Carcinogenicity of monomethylarsonous acid (MMAIII) and sodium arsenate (AsV) and identification of early warning biomarkers.

Krishnamohan, Manonmanii (2007). Carcinogenicity of monomethylarsonous acid (MMAIII) and sodium arsenate (AsV) and identification of early warning biomarkers. PhD Thesis, School of Medicine , University of Queensland.

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Author Krishnamohan, Manonmanii
Thesis Title Carcinogenicity of monomethylarsonous acid (MMAIII) and sodium arsenate (AsV) and identification of early warning biomarkers.
School, Centre or Institute School of Medicine
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Supervisor Associate Professor Jack Ng
Abstract/Summary Although inorganic arsenic is classified as a human carcinogen, lack of an appropriate animal model till recently made it difficult to understand the mechanism of its carcinogenicity. The first inorganic arsenic-induced tumour study was reported by Ng et al. (1998) in C57Bl/6J mice exposed to 500 μg/L sodium arsenate in drinking water. Subsequently, Waalkes et al. (2003) demonstrated arsenite as a transplacental carcinogen in C3H mice exposed to 42.5 or 85 mg/L sodium arsenite between the 8th to 18th days of gestation. Recently monomethylarsonous acid (MMAIII), an intermediate metabolite of the arsenic methylation pathway was shown to be more acutely toxic and genotoxic in both in vitro and in vivo studies. However, its carcinogenic effect was unknown. The first aim of the present study is to investigate whether MMAIII was carcinogenic in a mouse model. The second aim was to investigate whether there was a difference between the spontaneous tumour seen in the controls and arsenic induced tumour which occurred in the test. The third aim was to confirm the carcinogenic effects reported by Ng et al. (1998) by exposing mice to three different concentrations of sodium arsenate (AsV) or Monomethylarsonous acid (MMAIII) in drinking water and to establish a dose response relationship for both arsenate and MMAIII in this mouse strain; and finally to investigate if porphyrin profile can be used as an early warning biomarker for chronic arsenic exposure prior to the onset of carcinogenesis. Female C57Bl/6J mice were exposed to drinking water containing AsV (sodium arsenate) or MMAIII (monomethylarsonous acid) at 0,100, 250 and 500 μg/L ad libitum respectively for two years. 24 hrs pooled urine samples were collected every 2 months for urinary arsenic and porphyrin analyses. Dimethylarsinic acid (DMAV) was found to be a major urinary metabolite in both AsV and MMAIII-treated mice. The study confirmed the carcinogenic effects of AsV in this mouse strain and for the first time, demonstrated MMAIII to be similarly carcinogenic. Significant increases in the level of urinary prophyrins were observed in both AsV and MMAIII-treated mice compared to the control group. Histological examination of tumour masses and tumour bearing organs showed lymphoma was the major type of tumour observed in both control and treated groups. Tumours generally occurred 18 months post treatment. Tumour-bearing animals appeared to remain healthy until the terminal stages of the experiment. The increased incidences of lymphomas were dose dependent for both AsV and MMAIII -treated groups. Other types of tumours and multiplicity of tumours also showed a significant dose response relationship in the AsVtreated groups. Mesenteric lymph node lymphoma and metastatic lymphoma in the liver showed significant dose response relationship in MMAIII-treated mice. The incidence of other types of tumours histiocytic sarcoma was higher in both AsV and MMAIII-treated mice compared to the controls. Plasmacytoid lymphomas were observed only in treated mice. Chronic dermatitis and other degenerative skin lesions were seen only in the AsV and MMAIII-treated mice and not in the control. Keratoacanthoma of the skin, epidermoid carcinoma and rhabdomyosarcoma were only seen in the MMAIII treated mice and not in the AsV-treated mice. Immunohistological examination showed the lymphomas to be of B cell origin. Microarray was performed in selected tumour and non-tumour liver tissues from control, 100 and 500 μg/L groups from both AsV and MMAIII-treated animals. Oncogenes, genes involved in cell division and cell proliferation, chemokines, cyclin dependent kinases, tumour necrosis factor genes (TNF), Mitogen activated protein kinase (MAPK) family genes, Signal transducer and activator of transcription (STAT) family genes and DNA damage genes were highly expressed in the MMAIII-treated groups compared to the control group. Genes involved in the Nuclear factor of kappa light chain gene enhancer in B-cells (NFκB) signaling pathway like TNF receptorassociated factor (TRAF), IκBKβ, TRAF family member-associated NF-kappa B activator (TANK) and B-cell leukemia/lymphoma 2 (BCL2) showed more than 32 fold increases in the MMAIII-treated tumours compared to the control tumours. Also inflammatory and B-cell leukaemia and lymphoma genes were expressed in MMAIIItreated tumours only. Genes expressed in the MMAIII-treated tumours showed interesting pathways, the antiapoptotic signaling mediated by the TNF-α induced AKT pathway and prosurvival pathway by TNF-α induced TRAF1 and TRAF2 mediated NFκB activation. The present study is the first low dose chronic study of MMAIII, and both AsV and MMAIII demonstrated to be carcinogenic in C57Bl/6J female mice. Higher incidences of all types of tumours in MMAIII-treated mice and incidences of various types of tumours only in MMAIII-treated groups suggested that MMAIII could be more carcinogenic in vivo than AsV. MMAIII also appeared to have induced a greater variety of genes involved in tumorigenesis compared to AsV. In conclusion, this study supports the contention that the arsenic methylation pathway is not necessarily a detoxification pathway but may in fact in some circumstances enhance the toxicity of the element, and that MMAIII might play a significant role in mammalian arsenic carcinogenicity.

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Created: Fri, 21 Nov 2008, 16:35:48 EST