Cancer Letters

Cancer Letters

Volume 125, Issues 1–2, 13 March 1998, Pages 83-88
Cancer Letters

Dimethylarsinic acid, a main metabolite of inorganic arsenics, has tumorigenicity and progression effects in the pulmonary tumors of A/J mice

https://doi.org/10.1016/S0304-3835(97)00484-9Get rights and content

Abstract

The pulmonary tumorigenicity of dimethylarsinic acid (DMAA), a main metabolite of inorganic arsenics, was examined in A/J mice fed with drinking water containing DMAA for 25 and 50 weeks. Mice fed with 400 ppm DMAA for 50 weeks produced more pulmonary tumors than untreated mice (mean number per animal 1.36 versus 0.50; P<0.05). Histological examination revealed that the number of mice which bore adenocarcinomas or papillary adenomas correlated with the concentration of DMAA given (untreated versus 400 ppm; P=0.002), suggesting that DMAA could promote tumorigenic processes. These results are consistent with the epidemiological studies on the pulmonary carcinogenesis of arsenics and suggest that DMAA alone can act as a carcinogen in mice.

Introduction

Numerous epidemiological investigations have shown that inorganic arsenics are carcinogenic to humans, particularly in the skin and lungs 1, 2. High mortality rates for malignant neoplasms, including lung cancer, have been reported in an area on the southwest coast of Taiwan, where blackfoot disease is endemic and high-arsenic artesian wells were used as the drinking water source [3]. Occupational 4, 5and iatrogenic arsenical exposures [6]have been reported to lead to various diseases, especially cancers of the respiratory tract and skin. Recent studies have shown adverse health effects due to serious arsenic contamination of the ground water in West Bengal State, India 7, 8. The arsenic-affected population in the State was estimated to be 4.4 million and the disorders so far identified include skin cancer and respiratory disease. However, experimental investigations using animals have not fully succeeded in proving the carcinogenicity of arsenic 1, 2and no promoting effect was demonstrated in spontaneous pulmonary tumorigenicity in mice [9].

Dimethylarsinic acid (DMAA) is a main metabolite of inorganic arsenics and is eliminated from the kidney and excreted in urine [4]. Recent findings have revealed that DMAA induces lung-specific genetic damage in mice and in cultured cells. Oral administration of DMAA induced an increase of heterochromatin in venular endothelium of the lungs [10]. Also, single-strand DNA breaks in the lungs due to the actions of active oxygens and dimethylarsenic peroxyl radicals, both of which were produced in the metabolism of DMAA in mice 11, 12, 13, were induced. Using the human alveolar type II cell line (L-132), DMAA exposure causes DNA single-strand breaks, suppression of replicative DNA synthesis [14], DNA–protein crosslinks [15]and formation of apurinic/apyrimidinic sites in DNA [16]. Recently, Yamanaka et al. [17]reported that exposure of L-132 cells to DMAA induced the activation of DNA repair due to the formation of DNA adducts.

In the previous study, we showed that DMAA acts as a promoter in ddY mice lung tumorigenesis initiated by 4-nitroquinoline 1-oxide (4NQO) [18]. In the present study, we investigated lung tumorigenicity and progression activity by oral administration of DMAA on A/J mice which are susceptible to lung tumorigenesis [19].

Section snippets

Animals

Five-week-old male A/J mice were obtained from Japan SLC (Hamamatsu, Japan). Four or five mice were housed in a cage for 25 or 50 weeks and were maintained under conventional clean conditions with a 12 h light/dark cycle at 24±1°C and 55±5% relative humidity. Mice were fed with commercial pellets (Oriental Yeast, Tokyo, Japan) and were given free access to food and drinking water.

Tumorigenesis experiments

The mice were divided into eight groups of 24 each and given tap water (control), or a 50, 200 or 400 ppm DMAA

Incidence and size of the tumors

Among the groups at 25 weeks, there were no significant differences in the percentage of tumor-bearing mice (20–40%), the total number of tumors, or the size of the tumors (Table 1). At 50 weeks, the percentage of tumor-bearing mice and the total number of tumors increased and the size of the tumors was enlarged compared to the mice at 25 weeks. Although significant differences were not observed in the percentage of tumor-bearing mice among the 50-week groups (50–78.6%), the number of tumors

Discussion

Yamamoto et al. [21]have proposed that DMAA acts as a tumor promoter in various organs except the lungs. In our previous study using ddY mice [18], we showed that the promoting effect of DMAA to pulmonary tumorigenesis was stronger than glycerol, a known potent promoter for lung tumors induced by 4NQO [22]. However, no increase in lung tumor incidence was observed by DMAA administration alone. In the present study, we demonstrated carcinogenic activity of DMAA in animal experiments for the

Acknowledgements

This work was supported in part by grants from the Smoking Research Foundation Grant for Biomedical Research and the Japanese Ministry of Education, Science, Culture and Sports. We thank the technical staff of our department for assistance.

References (32)

  • J.C. Ives et al.

    Environmental associations and histopathologic patterns of carcinoma of the lung: the challenge and dilemma in epidemiologic studies

    Am. Rev. Respir. Dis.

    (1983)
  • M.N. Bates et al.

    Arsenic ingestion and internal cancers: a review

    Am. J. Epidemiol.

    (1992)
  • D.N. Mazumder et al.

    Environmental pollution and chronic arsenicosis in South Calcutta

    Bull. World Health Org.

    (1992)
  • A.K. Chakraborty et al.

    Arsenical dermatosis from tubewell water in West Bengal

    Indian J. Med. Res.

    (1987)
  • M. Kanisawa et al.

    Life term studies on the effects of arsenic, germanium, tin, and vanadium on spontaneous tumors in mice

    Cancer Res.

    (1967)
  • M. Nakano et al.

    Preferential increase of heterochromatin in venular endothelium of lung in mice after administration of dimethylarsinic acid, a major metabolite of inorganic arsenics

    Carcinogenesis

    (1992)
  • Cited by (67)

    • Joint effects of genomic markers and urinary methylation capacity associated with inorganic arsenic metabolism on the occurrence of cancers among residents in arseniasis-endemic areas: A cohort subset with average fifteen-year follow-up

      2021, Biomedical Journal
      Citation Excerpt :

      In the present study, however, we found that a high PMI and a low SMI seemed to be associated with a high risk of developing cancers. It is possible that arsenic aids the carcinogenesis by mechanisms linked to methyl donor and glutathione (GSH) depletion [28] as well as their subsequent genotoxic effects such as induction of oxidative stress, interference with signal transduction, or gene expression [30]. Many studies have explored alternative models.

    • Review of arsenic toxicity, speciation and polyadenylation of canonical histones

      2019, Toxicology and Applied Pharmacology
      Citation Excerpt :

      Significant tumor promotion of drinking water exposure at 10–100 ppm for 32 weeks to DMAV was also reported in another tumor model in rats (Wanibuchi et al., 1996) and at 400 ppm for 25 weeks in mice. Additional studies showed that DMA(V) in drinking water induced bladder tumors in F344 rats at 50 and 200 ppm for 2 years (Yamanaka et al., 1996) and augmented spontaneous lung tumors in A/J mice, at 400 ppm for 50 weeks (Hayashi et al., 1998). These doses of DMAV are very high in comparison as to what humans are exposed.

    • Differences in apoptotic signaling and toxicity between dimethylmonothioarsinic acid (DMMTA<sup>V</sup>) and its active metabolite, dimethylarsinous acid (DMA<sup>III</sup>), in HepaRG cells: Possibility of apoptosis cascade based on diversity of active metabolites of DMMTA<sup>V</sup>

      2018, Journal of Trace Elements in Medicine and Biology
      Citation Excerpt :

      On the other hand, the metabolic methylation pathway from inorganic arsenic to DMAV has long been considered as a detoxification process for inorganic arsenic, at least for its acute toxicity [8]. However, since recent reports have indicated that metabolic intermediates of DMAV, e.g., probably its trivalent form, dimethylarsinous acid [(CH3)2AsOH, DMAIII], are highly toxic and that DMAV has a carcinogenic action in rodents [9,10], the dimethylated arsenic produced in metabolic methylation as well as inorganic arsenic are presumed to possibly play an important role in the carcinogenic mechanism of arsenic in humans [11–15]. Consequently, arsenic compounds have greatly different toxicities that depend on their chemical forms, therefore, toxicity evaluation of each individual chemical is important and necessary.

    • A novel metabolic activation associated with glutathione in dimethylmonothioarsinic acid (DMMTA<sup>V</sup>)-induced toxicity obtained from in vitro reaction of DMMTA<sup>V</sup> with glutathione

      2016, Journal of Trace Elements in Medicine and Biology
      Citation Excerpt :

      On the other hand, the metabolic methylation pathway from inorganic arsenic to DMAV has long been considered as a detoxification process for inorganic arsenic, at least for its acute toxicity. However, because recent reports have indicated that metabolic intermediates of DMAV, e.g., probably its trivalent form, are highly toxic and that DMAV has a carcinogenic action in rodents [6,7], the dimethylated arsenic produced in the metabolic methylation as well as inorganic arsenic are now presumed to possibly play an important role in the toxic mechanism of arsenic [8–12]. Therefore, the International Agency for Research on Cancer (IARC) has classified DMAV into group 2B, a possible carcinogen in humans [13].

    • Renal, hepatic, pulmonary and adrenal tumors induced by prenatal inorganic arsenic followed by dimethylarsinic acid in adulthood in CD1 mice

      2012, Toxicology Letters
      Citation Excerpt :

      Nonetheless, DMA in the drinking water at doses similar to the present study can increase lung tumor incidence in adult A/J mice (Hayashi et al., 1998) and in adult Ogg −/− mice (Kinoshita et al., 2007). The A/J mouse strain is highly susceptible to lung carcinogenesis while Ogg −/− mice cannot repair certain types of oxidative DNA damage (Hayashi et al., 1998; Kinoshita et al., 2007). So the present data, where DMA alone in adult mice induces lung adenocarcinoma, support this prior work showing lung carcinogenesis in mice (Hayashi et al., 1998; Kinoshita et al., 2007).

    View all citing articles on Scopus
    View full text