Immunohistochemical analysis of oxidative DNA damage in arsenic-related human skin samples from arsenic-contaminated area of China

doi:10.1016/j.canlet.2004.04.005

Cancer Letters

Volume 214, Issue 1, 8 October 2004, Pages 11-18

https://doi.org/10.1016/j.canlet.2004.04.005 Get rights and content

Abstract

The appearance of 8-oxo-2′-deoxyguanosine (8-oxodG) was examined immunohistochemically using an 8-oxodG-monoclonal antibody in 28 cases of arsenic-related human skin tumors and in 20 cases of arsenic-unrelated human skin cancer to determine if the induction of oxidative stress participates in skin tumorigenesis caused by arsenics. The rate of 8-oxodG-positive was significantly higher in arsenic-related human skin cancer (28 of 28, 100%) than in arsenic-unrelated human skin cancer (3 of 20, 15%, P<0.01 by χ² test). Moreover, in all the arsenic-related skin samples, 8-oxodG was detected not only in tumor tissues but also in keratosis and normal tissues. These results suggest that the induction of oxidative stress may play an important role in arsenic carcinogenesis.

Introduction

Inorganic arsenic is carcinogenic in skin, lung, liver, and urinary bladder in humans; nevertheless, there is insufficient evidence of its carcinogenicity in animals [1]. Because of this lack of adequate evidence, a putative mechanism for understanding arsenic carcinogenicity remains vague. Recently, some reports [2], [3], [4], [5], [6] have proposed a hypothesis that oxidative stress plays an important role in the toxicity and carcinogenicity of arsenics [7]. This hypothesis is readily acceptable because of the production of reactive oxygen species (ROS), which is probably dependent on a redox system that has arisen from inorganic arsenic itself [8], [9] and its methylated metabolites [10], [11]. We have reported that dimethylated arsenics metabolically produced from inorganic arsenics induce oxidative stress in mice in vivo and that the stress participates in mouse lung and skin tumorigenesis, particularly in their promotion steps [12], [13], [14], [15].

Some reports have indicated that oxidative damage of DNA, being reflected in the formation of 8-oxo-2′-deoxyguanosine (8-oxodG), participates in mutagenesis, carcinogenesis, and the ageing process [16]. Our recent and other studies have demonstrated that oral administration of dimethylarsinic acid [(CH₃)₂AsO(OH), DMA], a main metabolite of inorganic arsenics, could lead to a higher level of 8-oxodG formation in the target organs (kidney [6] and liver [2] in rats, and skin, lung, liver and urinary bladder in mice [17]) for arsenic carcinogenesis and also in urine [14]. With regard to the detection of 8-oxodG in human arsenical skin lesions, there is only one report so far, and the samples are limited to arsenic-induced Bowen's disease and Bowen's carcinoma [18]. Therefore, in the present study, we investigated the induction of oxidative stress in arsenic carcinogenesis in human. We particularly focused our attention on the formation of 8-oxodG, a major ROS-induced DNA damage product and biomarker of oxidative stress to DNA, in human skin cancer with and without arsenic exposure.

Section snippets

Arsenic-related and arsenic-unrelated skin samples

Specimens were collected from surgically resected skin lesions in the 1980s at the Workers' Hospital of Yunnan Tin Corporation (YTC) in Gejiu city, Yunnan Province, China. YTC, which is a major producer of nonferrous metal in China under a long history—the mining in the area has been carried out for approximately 2000-year-period. The environment, air, soil, and drinking water, around the mines were polluted by heavy dust containing arsenic, which was the principal carcinogen [19], [20], [21],

Results

To determine if the induction of oxidative stress participates in arsenic skin tumorigenesis, 8-oxodG levels in the arsenic-related skin samples were examined immunohistochemically using 8-oxodG monoclonal antibody. Light micrographs of several skin samples are shown in Fig. 1, Fig. 2. Positive stains for 8-oxodG were observed in arsenic skin samples from squamous cell carcinoma (SCC; a in Fig. 1, Fig. 2), basal cell epithelioma (BCE; b in Fig. 1, Fig. 2), and arsenic keratosis (c in Fig. 1,

Discussion

Oxidative DNA damage may participate in ROS-induced carcinogenesis [29]. The formation of 8-oxodG, which is believed to be important in chemical carcinogenesis, is known as a marker of nuclear-base damage [30], [31]. It is well known that the formation of 8-oxodG by common ROS causes G:C to T:A transversions [31], [32]. In the present study using arsenic-related human skin samples, 8-oxodG was detected by immunohistochemical analysis using MOG-020 monoclonal antibody (Table 1 and Fig. 2). We

Acknowledgements

This study was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to promote multidisciplinary research projects, a Joint Research Grant from Nihon University College of Pharmacy, and a Grant-in-Aid for Scientific Research (C) (No. 14572114) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Immunohistochemical analysis of oxidative DNA damage in arsenic-related human skin samples from arsenic-contaminated area of China

Abstract

Introduction

Section snippets

Arsenic-related and arsenic-unrelated skin samples

Results

Discussion

Acknowledgements

Cancer Lett.

Toxicol. Lett.

Arch. Biochem. Biophys.

Toxicol. Lett.

Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Toxicol. Appl. Pharmacol.

Biochem. Biophys. Res. Commun.

J. Invest. Dermatol.

Toxicol. Lett.

IARC monographs on the evaluation of the carcinogenic risks of the chemicals to humans

Promotion of rat hepatocarcinogenesis by dimethylarsinic acid: association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver

Jpn. J. Cancer Res.

Is the genotoxic effect of arsenic mediated by oxygen free radicals?

Hum. Hered.

Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species

Proc. Natl Acad. Sci. USA

DNA-strand breaks induced by dimethylarsinic acid, a metabolite of inorganic arsenics, are strongly enhanced by superoxide anion radicals

Biol. Pharm. Bull.

Acute arsenic-induced free radical production and oxidative stress-related gene expression in mice

Toxicologist

Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity

Proc. Natl Acad. Sci.