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Chapter 2 Literature Review
Arsenic species
Arsenic compounds are divided into three major groups: inorganic arsenic compounds; organic arsenic compounds; and arsine gas (ATSDR 2010). They are further classified into four valence states namely; 0 oxidation state [AS(O), metalloid arsenic], trivalent, 3 oxidation state [AS(III), arsenites], pentavalent, 5 oxidation State [As(v), arsenate] and -3 oxidation state (arsine gas) (ATSDR 2007a;ATSDR 2010). The different arsenic species differ in their toxicity, biochemical and environmental behaviours (Alava et al. 2012;Gong et al. 2002). The most common arsenic species and their oxidation states are shown in Table 1. Arsenate [As (V)] is the most common environmental form of inorganic arsenic, but arsenite [As (III)] is more toxic and the most likely carcinogenic species (Bertolero et al. 1987;Lerman et al. 1983;Tinwell et al. 1991).
Routes of Exposure
Arsenic is released from both natural and anthropogenic sources. Environmental arsenic contamination occurs from industrial smelting of metals, power generation with coal, and applications of pesticides and herbicides (NEUBAUER 1947;USEPA 2006).
Human exposure occurs mainly through, food, water, air and soil as well as the natural accumulation of soil arsenic into grains, vegetables, fish, and meats (ATSDR 2007a;Hughes et al. 2011;Liu et al. 2010). Arsenic may enter the organism by dermal contact, inhalation, or ingestion of contaminated drinking water, foodstuffs or medication (IARC 1998). Understanding the environmental levels of arsenic that can cause a public health concern is crucial in planning mitigation strategies
Arsenic contamination of Drinking Water
The main source of high exposure of general population to arsenic compounds is water (Liu et al. 2010). The United States (U.S.) Public Health Service and the World Health Organization have set the guideline for arsenic in drinking water as 10µg/l but in endemic developing countries arsenic drinking water standards is relaxed to 50µg/l (Petrusevski et al. 2008;Smith et al. 2004). High arsenic levels have been detected in groundwater of different parts of the world, (Nordstrom 2002). Bangladesh and West Bengal (India) are the most affected areas of the world with arsenic concentration in groundwater in some area up to 3200 μg/L (Chakraborti et al. 2010;Chakraborti et al. 2011). The inorganic form of arsenic is the most common found in water. It can be stable as both arsenite and arsenate inorganic arsenicals (Khan et al. 2006;Saxe et al. 2007). Arsenite is the most prevalent species in the groundwater while arsenate species more significant in the surface water of the rivers (Pandey et al. 2006). The major source of arsenic in underground water is through the reductive dissolutions of arsenic-rich Fe (III) oxyhydroxides and/or al-hydroxides present in aquifer. Other processes that introduce arsenic into underground water may include oxidation of aquifer arsenical pyrite and other arsenic-bearing sulphide minerals, and the exchange of adsorbed arsenic with other competitive anions (phosphate, bicarbonate and silicate) (McArthur JM 2001;Nickson RT 2000;Pandey et al. 2006). In a U.S. Geological Survey (USGS) report, the median ground water concentration was estimated to be 1 μg/L or less, with much higher levels in some groundwater aquifers, particularly in the western U.S. such as Nevada which have median levels of about 8 μg/L (Focazio 1999). High natural occurring arsenic levels of up to 1,000μg/L have been reported in the U.S. in drinking water (Lewis et al. 1999;Steinmaus et al. 2003). The shallow ground water of the western United States, Arizona, Utah, Nevada, California and Washington in particular are hotspots for arsenic contamination (Twarakavi 2006). In a research conducted in Bangladesh, a range of 0.05 to 2.50 µg/ml arsenic levels in drinking water was reported (Anawar et al. 2002) and concentrations of up to 3.4 µg/ml of arsenic were recorded in drinking water source in West Bengal, India (Guha Mazumder et al. 1998).
Arsenic food contamination
In the mid-19th century, arsenic was intentionally added to food as a preservative prior to the discovery of its deleterious effects on human health (Hughes et al. 2011). Food especially seafood has proven to be a major source of arsenic exposure to human (Uneyama et al. 2007). In a survey of heavy metals in commercial fish in New Jersey, USA, arsenic levels in fish including Chilean sea bass, croaker, flounder, porgie, and whiting exceeded the U.S. Environmental Protection Agency (EPA) regulatory limit by 1.3 µg/ml (Burger et al. 2005). Apart from drinking water, diet is a major source of both inorganic and organic arsenic and estimates of dietary inorganic arsenic intakes vary. Arsenic could enter the food cycle by growing the crop on arsenic contaminated soil or by irrigating the farm with arsenic contaminated water (Das et al. 2004). At a rice paddy in Bangladesh, rice grain grown in soil with high arsenic concentrations resulted in rice grain samples with arsenic levels above 1.7 µg/g dry weight (Meharg et al. 2003). In the U.S., estimates indicate that adults and children consume an average of 3.2μg/day with a range of 1-20μg/day (Cullen et al. 1995;Schoof et al. 1999). The estimated arsenic daily intake in Europe by the European Food Safety Authority is 0.13 to 0.56 μg/kg/day for average consumers and 9.1 to 39.2 μg/day for a 70-kg adult (EFSA 2009) with respect to the ratio of inorganic arsenic to total arsenic in food. In India, it was observed that cooked foods had higher levels of arsenic than raw foods. Daily dietary intakes of arsenic from the foodstuffs for adults were from 171.20 – 189.13 μg/day, while the range for children was 91.89 – 101.63 μg/day (Roychowdhury et al. 2002).
Arsenic from the Soil
The natural content of arsenic in soils globally ranges from 0.01 to over 600 mg/kg, with an average of about 2 to 20 mg/kg (Kabata-Pendias A 1992;Yan-Chu 1994). The major source of arsenic in soil is the parent rock from which soils are formed, and thus the lithology of parent rock materials, volcanic activity, bioactivity, weathering history, transport, sorption, and precipitation all contribute to the nature of arsenic in soil (U.S.EPA 1987). The biotransformation of arsenic species mainly occur in the soil and the three major modes of biotransformation observed include: the biosynthesis of organoarsenic compounds, redox transformation between arsenite and arsenate, and the reduction and methylation of arsenic (Andreae et al. 1983). Arable lands could be contaminated with arsenic from run-off water and the use of arsenic-rich ground water for irrigation (Meharg et al. 2003;Saha et al. 2007). A nationwide survey in the U.S. conducted in areas perceived to have no anthropogenic sources of arsenic reported a natural background concentrations in soil ranged from < 1 to 97 mg/kg (Shacklette 1984). In South Africa, elevated total arsenic levels (1,033–1,369 µg/ml) were detected in the soils contaminated by historically cattle tick dip operations (Okonkwo 2007). The greatest arsenic value (1,369 µg/ml) was obtained at the surface, indicating that arsenic was still abundant at the surface even though the dip is no longer in operation (Moremedi 2007). Inorganic arsenic is the major form of arsenic in soil but high levels of organic forms are also seen in soils. However, pentavalent arsenic is more commonly seen in soil as trivalent arsenical are easily oxidized (Gong et al. 2002). Major contributors of arsenic to the soil are anthropogenic activities such as mining manufacturing activities, and application of arsenic-containing pesticides (Roberts et al. 2002). High soil arsenic are seen at mine tailings, smelter facilities, cattle dip sites, electric substations, wood treatment (chromated copper arsenate) sites, pesticide treatment areas, railroad rights-of-way, golf courses, and dumps (Roberts et al. 2002). Although exposure to soil arsenic could be via inhalation of soil particles blown by wind and dermal absorption, the amount of arsenic in ambient air is low; also, arsenic is poorly absorbed through the skin from the soil (U.S.EPA 2001). Thus, incidental ingestion is the main source of exposure to arsenic in soil but when compared with the other natural routes of exposure, the amount of arsenic from soil is far less than the amount from drinking water and diet (Boyce et al. 2010). This is likely because there is reduced amount of inorganic arsenic as well as reduced bioavailability of arsenic in soil compared to water (Roberts et al. 2002).
Chapter 1 Introduction
1.1 Overview
1.2 Motivation
1.3 Research Goal, Purpose, Hypothesis and Objectives
Chapter 2 Literature Review
2.1 Arsenic species
2.2 Routes of Exposure
2.3 Arsenic mechanism of action
2.4 Biotransformation of arsenic by human microbiome
2.5 Skin Cancer overview
2.6 Skin Cell Culture System
2.7 Microarray/PCR Technologies
2.8 Computational Biology, Bioinformatics tools and data bases
2.9 Visual Analytics
Chapter 3 Research Methodology
3.1 Materials/Methods
3.2 Experimental Design
3.3 Wet laboratory experiments
3.4 Gene Expression studies in HaCaT Keratinocytes Chronically Exposed to ATO
3.5 Statistical Analysis
3.6 Bioinformatics analyses
Chapter 4 Results
4.1 MTT Assay 1
4.2 MTT Assay 2
4.3 DNA Damage Assay (Comet Assay)
4.4 Aberrant Gene Expression Studies in HaCaT keratinocytes chronically exposed to ATO
4.5 Biological pathway analysis
4.6 Arsenic Up-regulated Membrane Proteins
4.7 Prediction of cysteine state and disulphide bond partner
4.8 Prediction of Biological Networks
Chapter 5 Discussion
Chapter 6 Conclusions, Recommendations, Future Studies
6.1 Conclusion
6.2 Significance
6.3 Recommendation
6.4 Future Studies
References
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