based on chronic kidney disease of unknown
37
38
etiology (CKDu) in Sri Lanka, recently managed to establish a possible association between
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39
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41 arsenic exposure through agrochemicals and prevalence of CKDu. Histopathological studies
ce

42
43 have shown an association between arsenic induced tubular interstitial nephritis and glomerular
44
45
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46 atrophy and glomerular loss. Moreover high urinary arsenic, tubular proteinuria and high urine
47
48 Neutrophil gelatinase-assoicated lipocalin (NGal) levels (>300ug/mg creatinine/dL) were
49
50
51 reported in CKDu cases (Jayasumana et al., 2013). Arsenic induced renal toxicity majorly occurs
52
53 due to increased ROS activity and oxidative stress which significantly increases the expression
54
55
56
of Hemeoxygenase-1, Mitogen Activated Protein Kinase (MAPK) and other signaling pathways
57
58 that regulate transcription factors such as activating transcription factor-2, activator protein-1
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4 and ETS domain containing protein ELK-1 causing renal toxicity (Parrish et al., 1999; Sasaki et
5
6
7 al., 2007) (Figure 12). Other mechanism such as lipid peroxidation and renal cell damage due to
8
9 increase ROS activity/oxidative stress may also cause renal toxicity (El-Demerdash et al., 2009;
10
11
12 Kokilavani et al., 2005) (Figure 12).

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14 2.10. Effects of Arsenic on reproductive system and development:
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16
Arsenic is a well-known teratogen and affects the development of fetus. Animal studies have

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19 shown reproductive and developmental toxicity due to iAs exposure. Moreover, dose and

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21 duration of arsenic exposure critically influences growth retardation and fetal death (Golub et al.,
22
23
24 1998; Tabocova et al., 1996). Arsenic affects the male and female sex organs and may cause

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26 fertility issues in both genders. In males, arsenic may induce gonad dysfunction through declined
27
28
testosterone synthesis, apoptosis and necrosis (Davila-Esqueda et al., 2012; Shen et al., 2013).
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31 Arsenic exposure through drinking water and pregnancy complications (i.e. fetal loss and
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33
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34 premature delivery) has been reported (Chakraborti et al., 2003). A recent study with zebra fish
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36 animal model revealed that arsenic exposure impaired embryonic development through down
37
38
regulation of Dvr1 expression, a key player in establishing left-right embryo asymmetry. It
p

39
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41 indicates arsenic induced embryo toxicity and its relationship with Dvr1 (Li et al., 2012). But,
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43 only few studies have shown a direct relationship between arsenic exposure and reproductive
44
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46 health in human beings (Golub et al., 1998; Hopenhayn-Rich et al., 2000; Kwok et al., 2006).
47
48 During the time of pregnancy, arsenic exposure (<50 µg/L) via drinking water affects uterus and
49
50
51 placental growth results in progeny birth weight (Hopenhayn et al., 2003). Based on a cross
52
53 sectional study, arsenic exposure through drinking water (range 0-1710 µg/L) has shown a strong
54
55
56
association with spontaneous abortion, still birth and neonatal death in Bangladesh (Milton et al.,
57
58 2005). Vitally, risk of still birth was higher due to arsenic contamination in drinking water
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4 (Cherry et al., 2008). In an arsenic endemic area at Northeastern Taiwan has shown an
5
6
7 association between drinking well water with arsenic contamination (range 0.15−3585µg/L) and
8
9 preterm delivery (although not significant) along with low birth weight (Yang et al., 2003).
10
11
12 However, arsenic exposure had no strong association with birth complications such as still birth,

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14 low birth-weight and childhood stunting/under-weight (Kwok et al., 2006). In addition, a study
15
16
conducted in Inner Mongolia, China has also found no relationship between maternal arsenic

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19 exposure and still birth (Myers et al., 2010).

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21 In utero arsenic exposure and birth defects are warranted. At any levels of arsenic exposure, the
22
23
24 risks of birth defects are subsequently high (Wu et al., 2011). Moreover, chronic arsenic

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26 exposure increases the risk of late fetal and infant mortality (Hopenhayn-Rich et al., 2000). It has
27
28
been shown that, arsenic was actively transported to fetus and induced developmental toxicity
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31 (i.e. malformation, growth retardation and death). Furthermore, developmental toxicity critically
32
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34 depends on dose, route and gestation day following the arsenic exposure (Golub et al., 1998) and
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36 arsenic exposure through soil increased the risk of birth defects (Wu et al., 2011). In zebra fish
37
38
model, arsenic exposure and mechanisms involved in developmental failure during early
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41 embryogenesis was explained explicitly (Li et al., 2009). Altered cell proliferation, apoptosis and
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43 abnormal DNA methylation patterns were the major mechanisms affecting embryogenesis due to
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46 arsenic exposure (Li et al., 2009). In utero and early childhood exposure to arsenic could hinder
47
48 lung function in children (Recio-Vega et al., 2014) and increase susceptibility towards
49
50
51 respiratory infections and development of bronchiectasis (Ramsey et al., 2013). Moreover,
52
53 during 1958 − 1970, a steep increase in adult mortality due to lung and bladder cancer was
54
55
56
observed in Chilean population due to In utero and early life arsenic exposure (Steinmaus et al.,
57
58 2014).
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4 3. Arsenic exposure induced epigenetic modifications:
5
6
7 In 1942, Waddington coined the term “epigenesis” (Waddington, 2012) but later in 1958, it was
8
9 formally termed as “epigenetics” (Nanney, 1958). Epigenetics is described as the heritable
10
11
12 changes in gene expression without any dependence on the DNA sequence (Eccleston et al.,

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14 2007; Nanney, 1958). Some of such major changes includes acetylation, ubiquitination, histone
15
16
phosphorylation, (DNA & histone) methylation and MicroRNA expression (Collotta et al., 2013;

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19 Heerboth et al., 2014). Epigenetic changes have been linked with wide range of diseases

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20
21 involving cardiovascular (Lund and Zaina, 2011; Ordovas and Smith, 2010), cancer (Sarkar et
22
23
24 al., 2013), neurological complications (Kleefstra et al., 2014; Rudenko and Tsai, 2014) and

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26 metabolic disorders (Sterns et al., 2014). In mammals, epigenetic mechanisms are essential to
27
28
maintain genomic stability, parent specific imprinting patterns, blocking endogenous
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31 retrotransposson activity (Smith et al., 2012c). Growing evidence suggests gene methylation
32
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34 might be responsible for mediating arsenic toxicity and carcinogenicity (Reichard and Puga,
35
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36 2010; Ren et al., 2011). Moreover, epigenetic modifications could be a potential reason behind
37
38
diverse arsenic induced diseases. Environmental toxicants such as arsenic and other trace
p

39
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41 elements induced regulatory changes in human epigenetics including DNA methylation,
ce

42
43 microRNA expression and post translational histone modifications (Bailey and Fry, 2014;
44
45
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46 Marsit, 2015). A recent epigenome wide association study conducted in Bangladesh has shown a
47
48 positive association between arsenic exposure and gene specific differential white blood cell
49
50
51 DNA methylation (Argos et al., 2015). On the other hand, persistent arsenic exposure has been
52
53 associated with longer telomere length (Zhang et al., 2013b).
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Arsenic’s capability of crossing placental barrier increases its accumulation in the fetus and
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58 maternal exposure to arsenic may significantly hinder epigenetic imprinting leading to serious
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4 complications including impaired fetal growth, fetal death, birth defects, impaired cognition and
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7 also may develop susceptibility towards various diseases in later stages of life (Vahter, 2009). In
8
9 fact, in vitro arsenic exposure confirmed downregulation of gene expression in all three germ
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12 layers of embryoid bodies inducing mortality and birth defects (Flora and Mehta, 2009).

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14 Furthermore, recent studies have shown health related complications being developed over time
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in later stages of life due to prenatal iAs exposure was a consequence of epigenetic modifications

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19 (Farzan et al., 2013; Smith et al., 2012a).

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21 Being labeled as nonmutagenic human carcinogen, arsenic induced tumorigenesis is one of the
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24 most common human diseases influenced by epigenetic modifications. Global DNA

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26 hypomethylation and site specific DNA hypermethylation are the most common mechanisms to
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carcinogenesis (Suzuki et al., 2013). Moreover, gene methylation changes mediated by arsenic
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31 exposure are also capable of expressing oncogenes and/or downregulate tumor suppressor genes
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34 (Feinberg and Tycko, 2004).

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36 Aberrant DNA methylation was associated with increased risk of arsenic induced skin lesions
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38
(Pilsner et al., 2009). A case control study has shown association between hypermethylation of
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41 death-associated protein kinase (DAPK) and tumor suppressor protein p16 genes and arsenic
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43 induced skin lesions and non-dermatological health effects. Due to epigenetic modifications,
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46 down regulation of DAPK and tumor suppressor protein p16 genes was observed with increased
47
48 susceptibility towards arsenic induced skin lesions (Banerjee et al., 2013). Moreover
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51 hypermethylation of rhomboid family member 1 (RHBDF1) gene has shown association with
52
53 arsenic induced skin lesions (Smeester et al., 2011). However, a recent study into DNA
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methylation of RHBDF1 gene has shown no such significance in arsenic induced skin lesions
57
58 over time (Seow et al., 2014).
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4 Epigenetic modifications of Arthrobacter luteus (Alu) and long interspersed element-1 (LINE-1)
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7 elements have been associated with aging. Increased arsenic exposure has shown interference
8
9 with aging process via increased Alu DNA methylation and decreased LINE-1 DNA
10
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12 methylation. Moreover, nutritional factors such as methyl nutrients exhibit critical role inducing

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14 arsenic toxicity in human population (Lambrou et al., 2012). Activity and expression of DNA
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16
methyltransferase plays a critical role in regulating arsenic mediated epigenetic disruption

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19 (Bestor, 2000; Lan et al., 2010; Reichard and Puga, 2010). Arsenic induced oxidative stress may

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21 increase the activity of transufuration pathway and decrease the availability of
22
23
24 hydrofolatehomocysteine (HCY) and S-adenosylmethionine (SAM). Such decrease in HCY and

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26 SAM along with the increased consumption of SAM and glutathione leads to DNA
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hypomethylation and increases the susceptibility towards various types of diseases (Reichard and
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31 Puga, 2010). Some of the key arsenic exposure induced mechanisms causing human diseases are
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34 shown in (Figure 13).

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37 4. Arsenic exposure and Cancer development:
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Arsenic is a well-known human carcinogen since late 17th century (Kligerman and Tennant,
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42 2007) and it has been classified as a group-1 carcinogen by International Agency for Research on
43
44 Cancer (IARC) with supporting evidence of inducing carcinogenicity in humans (Chen et al.,
45
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47
2003). Arsenic exposure has shown the ability to induce tumorigenesis in humans in skin (Surdu,
48
49 2014), lung (Celik et al., 2008), bladder (Radosavljević and Jakovljević, 2008), liver (Wang et
50
51 al., 2014a), and prostates (Benbrahim-Tallaa and Waalkes, 2008). However, mechanisms behind
52
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54 development of cancer in the human body still remain subtle and are still under investigation.
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56 4.1. Skin:
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4 Chronic consumption of arsenic from drinking water is referred to the development of skin
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6
7 cancer (Yu et al., 2000). High prevalence of chronic arsenic poisoning has been monitored in the
8
9 Southwest coast of Taiwan where overall prevalence rates for skin cancer, hyperpigmentation
10
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12 and keratosis were 10.6/1000, 183.5/1000 and 71.0/1000, respectively (Tseng et al., 1968).

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14 Additionally, arsenic-induced skin cancer due to high contamination of arsenic in drinking water
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16
has also been observed in China, Bangladesh and India (Guo et al., 2001; Haque et al., 2003;

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19 Tondel et al., 1999). The study by Surdu, 2014 reported that ultraviolet (UV) light and arsenic

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21 play important roles in the development of two major types of non-melanoma skin cancer
22
23
24 (NMSC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Epidemiological

an
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26 studies conducted on USA population evaluating the effect of drinking water arsenic exposure on
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28
risk of non-melanoma skin and bladder cancer (Karagas et al., 1998). A case-control study
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31 conducted on citizens of Hungary, Romania, and Slovakia showed positive associations between
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34 long-term exposure to iAs < 100 μg/L in drinking water and BCC of the skin (Leonardi et al.,
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36 2012).
37
38
4.2. Lungs:
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41 Arsenic in drinking water has been classified as a known cause for the lung cancer by IARC in
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43 2002. Various studies showed the susceptibility of human lungs towards arsenic consumption
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45
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46 (Celik et al., 2008; Gibb et al., 2011; Guha Mazumder, 2007) and managed to setup a link
47
48 between ingestion of iAs through drinking water and human lung cancer development (Ferreccio
49
50
51 et al., 2000). Nevertheless, lungs are one of the major targets for tumorigenesis due to arsenic
52
53 exposure (Hubaux et al., 2013). High mortality rate of patients due to lung cancer has been
54
55
56
reported (Hopenhayn-Rich et al., 1998; Lamm et al., 2013; Smith et al., 2012b). In North
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58 America lung cancer, is one of the leading causes of mortality. Arsenic’s capability of inducing
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4 specific alterations into pathways that regulate tumor formation in lung cells has been elucidated
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6
7 by Hubaux and colleagues (Hubaux et al., 2013) (Figure 14). Increased exposure of arsenic
8
9 concomitantly increased the susceptibility of lung cancer both in smokers and non-smokers
10
11
12 (Järup and Pershagen, 1991). For the most part, smoking cigarettes prominently increased the

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14 risk of lung cancer (Chen et al., 2004; Mostafa et al., 2008). However, a recent study showed no
15
16
such interaction between smoking and arsenic induced lung cancer (Heck et al., 2009). Above

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19 all, low to moderate levels of arsenic exposure (<100µg/L) has shown an increased risk of lung

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21 cancer (small cell and SCC) in USA population (Heck et al., 2009). In contrary, a case control
22
23
24 study in USA population revealed that drinking water arsenic concentrations near 100µg/L

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26 showed no association with high risks of lung cancer (Dauphiné et al., 2013).
27
28
4.3. Liver:
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31 Liu and Waalkes reported that liver could be an important target of arsenic carcinogenesis (Liu
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33
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34 and Waalkes, 2008) and a meta-analysis denoted that long-term iAs exposure through drinking
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36 water increases the risk of cancer mortality (Wang et al., 2014a). A recent study conducted on
37
38
liver cancer patients (802 male and 301 female) from 138 villages of southwest coast areas of
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41 Taiwan showed significant cancer incidences in both genders that consumed high level of arsenic
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42
43 in drinking water. However, effects were not prominent at exposure levels lower than 0.64 mg/L
44
45
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46 (Lin et al., 2013). An investigation of childhood liver cancer in Chile revealed that liver cancer
47
48 mortality between ages 0 and 19 years was especially high due to exposure to arsenic in drinking
49
50
51 water (Liaw et al., 2008). On the other hand arsenic exposure expedites decreasing of mRNA
52
53 levels and DNMT activity and reactivates the partially or fully silenced genes in liver cancer cell
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56
(Cui et al., 2006).
57
58 4.4. Bladder and Kidney:
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4 Presence of arsenic in drinking water may be responsible for the occurrence of bladder cancer
5
6
7 (Radosavljević and Jakovljević, 2008). An increased risk of bladder cancer has been observed in
8
9 Southwestern Taiwan resulting association between secondary arsenic methylation index (SMI)
10
11
12 and cumulative arsenic exposure (CAE, mg/L-year) (Chen et al., 2003). Several studies in

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14 Argentina, Taiwan and Chile ensured that bladder cancer standardized mortality ratios (SMRs)
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16
were high due to presence of iAs in drinking water (Chiou et al., 2001; Hopenhayn-Rich et al.,

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19 1996; Smith et al., 1998). Certain case studies in U.S. population showed no association between

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21 arsenic related mortality for exposures below 100 μg/L and bladder cancer (Lamm et al., 2004;
22
23
24 Meliker et al., 2010). However, it has been reported that lower level of arsenic exposure may

an
25
26 affect bladder cancer incidences particularly in certain subgroups such as cigarette smokers
27
28
(Karagas et al., 2004). A recent finding also suggested that people co-exposed to arsenic,
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31 smoking and other known or suspected carcinogens, including asbestos, silica, and wood dust
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34 have higher risk for lung and bladder cancer (Ferreccio et al., 2013b). Consumption of water
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36 from drilled wells contaminated with arsenic provided a convincing evidence of increased
37
38
susceptibility towards bladder and kidney cancer in a Finland population (Kurttio et al., 1999).
p

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41 Whereas, lung and kidney cancer mortality was associated with arsenic exposure through
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43 drinking water in Argentinian population during the period 1986-1991 (Hopenhayn-Rich et al.,
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45
Ac

46 1998). Some of the vital risk factors influencing renal cell carcinoma (occurs in renal cortex)
47
48 includes diet, obesity, lifestyle and habits (Pascual and Borque, 2008). A case-control study
49
50
51 performed in 2007-2010 with patients of kidney cancer revealed that drinking water containing
52
53 arsenic (in a dose dependent manner) may cause renal pelvis and ureter cancer (Ferreccio et al.,
54
55
56
2013a). In utero and early life arsenic exposure markedly increased the rate of lung and bladder
57
58 cancer manifestation in adult population of Northern Chile (Steinmaus et al., 2014).
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4 4.5. Prostate Cancer:
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7 Prostate cancer is an abnormal proliferative disease that develops over time in an age dependent
8
9 manner (Crawford, 2003). Prostate cancer is the most common type of cancer that develops in
10
11
12 men and considered as a major cause of increased men mortality (Crawford, 2003; Siegel et al.,

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14 2013). Some of the major risk factors include age, diet, ethnicity, family history, socioeconomic
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16
status, occupation, smoking, heavy metal exposure, vasectomy, benign prostatic hyperplasia,

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19 hormones, sexual activity and sexually transmitted infections for the development of prostate

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21 cancer (Crawford, 2003; Haas and Sakr, 1997). Based on the evaluation of in vitro and human
22
23
24 population studies, prostate gland is considered to be a potential target for iAs induced

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26 carcinogenesis (Benbrahim-Tallaa and Waalkes, 2008). A significant association was revealed
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28
between dose dependent iAs exposure and occurrence of various types of cancers including
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31 prostate cancer (Chen and Wang, 1990). Apart from other cancers types, ingested iAs could
32
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34 increase the risk of death likely due to prostate carcinogenesis (Chiou et al., 1995). A generalized
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36 illustrative portrayal of various complex mechanisms involved in the development of Cancer due
37
38
to chronic arsenic exposure has been unfolded in (Figure 15) (Hughes, 2002; Kligerman and
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41 Tennant, 2007).
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43 5. Conclusion:
44
45
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46 In conclusion, Arsenic affects almost all cellular processes and organ functions in our body.
47
48 Current review manages to highlight certain effects and respective molecular mechanisms of
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50
51 arsenic induced complications in assorted organ systems of human body comprehensively.
52
53 Moreover, it is clearly evident that in utero exposure to arsenic can induce epigenetic effects and
54
55
56
increase disease susceptibility in later stages of life. Development of cancer in skin, lung, liver,
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58 bladder, kidney and prostate due to arsenic is widely accepted. In current review, we also
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4 managed to describe some of the crucial mechanisms that are affected by arsenic causing
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7 epigenetic modifications and tumorigenesis.
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9 Conflict of interest:
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12 The authors declare that they have no conflicts of interest.

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14 Acknowledgement:
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This project was supported by TURIS grant (RU/TURIS/PhD/02).

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4 References:
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12 Ahmed, S., Ahsan, K.B., Kippler, M., Mily, A., Wagatsuma, Y., Hoque, A.M.W., Ngom, P.T.,

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14 Arifeen, S.E., Raqib, R., Vahter, M., 2012. In utero arsenic exposure is associated with impaired
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neurological functions, and biomarkers for respiratory and cardiovascular diseases: review of
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4 recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh.
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9 Chen, Y., Wu, F., Parvez, F., Ahmed, A., Eunus, M., McClintock, T.R., Patwary, T.I., Islam, T.,
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192-207.

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4 Figure Legends:
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8 Figure 1: The key effects of arsenic on major organ systems.
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11 Figure 2: Stages of clinical manifestations in arsenic toxicity. Clinical manifestations alters with
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13 the stages of arsenic toxicity. 1) Preclinical stage− initial stage of arsenic toxicity defined by high

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16 levels of arsenic metabolites in biological samples with no signs of clinical symptoms. 2)

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18 Clinical stage− with confirmed arsenic toxicity based on biological sample analysis. It is the
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21 considered to be the stage of developing visible clinical symptoms (i.e. major and minor
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23 dermatological detections). 3) Internal complications stage− in this stage major internal organs
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develop non-dermatological symptoms. 4) Malignancy stage− development of tumor and other
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28 complications in various organs of the body and eventually causing death.
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31 Figure 3: Arsenic exposure induced major dermatological signs and symptoms. Classification is
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based on the type of symptoms observed following arsenic exposure. Modified from Saha et al.,
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36 1999.
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39 Figure 4: Molecular mechanisms of arsenic induced neurotoxicity. Three major mechanisms

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involving arsenic induced neurotoxicity have been elucidated here. 1) Followed by arsenic
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44 exposure increase in ROS activity, lipid peroxides and decrease in superoxidase dismutase
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46 activity leads to oxidative stress causing neurotoxicity. 2) Arsenic exposure leads to up-regulate
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49 p38 MAPK, JUNK3 pathways causing apoptosis in cerebral neurons and responsible for toxicity
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51 in brain. 3) Destabilizing and disrupting cytoskeletal frame work is a well-considered mechanism
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54 of arsenic induced neurotoxicity. (Abbreviations: ROS, reactive oxygen species; p38 MAPK,
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56 p38 mitogen activated protein kinase; JNK3; c-jun N-terminal kinase3.)
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4 Figure 5: Possible mechanisms involved in arsenic exposure induced atherogenicity. Arsenic
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7 exposure may induce atherogencity following certain key molecular mechanisms that triggers
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9 complications of hypertension, diabetes; trace element interactions; increased apoptosis; nitric
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12 oxide impairment; smooth muscle cell proliferation; expression of inflammatory and coagulation

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14 factors; proliferating smooth muscle cells and altering nitric oxide levels/functions.
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17 Figure 6: Mechanisms of arsenic induced cardiovascular complications. Arsenic exposure
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increases the reactive oxygen species and oxidative stress causing decrease in the bioavailability

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22 of nitric oxide. On the other hand, arsenic exposure increases its interaction with the sulfhydryl
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25 groups and obstruct metabolism in the cells. Both these consequences independently leads to the
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27 development of endothelial insufficiency, increased expression of cytokines, inflammatory
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mediators and atherosclerotic genes causing atherogenesis and other cardiovascular
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32 complications. (Abbreviation: ROS, reactive oxygen species.)
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35 Figure 7: Mechanisms of arsenic exposure induced hemolysis. Arsenic exposure may cause
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Anemia, hemolysis and erythrophagocytosis. Increased oxidation of sulfhydryl groups in
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40 hemoglobin and reduced uptake of oxygen by cells occurs due to decreased intracellular
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42 glutathione reducing the lifespan of erythrocytes. On the other hand, arsenic exposure may also
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45 cause a series of changes such as increasing cytosolic calcium levels, ceramide formation,
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47 membrane disintegration along with the decrease in ATP levels and cell membrane integrity
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50 affecting the lifespan of erythrocytes.(Abbreviation: ATP, adenosine triphosphate.)
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53 Figure 8: Plausible mechanisms involved in arsenic induced immunosuppression. Arsenic may
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55 induce immune suppression following a variety of mechanisms such as 1) inducing apoptosis, 2
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58 induce changes in gene expression of immune regulators, 3) induce oxidative stress and
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4 inflammation in peripheral blood mononuclear cells, 4) impair lymphocyte activation, 5) induce
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7 changes in cellular and humoral immunity and 6) may impair macrophage functions.
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10 Figure 9: Mechanisms of Heavy metals (i.e. As, Cd, Hg, Pb) induced endocrine toxicity (i.e.
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adrenal, pituitary, thyroid and pancreas). Heavy metals alters release of catecholamines,and
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15 hinders the functions and responses of cortisol secretion causing toxicity in adrenal gland.
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stimulating hormone, adrenocorticotrpic hormone) along with chronotoxicity may lead to

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22 toxicity in pituitary gland. Mechanisms of inducing toxicity in thyroid gland includes prevention
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24

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25 of thryoid hormone synthesis and increased proliferation of thyroid follicles. Arsenic induce
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27 diabetes damaging pancreatic β cells inducing toxicity in pancreas.
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30 Figure 10: key mechanisms behind development of diabetes due to arsenic exposure. In
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33 pancreas arsenic induce oxidative stress and increase the activity of ROS. Oxidative stress and
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35 ROS may increase amyloid formation, damage and malfunction of pancreatic β cells and induce
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diabetes. In liver, arsenic may increase its interactions with the phosphate or sulfhydryl groups
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40 and impair glucose transport, metabolism and energy production leading to cause diabetes. In fat
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42 and muscle, arsenic alters gene expression by upregulating the activity of NF-κB, TNFα, IL-6
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45 and downregulate PPARγ activity causing diabetic complications through increased insulin
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47 resistance and decreased insulin sensitivity. (Abbreviations: ROS, reactive oxygen species; NF-
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50 κB, nuclear factor-κB; TNFα, tumor necrosis factor α; IL-6, interleukin-6; PPARγ, peroxisome
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52 proliferator activated receptor γ.)
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55 Figure 11: Mechanisms of arsenic exposure induced liver toxicity. Arsenic exposure may
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58 increase ROS activity and induce oxidative stress. This leads to the increased activity of JNK,
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60 p38MAPK and cytochrome P450 inducing hepatic toxicity by causing cell injury, apoptosis and
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4 accumulation of bile acids in liver. On the other hand liver toxicity may occur due to lipid
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7 peroxidation and liver cell damage due to arsenic induced oxidative stress and increased ROS
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9 activity.(Abbreviation: ROS, reactive oxygen species.)
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Figure 12: Mechanisms of arsenic induced renal toxicity. Arsenic exposure induce oxidative
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15 stress and increased ROS activity. This leads to increase lipid periodization and renal cell
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expression of hemeoxygenase-1 and MAPK causing severe renal toxicity by regulating various

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22 transcription factors such as ATF-2, AP-1 and ELK-1.(Abbreviations: ROS; reactive oxygen
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25 species; ATF-2, activation transcription factor-2; AP-1, Activator protein-1; ELK-1, ETS domain
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27 containing protein ELK-1.)
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30 Figure 13: Arsenic exposure induced possible mechanisms causing human diseases.
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33 Susceptibility towards arsenic induced diseases may occur due to increase consumption of S-
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35 adenosylmethionine and glutathione causing DNA hypomethylation and increase susceptibility.
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Arsenic may also increase oxidative stress and transulfuration pathway activity which leads to
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40 decrease in the availability of hydrofolatehomocysteine and S-adenosylmethionine availability.
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42 On the other hand, arsenic may also inhibit the activity and expression of a key enzyme “DNA
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45 methyltransferase”. Both mechanisms cause demethylation of whole genome and specific genes
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50 Figure 14: Mechanisms of lung tumorigenesis development due to arsenic exposure. Arsenic
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53 may interact with three key signaling pathways (i.e. EGFR pathway, PI3K/AKT pathway and
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55 NRF2/KEAP1 pathway) to induce lung tumorigenesis. 1) EGFR pathway: arsenic induced lung
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58 tumorigenesis could occur due to the activation of EGFR pathway. Increased activity of C-Src,
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60 MAPK and reduced activity of JAK-STAT leads to increased activity of EGFR. EGFR activity
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4 regulates cell survival and proliferation of lung cancer. 2) PI3K/AKT pathway: arsenic may
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7 regulate the activity of PI3/AKT pathway by increasing the activity of PI3K, AKT and reduce
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9 the activity of PTEN. This leads to increased activity of VEGF and other target proteins
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12 responsible for cell growth, survival and proliferation of cancer. 3) NRF2/KEAP1 pathway:

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reduce the formation of NRF2/KEAP1/CUL3 degradation complex. This leads to increase in the

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19 activity of NRF2 and protects the tumor cells from metabolites and xenobiotics increasing the

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21 survival of cancer cells in lungs. (Abbreviations: ROS, reactive oxygen species; C-Src, proto-
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24 oncogene tyrosine-protein kinase Src; JAK, janus kinase; STAT, signal transducer and activator

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26 of transcription; MAPK, mitogen-activated protein kinases; EGFR, epidermal growth factor
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receptor; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; AKT, protein kinase B; PTEN,
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31 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase; VEGF, vascular endothelial growth
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34 factor; NRF2, nuclear factor (erythroid-derived 2)-like 2; KEAP1, kelch-like ECH-associated

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36 protein 1; CUL3, cullin-3.)

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39 Figure 15: Mechanisms involved in the development of cancer due to arsenic exposure.
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42 Mechanisms such as 1) altered cell proliferation, 2) genotoxicity, 3) co-carcinogenesis, 4)

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44 changes in DNA methylation and 5) oxidative stress tumor promotion could collectively or
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independently induce tumorigenesis due to arsenic.
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Graphical Abstract

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