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Comparison of Genetic Damage, Biochemical Changes and Genetic Variants between Skin Symptomatic and Asymptomatic Individuals Exposed to Arsenic

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Title Comparison of Genetic Damage, Biochemical Changes and Genetic Variants between Skin Symptomatic and Asymptomatic Individuals Exposed to Arsenic
 
Creator Banerjee, Mayukh
 
Subject Molecular & Human Genetics
 
Description Arsenic is an element present ubiquitously in the earth’s crust. Chronic arsenic toxicity, primarily through contaminated groundwater used for drinking purposes is a global problem that has assumed imponderable proportions. An astonishing 137 million people in 35 countries all over the world are estimated to be exposed to this deadly toxicant, with 26 million of them being in West Bengal, India. This, in fact, has been regarded as the “greatest arsenic calamity of the world”. Chronic arsenic toxicity gives rise to a host of well characterized skin lesions (including raindrop pigmentation, Palmar and Plantar hyperkeratosis, hyperpigmentation and skin cancers like Bowen’s disease, squamous cell carcinoma and basal cell carcinoma), conjunctivitis, respiratory problems, neurological maladies, and cancers of internal organs like lungs, kidney, urinary bladder and so on. However, of this huge number of individuals exposed chronically to arsenic, only about 15 - 20% exhibit arsenic-induced skin lesions. This indicates towards and gene-environment interacting mechanism of arsenic susceptibility and carcinogenicity. In this present work, attempts have been made to decipher some of those molecular genetic, cytogenetic and biochemical forces that is responsible for endowment of such susceptibility.
An epidemiological survey was conducted to find out the prevalence of non-dermatological outcomes in the arsenic exposed populations and to quantify if the risk of development of such diseases is elevated by chronic arsenic exposure. Conjunctivitis, peripheral neuropathy and respiratory problems were detected with the help of experienced physicians in the control as well as exposed groups. The exposed group was further subdivided into with and without arsenic-induced skin lesions. Participants were so chosen as to eliminate confounding and the study populations were well matched as far as age, gender, smoking status and socio-economic status were concerned. Calculations showed that the risk of development of each of the three studied disease outcomes were much higher in both the exposed subgroups, compared to the unexposed controls [for exposed individuals with skin lesions (for conjunctivitis: OR = 37.22, 95% CI: 20.56 – 67.36; for peripheral neuropathy: OR = 15.61, 95% CI: 8.20 – 29.71; for respiratory problems: OR = 13.54, 95% CI: 7.45 – 24.62), and for exposed individuals
without skin lesions (for conjunctivitis: OR =4.66, 95% CI: 2.45 – 8.85; for peripheral neuropathy: OR = 3.99, 95% CI: 1.95 – 8.09; for respiratory problems: OR = 3.21, 95% CI: 1.65 – 6.26)]. Even within the exposed group, the individuals having arsenic-induced skin lesions had a higher risk of development of these maladies (for conjunctivitis: OR = 7.33, 95% CI: 5.05 – 10.59; for peripheral neuropathy: OR = 3.95, 95% CI: 2.61 – 5.93; for respiratory problems: OR = 4.86, 95% CI: 3.16 – 7.48) compared to the exposed individuals devoid of any such skin lesions.
Since, genetic variants were expected to play an important role in arsenic susceptibility and carcinogenicity, and DNA repair pathways were known to be implicated in multiple ways with arsenic toxicity, we explored the probable association of ERCC2 gene polymorphism with the development of premalignant hyperkeratosis. ERCC2 is a Nucleotide Excision Repair (NER) pathway gene and codon 751 A>C change (resulting in change of lysine residue into glutamine) had already been linked to development of several cancers. A case-control study was carried out and 318 genetically unrelated individuals were selected (165 with arsenic-induced hyperkeratosis and 153 without skin lesions) and were genotyped for ERCC2 codon 751 polymorphism via a Polymerase Chain Reaction – Restriction Fragment Length Polymorphism (PCR-RFLP) approach. Results showed that individuals bearing Lys/Lys genotype were at significantly higher risk (OR = 4.77, 95% CI = 2.75–8.23) of developing arsenic-induced premalignant hyperkeratosis compared to the individuals who had at least one Gln allele.
Thus, it seems that ERCC2 codon 751 Lys/Lys genotype is associated with sub-optimal DNA repair. In order to find out if that is true, we used chromosomal aberrations as a functional assay. CA was measured from each study participant. It was found that individuals with the risk genotype (Lys/Lys) had significantly higher incidence of chromosomal aberrations (both CA/cell and percent of aberrant cells) [p < 0.01] compared to the individuals bearing non-risk genotypes (Banerjee et al., 2007). Thus, this study validates our hypothesis that ERCC2 codon 751 Lys/Lys genotype gives rise to an increased risk of development of premalignant hyperkeratosis in arsenic exposed individuals, and also demonstrates that this occurs primarily by affecting adversely, the efficacy of DNA repair system
In order to find out the probable mechanistic pathway for arsenic susceptibility, we quantified the genetic damage induced by chronic arsenic exposure. Our studies showed that arsenic exposure gave rise to elevated level of DNA damage in exposed groups compared (without skin lesions and with arsenic-induced hyperkeratosis) to unexposed controls. The amount of DNA damage induced, however, was similar irrespective of the presence of hyperkeratosis. However, when chromosomal aberrations (CA) were quantified, it was found that not only both the exposed subgroups had elevated CA than the controls, but also, individuals with hyperkeratosis had higher CA than exposed individuals without skin lesions. In order to address this susceptibility to develop premalignant lesions, DNA repair efficacy was estimated by using challenge assay. The results of challenge assay proved that individuals with arsenic-induced hyperkeratosis had a sub-optimal DNA repair compared to exposed individuals without skin lesions, as the former group had a significantly higher DNA damage after induction of DNA damage and subsequent repair, although both the groups had similar amount of DNA damage initially. Thus, inefficient DNA repair capacity stands out to be one of the major factors behind arsenic susceptibility and carcinogenicity (Banerjee et al., 2008).
Thus, the present work addressed the critical questions pertaining to arsenic susceptibility and carcinogenicity, which has seldom been done before, if ever at all. Study of arsenic toxicity is difficult as it is, due to the absence of a suitable animal model. Herein lies the importance of this particular study, as it addresses the issues of arsenic toxicity and mechanisms thereof directly in human beings and in a minimum invasive way as well.
 
Date 2009
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/406/1/Thesis_Mayukh_Banerjee.pdf
Banerjee, Mayukh (2009) Comparison of Genetic Damage, Biochemical Changes and Genetic Variants between Skin Symptomatic and Asymptomatic Individuals Exposed to Arsenic. PhD thesis, Jadavpur University.
 
Relation http://www.eprints.iicb.res.in/406/