Cancer Letters

Cancer Letters

Volume 223, Issue 1, 1 June 2005, Pages 27-35
Cancer Letters

Mouse skin tumor promotion by sodium arsenate is associated with enhanced PCNA expression

https://doi.org/10.1016/j.canlet.2004.10.020Get rights and content

Abstract

Drinking water contamination by arsenicals remains a major public health problem in many parts of the world more particularly in India and Bangladesh. Despite arsenic being a health hazard and implicated in human carcinogenesis, the experimental evidence available is much limited even now and the mechanisms involved during carcinogenesis and tumor promotions are not clear. Accordingly, in this study, we have studied the tumor promoter effects of sodium arsenate on mouse skin tumor promoter model system using 9,10-dimethyl-1,2-benzanthracene (DMBA) as a initiating carcinogen. Our studies showed development of papillomas on mice skin treated with only DMBA. However, mice treated with DMBA on skin and administered arsenate (As) in drinking water showed development of well differentiated squamous cell carcinomas. Further, both by immunohistochemistry and western blotting analysis studies higher levels of proliferating cell nuclear antigen (PCNA) was observed in mice treated with DMBA plus arsenate compared to only DMBA treated group. PCNA is known to be associated with S phase and DNA replication of the cell cycle. The plain controls and arsenate controls did not show significant difference either in tumor development or in PCNA levels. The present study demonstrates mouse skin tumor promoting effect of arsenate which seems to be associated with abnormal cell proliferation as indicated by higher levels of PCNA expression.

Introduction

Drinking water contamination by arsenic remains a major public health problem in many parts of the world. Of these, most severe arsenic contamination of drinking water was observed in Asia, especially in Bangladesh; West Bengal; India; Inner Mongolia, China; and Taiwan [1]. The world's two biggest cases of groundwater contamination and those that affected the greatest number of people were in Bangladesh and West Bengal. Nine districts in West Bengal, India and 42 districts in Bangladesh have arsenic levels in ground water above the World Health Organization (WHO) maximum permissible limit of 50 μg/l. Chronic arsenic exposure at high doses has neurologic, dermatologic, vascular and carcinogenic effects. One hundred and fifty-one villages from Bangladesh and West Bengal were identified where people were suffering from arsenic induced skin lesions. More people are suffering from arsenical skin lesion in Bangladesh than in West Bengal.

Arsenic is considered as a potent human carcinogen. Squamous cell carcinoma, basal cell carcinoma, bowen disease and carcinoma affecting the lung, uterus, bladder, genitourinary tract, or other sites are often seen in patients with advanced arsenical toxicity cases. Also, complications such as hyperkeratosis, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), and fluid in the abdomen (ascitis) are seen in severe cases [2], [3].

Arsenic exists in many chemical forms with varying degrees of toxicity [4]. The more inorganic the form, the greater the virulence. For example arsenate and arsenite are known carcinogens. Methylated arsenic compounds, monomethyl arsinic acid and dimethyl arsinic acid are less toxic and organic arsenicals arsenobetaine and arsenocholine are relatively innocuous. So for causal factors in arsenic epidemiology, the focus has been on inorganic arsenite and arsenate, but experimental evidence was limited until recently [5]. Numerous experimental studies using laboratory animals have failed to show carcinogenic action of inorganic arsenics [6], [7]. However recent research demonstrated a promotion potential for dimethyl arsinic acid (a main metabolite of inorganic arsenics in mammals) in the urinary bladder, kidney, liver and thyroid gland using a multiorgan carcinogenesis bioassay in rats and also for tumorigenesis in mice [8], [9]. Furthermore it is well known that internationally, at least 1 million people are drinking arsenic contaminated water above WHO recommended value of 0.01 ppm and 200,000 people show skin lesions characteristic of arsenic poisoning [10]. Accordingly, we have made an attempt to investigate the tumor promoter effects of sodium arsenate; a form of inorganic arsenic, on DMBA initiated skin carcinogenesis. The promoter activities of non-genotoxic and genotoxic chemicals generally related to an increase in cell proliferation [11], [12] and accordingly we have studied PCNA expression. In the present study we would like to report tumor promoter effects of oral sodium arsenate using DMBA mouse skin tumor promoter model.

Section snippets

Chemicals

9,10-Dimethyl-1,2-benzanthracene (DMBA) was purchased from Sigma Chemical Company (St Louis, MO, USA). PCNA (PC10) mouse monoclonal antibody was purchased from Santacruz Biotechnology (Santacruz, CA, USA). Sodium arsenate AR was from s.d. Fine Chemicals Ltd, (Boisar, India). All other chemicals were from Sigma, unless otherwise specified.

Animals

A total of forty, 8 week old swiss-bald strain male hairless mice obtained from animal house of ACTREC were used. The animals were randomised and housed five

Survival and general conditions

No treatment related direct effects of Sodium arsenate on survival and general conditions were observed in any of treated groups. The dose of Sodium arsenate utilised was apparently well tolerated.

Skin tumor development

Representative gross lesions on the back skins of mice are shown in Fig. 2. No skin tumors developed in untreated mice and also in mice treated with As water (A and C). Small papillomas were found on mice treated with DMBA alone (B). Whereas large numbers of tumors were found on mice treated with DMBA

Discussion

The metalloid arsenic found in rocks and mineral formation in the earth's crust has long been associated with the development of the cancer in humans. In 1984 health assessment, the US Environmental Protection Agency (EPA) classified Arsenic as a class A human carcinogen based primarily on the epidemiologic evidence [17]. In certain parts of Bangladesh and West Bengal, India, as many as 5% of drinking water wells that are sampled had arsenic levels exceeding 1 mg/l and 27% of wells had levels

Acknowledgements

This work was supported in part by a CSIR Grant No. 37 (1141)/03/EMR-II, New Delhi, India to Dr K.V.K. Rao.

References (27)

  • IARC Monographs on the Evaluation of the carcinogenic risk of chemicals to humans

    (1980)
  • IARC Monographs on the Evaluation of the carcinogenic risk of chemicals to humans

    (1987)
  • S. Yamamoto et al.

    Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens

    Cancer Res.

    (1995)
  • Cited by (0)

    View full text