Abstract
Objective:Chronic exposure to inorganic arsenic (iAs) may cause a number of health problems including skin cancer. Present study is aimed to look into the potential of black tea extract (BTE) to prevent the development of skin carcinoma in Swiss albino mice. Methods:The study was done on Swiss albino mice, chronically exposed to inorganic arsenic. 150 mice were housed in different cages, 5 in each cage. The control mice did not receive any treatment. Mice were sacrificed at 30, 90, 180, 270 and 330 days. Development of carcinogenesis was assessed by histological studies. Generation of Reactive Oxygen Species (ROS) and Reactive Oxygen Species (RNS) were estimated using 2’,7’-dichlorodihydrofluorescein diacetate (DCFH-DA) and Greiss reagent respectively, and their consequences on DNA (by Micronuclei and Comet assay), protein (by protein carbonyl assay kit) and lipid (by lipid peroxidation) were estimated. Activity of antioxidant enzymes, along with total antioxidant capacity were measured by respective kits. Repair percentage was obtained by Comet assay. Western blotting was employed to study the expression of repair enzymes and expression of cytokines. Sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique was employed to study the activity of various cytokines. Results:At 330 days, invasive squamous cell carcinoma of the skin developed. With increasing time generation of ROS and RNS increased, causing damage to DNA, protein and lipid. Antioxidant defence system gets repressed with time. Capacity to repair the DNA damage is inhibited by iAs, due to alteration in repair enzymes - XRCC I, DNA Ligase I, PARP I, ERCC1, ERCC2, XPA, DNA Ligase IV, DNA PKc and Ku-70. Another consequence of iAs exposure is chronic inflammation due to disrupted cytokine level. Intervention with BTE reverses these deleterious effects, preventing development of skin carcinogenesis.
Highlights
Chronic exposure to the metalloid arsenic, which exists in both organic and inorganic forms, may cause numerous health hazards (Tchounwou et al, 2012), and the inorganic form is more toxic (Hughes et al, 2011)
Though not a classical mutagen, inorganic arsenic (iAs) has been listed as a class 1 carcinogen by International Agency for Research on Cancer (IARC) (Klein et al, 2007)
The exact mechanism of carcinogenesis by iAs is under investigation, generation of free radicals by this metalloid may be responsible for its carcinogenicity (Hu et al, 2020)
Summary
Chronic exposure to the metalloid arsenic, which exists in both organic and inorganic forms, may cause numerous health hazards (Tchounwou et al, 2012), and the inorganic form is more toxic (Hughes et al, 2011). Excess generation of reactive oxygen species (ROS) due to iAs is an important contributory factor to its carcinogenicity (Zhang et al, 2015). Higher level of ROS mediates its damage at the cellular level, affecting nucleic acids, lipids and proteins (Pizzino et al, 2017). Higher fluxes of ROS generation lead to formation of protein carbonyl due to oxidation of amino acid residues (Sinha et al, 2010). High level of ROS leads to lipid peroxidation of polyunsaturated fatty acids, generating malondialdehyde, which elicits cytotoxic effects and damage to cell membrane. Defragmentation of lipid chains, resulting in excess fluidity and enhanced permeability of the cell membrane may occur due to ROS (Yusupov et al, 2010).
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