Mutagenesis vol. 19 no. 3 pp. 223-229,
May 2004
© 2004 UK Environmental Mutagen Society/Oxford University Press
Effect of sodium arsenite on peripheral lymphocytes in vitro: individual susceptibility among a population exposed to arsenic through the drinking water
1Division of Human Genetics and Genomics, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata-700032, India, 2Department of Dermatology, School of Tropical Medicine, Kolkata-700073, India, 3Department of ToxicoGenetics, Leiden University Medical Center, The Netherlands and 4University of Tuscia, Viterbo, Italy
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Abstract |
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Arsenic (As) contamination in ground water has affected more than 19 countries. Approximately 36 million people in the Bengal delta alone are exposed to this toxicant via drinking water (>50 µg/l) and are at potential health risk. Chronic ingestion of As via drinking water is associated with occurrence of skin lesions, cancer and other arsenic-induced diseases in West Bengal, India. An in vitro cytogenetic study was performed utilizing chromosomal aberrations (CA) in lymphocytes treated with sodium arsenite (0–5 µM) in six symptomatic (having arsenic-related skin lesions) individuals, six age- and sex-matched As-exposed asymptomatic (no arsenic-related skin lesions) individuals and six control individuals with similar socio-economic status residing in non-affected districts of West Bengal with no evidence of As exposure. The mean As content in nails and hair was 9.61 and 5.23 µg/g in symptomatic, 3.48 and 2.17 µg/g in asymptomatic and 0.42 and 0.33 µg/g in the control individuals, respectively. The main aim of our study was to determine whether genotoxic effects differed in the lymphocytes of the control (no exposure to arsenic), asymptomatic and symptomatic individuals after in vitro treatment with sodium arsenite. Although both the exposed groups had chronic exposure to As through the drinking water, individuals with skin lesions accumulated more As in their nails and hair and excreted less in urine (127.80 versus 164.15 µg/l). The results show that sodium arsenite induced a significantly higher percentage of aberrant cells in the lymphocytes of control individuals than in the lymphocytes of both the exposed groups. Within the two exposed groups As induced higher incidences of CA in the symptomatic than the asymptomatic individuals. These results suggest that asymptomatic individuals have relatively lower sensitivity and susceptibility to induction of genetic damage by As compared with the symptomatic individuals.
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Introduction |
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Human beings are exposed to a wide variety of environmental toxicants or carcinogens and there exists an inter-individual variation in sensitivity to a particular toxicant to which they are exposed. A causal association between environmental exposure and health outcome is observed, which is often modified by individual susceptibility that influences genetic effect and other symptoms of the disease concerned (Bonassi, 1999
). Arsenic (As), a potent human carcinogen present in drinking water from both anthropogenic and naturally occurring sources, has affected millions of people around the globe with concentrations far above the 50 µg/l recommended by the World Health Organization. Both the Agency for Toxic Substances and Disease Registry (ATSDR) and the US EPA have given the highest priority to As and have ranked it number one on the list of most hazardous substances based on a combination of its incidence, toxicity and potential for human exposure (Agency for Toxic Substances and Disease Registry, 2003). Clinical manifestations of chronic arsenicosis involve effects such as skin lesions, keratosis, peripheral neuropathy, peripheral vascular diseases and various reproductive abnormalities. It also causes cancers in a number of organs, including skin, lungs, bladder, kidney and liver.
The enigma associated with As is that it is not a ‘classical’ mutagen (point mutations) but shows clastogenic effects in both animals and humans (Basu et al., 2001). Again, animal bioassays are either inconclusive or have failed to show any evidence of carcinogenesis. Thus, As is documented as a paradoxical human carcinogen interacting indirectly with DNA, the pathway of which remains elusive. Experimental studies indicate that As can also act as a co-mutagen with some selected agents like UV-radiation, X-rays, alkylating agents, etc., probably by altering DNA repair processes (Li and Rossman, 1989a,b; Rossman and Wang, 1999). To elucidate the exact cellular mechanism of As carcinogenicity and co-mutagenesis, many possible mechanisms have been proposed, which include chromosomal abnormalities (Basu et al., 2001), alterations in DNA repair mechanisms (Hu et al., 1998), oxidative DNA damage (Yamanaka et al., 1990; Yamanaka and Okada, 1994), aberrant DNA methylation (Mass and Wang, 1997; Zhao et al., 1997), increases in telomerase activity (Zhang et al., 2003), oxidative stress (Hei et al., 1998; Liu et al., 2003), inhibition of p53 (Mass and Wang, 1997), cellular differentiation (Bode and Dong, 2002) or by stimulating growth factors and cytokines (Do et al., 2001; Vega et al., 2001). Moreover, they are very much interlinked, as oxidative stress induced by As may be associated with chromosomal abnormalities while altered DNA repair may affect cell proliferation. Thus, numerous experimental studies suggest that the proposed modes may operate concurrently, sequentially or independently. However, in the absence of a valid and reproducible animal model no unified hypothesis on the precise cellular mechanism of carcinogenesis could be reached. Consequently, much of our knowledge is based on epidemiological or clinical studies. For risk assessment, investigations are being conducted directly on As-exposed populations, focusing primarily on the genetic mechanism, using classical cytogenetic techniques, and also at the molecular level, taking into consideration the genes involved in the proposed mechanistic pathway.
Epidemiological studies in West Bengal, India have reported that more than 6 million people residing in nine affected districts are exposed to As-contaminated drinking water and 
300 000 people show signs of As toxicity (Chakraborti et al., 2002). A strong relationship between As level in the water and the prevalence of keratosis and hyperpigmentation in the exposed individuals of West Bengal, India has been reported (Guha Mazumder et al., 1998). Long-term exposure to As-contaminated water has caused a wide range of adverse health effects, including skin pigmentations, keratosis, vascular diseases, neuropathy and lung diseases, along with non-melanocytic cancer of skin and different internal organs (Guha Mazumder et al., 1998).
Skin lesions are considered as the hallmark signs of chronic arsenic poisoning, with hyperkeratosis being a precursor of non-melanocytic skin cancer. Moreover, a considerable variation in the manifestation of skin lesions in individuals exposed to As-contaminated drinking water has been reported from West Bengal, India (Chowdhury et al., 1997). Epidemiological studies suggest that <25% of the exposed population manifest As-induced skin lesions, although a large number of individuals are exposed to this ubiquitous toxicant through contaminated water (Mandal et al., 1996). The cause of this variation is still not known, however, it is assumed that genetic variation might play an important role. During our survey we observed that some family members exhibit chronic arsenicosis whereas other siblings show no skin changes although they are exposed to the same contaminated water. Interestingly, the elevated levels of As in the nails and hair give evidence of long-term exposure to As. Similarly, respiratory problems among individuals with As-induced skin alteration are more prevalent compared with those without skin lesions (Guha Mazumder et al., 2000). These studies further indicate that among the exposed group individuals with dermatological changes are more susceptible to other As-related diseases.
Studies on different populations across the world exposed to comparable levels of As in their drinking water also show varying degrees of individual susceptibility to As-induced genetic damage, metabolism, methylation capacity and other health effects (Abernathy et al., 1999; Hopenhayn-Rich et al., 2000; Vahter, 2000; Basu et al., 2001). Similarly, in vitro studies also report that there exists a human polymorphism that confers differential sensitivity to sodium arsenite-induced chromosomal aberrations (CA) (Jha et al., 1992; Wiencke et al., 1992; Vega et al., 1995) and sister chromatid exchanges (SCE) (Hsu et al., 1997; Rasmussen et al., 1997). These studies suggest that both environmental exposure to As via drinking water and individual susceptibility may be involved in the manifestation of skin lesions, genetic damage and other symptoms of arsenicosis. It also indicates that the toxicity of As may be related to cell type, As species and length and duration of exposure. Unquestionably, among all this evidence induction of chromosomal abnormalities can be considered to represent one of the most important biomarkers of As exposure (Basu et al., 2004; Mahata et al., 2004).
A large number of studies utilizing cytogenetic techniques are available in the literature on populations chronically exposed to As either occupationally or environmentally. Higher incidences of CA, micronuclei (MN), SCE and aneuploidy have been found in the peripheral blood lymphocytes of As-exposed individuals compared with the controls (Lerda, 1994; Dulout et al., 1996; Gonsebatt et al., 1997; Liou et al., 1999). The extent of the effect is correlated with the extent and duration of the exposure. Inter-individual variations in susceptibility to the clastogenic effects of As have been observed in lymphocyte cultures (Wiencke et al., 1992; Vega et al., 1995; Hsu et al., 1997). Recently, in a cohort study we reported an enhanced frequency of MN (Basu et al., 2002), CA and SCE (Mahata et al., 2003) in the exposed individuals residing in As prone districts of West Bengal, India. We have also observed inter-individual variations in susceptibility to As-induced genotoxicity in lymphocyte cultures, as reported earlier (Wiencke et al., 1992; Vega et al., 1995; Hsu et al., 1997).
In the present work the genotoxic effects were studied as measured as CA after in vitro exposure to sodium arsenite of lymphocyte cultures of control, symptomatic and asymptomatic individuals (exposed to As-contaminated water). Our principal aim was to examine whether sodium arsenite-induced genotoxicity differs between the control, symptomatic and asymptomatic individuals. Furthermore, we wanted to see whether the exposed group, including both the symptomatic and asymptomatic individuals, showed any adaptive response when given an additional challenging dose of As after in vitro treatment compared with the controls. Since the mechanism of As-induced carcinogenesis and susceptibility of humans is not fully elucidated, findings from this investigation may enable us to determine whether the in vitro As-induced genetic damage differs in control, symptomatic and asymptomatic individuals and to identify the potentially susceptible subgroups among the exposed group.
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Materials and methods |
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Study area and individual selection
One of the As endemic villages of North 24 Parganas was selected as the study area. The human ethical committee of the institute first approved this biomonitoring study. Residents of this area have been using contaminated water for more than 10 years. Individuals selected in this study were a subset of a larger investigation reported earlier where the As level in nail, hair, urine and water along with their As-related skin lesions had already been identified (Mahata et al., 2003
). Six individuals (three males and three females) with As-induced skin lesions were classified as symptomatic (S), whereas six individuals (three males and three females) devoid of any As-induced dermatological features were selected as asymptomatic (NS). For this purpose after initial screening a total of eight families were finally selected from the total exposed population. Out of these eight families, four have contributed both symptomatic and asymptomatic individuals, as shown in Table I. Similarly, other symptomatic and asymptomatic individuals were unrelated but were residents of the same village consuming As-contaminated drinking water for a more or less similar duration (see Table I).
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For comparison six individuals (three males and three females) of similar socio-economic status residing in an unaffected village in the district of East Midnapur, West Bengal were considered as controls (C). Physicians and dermatologists examined each participant for clinical symptoms of As toxicity, with greater emphasis on skin lesions. Each individual was personally interviewed using a structured questionnaire to obtain information about socio-demographic characteristics, addiction, medical treatment, residence and duration of drinking water to evaluate the confounding factors. Prior to collecting the biological samples a signed informed consent form was obtained from all individuals following the norms of the ethical committee.
Biomarkers used
As content in nails, hair and urine were used as bio-indicators for exposure assessment. As accumulates in keratin-rich tissues such as nails and hair, thus reflecting cumulative exposure to As over a long period (Agahian et al., 1990). More than 60% of the ingested As is excreted in urine, so it is considered as the best index of current exposure (Buchet et al., 1981). Since CA are considered as biomarkers of early biological effects of carcinogen exposure as well as a biomarker of cancer risk assessment (Hagmar et al., 1994; Bonassi et al., 1995), we chose to study the extent of genetic damage as measured as CA in peripheral lymphocytes as these cells reflect similar events in the target tissues.
Chemicals
RPMI 1640 medium (supplemented with L-glutamine and 25 mM HEPES buffer), heat-inactivated fetal calf serum (FCS), phytohemagglutinin (PHA M-form, lyophilized) and penicillin/streptomycin were purchased from Gibco (Invitrogen Corp., USA). Colchicine (95% pure, HPLC grade), sodium arsenite and Giemsa stain were purchased from Sigma Aldrich Chemical Co. (St Louis, MO). Sodium bicarbonate (GR), concentrated HCl, nitric acid (minimum 69% GR), sulfuric acid, glacial acetic acid, methanol and potassium chloride (AR) were obtained from E.Merck (India) Ltd.
Collection of water, urine, nail and hair samples
For each participant drinking water samples (100 ml) were collected in polypropylene bottles pre-washed with nitric acid:water (1:1) into which nitric acid (1.0 ml/l) was added as a preservative (Chatterjee et al., 1995). First morning voids (100 ml) were collected in pre-coded polypropylene bottles to which concentrated HCl (1 ml/100 ml) was added to stop bacterial growth (Vahter et al., 1995). Nails (500 mg) and hair (500 mg) from each participant were collected. Exogenous As in nails and hair was removed following the method of Curatola et al. (1978) and Agahian et al. (1990). Analysis of As content was carried out at The Institute of Wetland Management and Ecological Design, Kolkata.
Experimental set-up and lymphocyte culture
From each subject 5–7 ml of venous blood was drawn and lymphocyte cultures were set up following the standard protocol (Mahata et al., 2003). Whole blood (0.5 ml) was added to 7 ml of RPMI 1640 supplemented with L-glutamine, 15% FCS, penicillin (100 IU/ml), streptomycin (100 µg/ml) and 2% PHA M-form. Duplicate cultures were maintained for each dose. The cultures were incubated at 37°C. A stock solution of sodium arsenite was prepared immediately before use in sterile water and filtered. Aliquots were added to the cultures after 24 h initiation to give the desired final concentrations (0, 1, 2.5 and 5 µM). The cells were then allowed to grow for a further 48 h. Two hours before fixation colchicine was added to arrest cells in metaphase. At 72 h cells were collected by centrifugation (120 g, 10 min) and exposed for 8 min to 0.075 M KCl at 37°C. It was again centrifuged (120 g, 10 min) and fixed in methanol/acetic acid (3:1). The fixed cell suspension was dropped on coded clean glass slides, air dried and stained with aqueous Giemsa. For each individual 100 metaphases were randomly scored for CA (chromatid and chromosome type) for each concentration tested. Gaps were also recorded. For mitotic index (MI), 1000 cells/individual were scored from the same slides and expressed as a percentage.
Exposure assessment in nails, hair, water and urine
The nails and hair samples were digested with 5 ml of concentrated nitric acid and 3 ml of concentrated sulfuric acid before estimation following the method of Agahian et al. (1990). An alkali-induced sample digestion procedure was used for the analysis of water and urine (Guha Mazumder et al., 2001). Flow injection, hydride generation, atomic absorption spectrometry (FI-HG-AAS) was used for the estimation of As in the biospecimens collected. A Perkin-Elmer Model Analyst100, Fias100AAS was utilized for this purpose.
Statistical analysis
The As content of water, nails, hair and urine of the control, symptomatic and asymptomatic individuals were compared using a paired t-test. Dunnett’s multiple comparison was used to compare the results of CA and MI for all the treated groups with respective controls (untreated group). Comparison of CA and MI between the same concentrations among the three groups was carried out by one-way ANOVA followed by Duncan’s multiple range test.
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Results |
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Table I shows the individual As contents in drinking water, nail, hair and urine samples along with types of skin lesions, age and gender distribution. The average ages of the control, asymptomatic and symptomatic groups were 34.67, 34.17 and 38 years, respectively. Table II represents the mean (± SE) of As indices in the control, asymptomatic and symptomatic individuals. Compared with the control group the exposed individuals had significantly higher (P < 0.01) As contents in water, urine, nail and hair. The mean urinary As content in the symptomatic individuals was lower than in asymptomatic individuals (127.80 versus 164.15 µg/l). The data also indicate that As content in nails and hair of symptomatic individuals was significantly higher (P < 0.05) compared with asymptomatic individuals (see Table II). The mean frequencies of CA ± SE and MI of sodium arsenite-treated and untreated lymphocytes of six control, asymptomatic and symptomatic individuals are shown in Table III. Within each group, i.e. control, asymptomatic and symptomatic, a dose-dependent increase in CA was observed (Table III). The increase in percentage of aberrant cells at 1, 2.5 and 5 µM sodium arsenite compared with the non-treated (0 µM) group was statistically significant (P < 0.01) in all three groups. MI showed a significant dose-dependent decrease after in vitro treatment with sodium arsenite within the groups. MI was also found to be lower in symptomatic than the asymptomatic individuals at all concentrations tested.
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Table IV represents a comparison of the percentage of aberrant cells between the control, asymptomatic and symptomatic groups treated with sodium arsenite. A significant increase in the percentage of aberrant cells in the untreated groups of asymptomatic and symptomatic individuals was observed when compared with the untreated control group. Interestingly, a significant increase in CA was observed at sodium arsenite concentrations of 2.5 and 5 µM in the control group when compared with either the asymptomatic or symptomatic groups (Table IV). Compared with the asymptomatic exposed group, the symptomatic group (individuals with As-induced skin lesions) had a significantly higher (P < 0.05) spontaneous percentage of aberrant cells (see Table IV). Sodium arsenite at concentrations of 1, 2.5 and 5 µM produced a weak but significantly elevated (P < 0.05) percentage of aberrant cells in the symptomatic group when compared with the same concentration in the asymptomatic group (Table IV). The mean
percentage of aberrant cells indicates the difference calculated by deducting the non-induced value (0 µM) from the sodium arsenite-induced value (1, 2.5 and 5 µM) for the same individual. This was performed in order to determine the net increase in CA due to in vitro treatment with sodium arsenite. The percentage of aberrant cells of the control was statistically significant when compared with the asymptomatic and symptomatic groups. However the percentage of aberrant cells between the asymptomatic and symptomatic individuals was not statistically significant (Table IV).
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Discussion |
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The primary aim of this work was to explore whether there is any differences in As-induced cytogenetic damage between individuals with cutaneous lesions and asymptomatic individuals drinking As-contaminated water. Attempts were also made to compare these results with sodium arsenite-induced CA in the lymphocytes of control individuals who had no exposure to As in their drinking water. Out of six individuals in the exposed groups four symptomatic and four asymptomatic individuals were selected from four families (one symptomatic and one asymptomatic from each family). Since two other symptomatic and asymptomatic age- and sex-matched individuals were not available from the same family they were selected from different unrelated families. In the lymphocyte cultures of both symptomatic and asymptomatic individuals spontaneous cytogenetic damage, measured as CA, was significantly higher when compared to the spontaneous CA of non-exposed control individuals. The level of spontaneous genetic damage is more in the symptomatic than asymptomatic individuals. Similarly, after in vitro treatment with sodium arsenite, although symptomatic individuals showed significantly higher incidence of CA than asymptomatic individuals, it was not statistically significant when the differences in CA between the asymptomatic and symptomatic groups were compared after deducting the non-arsenite-induced (0 µM) CA value from the respective arsenite-induced value (see Table IV). This may be due to a higher spontaneous frequency of CA in the symptomatic individuals than the asymptomatic group, as is evident from
values. It appears that the lymphocytes of the control group showed more sensitivity to sodium arsenite than either the symptomatic or asymptomatic groups. This implies that long-term exposure to As may have caused lymphocytes in the exposed group to respond less after in vitro treatment with arsenite than the unexposed control group. This difference in As-induced genetic damage may be due to acquired susceptibility or due to some adaptive variation. Chromatid breaks and gaps were the most frequent types of damage observed. Similarly, elevated levels of CA after exposure of human lymphocytes to arsenite have also been reported by several authors (Nakamuro et al., 1981; Vega et al., 1995). Heterogeneity in the individual susceptibility to the clastogenic effects of sodium arsenite treatment was noted in all the groups.
We observed that asymptomatic participants excreted higher amounts of total As in the urine than the symptomatic participants, which suggests the existence of genetic polymorphism in the metabolic pathway, as suggested by others (Vahter, 2000; Yu et al., 2000). The increased As content in both the exposed groups provides a quantitative measure of chronic exposure to As-contaminated drinking water. In addition, our analysis shows that asymptomatic individuals deposit less As in their nails and hair than the symptomatic individuals, but it is still far above the normal level.
Similarly to this investigation, Hsu et al. (1997) reported an elevated level of spontaneous and As-induced SCE in Bowen’s disease patients and matched controls living in arsenic hyper-endemic villages in Taiwan. In our study all the subjects within the exposed group had chronic exposure to As through their drinking water and demonstrated increased prevalences of cytogenetic damage. The individuals selected were part of a large group in which we earlier reported the induction of genetic damage due to long-term As exposure. An important genetic event in tumor initiation and progression is an increased incidence of CA. In the present study the symptomatic group showed an almost 2-fold increase in the mean spontaneous frequency of CA compared to the asymptomatic group (9.00 ± 0.46 versus 5.17 ± 0.64). Moreover, arsenite tolerance could also be induced by exposure to low concentrations of As when exposed for a long time (Zhao et al., 1997). So it is very important to know the extent of exposure and compare subjects with similar histories of exposure to As. Similarly, recent evidence showed that dietary folate deficiency is known to enhance As-induced clastogenesis (McDorman et al., 2002). Therefore, further analysis of other potential contributors to arsenic genotoxicity in these exposed individuals is necessary to correlate susceptibility to induction of genetic damage with As exposure and disease status.
Thus, it can be summarized that although the asymptomatic individuals show no cutaneous signs of As toxicity, they form a subgroup within the large exposed population and may be subclinically affected while the symptomatic individuals form the sensitive group. Further investigations are in progress to identify single nucleotide polymorphisms and gene expression studies are being carried out, using microarrays, in both the symptomatic and asymptomatic individuals to identify any specific genes responsible for As susceptibility.
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Acknowledgements |
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We are grateful to the Director, Indian Institute of Chemical Biology, for his kind help and cooperation to work on the arsenic-exposed population of West Bengal. We are thankful to the Indian Council of Medical Research (ICMR), Government of India, for providing Senior Research fellowship to J.M. Thanks are also due to Dr Partha Bhowmik, All India Institute of Hygiene and Public Health, Kolkata, for helping us with the statistical analysis of the whole experiment.
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Notes |
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5To whom correspondence should be addressed. Tel: +91 33 2473 0492; Fax: +91 33 2473 5197; Email: akgiri15{at}yahoo.com
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References |
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