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Abstract
Research in our laboratory has demonstrated that a trivalent form of arsenic such as arsenic trioxide (AT) has the ability to cause significant cytotoxicity, and induction of a significant number of stress genes in human liver carcinoma cells (HepG2). However, the literature also indicates that the toxicity of arsenic depends on its chemical form. To test this hypothesis, we further evaluated the cellular and molecular responses of HepG2 cells following exposure to monosodium acid methanearsonate (MSMA), a pentavalent and organic form of arsenic. Cytotoxicity was evaluated using the MTT-assay for cell viability, while the gene profile assay was performed to measure the degree of gene induction in 13 different recombinant cell lines generated from a parental HepG2 cell line. Cytotoxicity experiments yielded LC50 values of 11.9 + 2.6 μg/mL for AT, and 257.3 + 51.4μg/mL for MSMA; indicating that AT was about 20 times more toxic than MSMA. Exposure of HepG2 cells to MSMA also resulted in a significant reduction (p < 0.05) in the number of stress genes induced, compared to AT. Upon MSMA exposure, only 2 (HMTIIA and HSP70) out of the 13 constructs evaluated yielded inductions to statistically significant levels (p < 0.05), compared to 11 (GSTYa, XRE, HMTIIA, c-fos, NF-kBRE, HSP70, p53RE, GADD153, GADD45, and GRP78) for AT. These results greatly support the hypothesis that the toxicity of arsenic compounds highly depends on their chemical forms; with the inorganic forms being more potent than the organic ones.
Highlights
Arsenic is released to the environment from natural sources as a result of natural phenomena such as erosion of mineral deposits and volcanoes, but releases from human activities such as metal smelting, coal combustion, chemical production and use, and waste disposal can lead to substantial contamination of the environment [1]
LD50 values of 11.9 + 2.6 μg/mL, and 257.3 + 51.4 μg/mL were computed for arsenic trioxide, and MSMA, respectively; indicating that arsenic trioxide was about 20 times more toxic than monosodium acid methanearsonate
Gene Profile Assay The induction levels of the metallothionein in human liver carcinoma cells exposed to arsenic are presented in Figures 3 and 4 for arsenic trioxide, and monosodium acid methanearsonate, respectively. Data presented in these figures indicate a strong dose-response relationship with respect to arsenic induction of the HMTIIA gene promoter
Summary
Arsenic is released to the environment from natural sources as a result of natural phenomena such as erosion of mineral deposits and volcanoes, but releases from human activities such as metal smelting, coal combustion, chemical production and use, and waste disposal can lead to substantial contamination of the environment [1]. More than 80% of arsenic compounds are used to manufacture products with agricultural applications such as insecticides, herbicides, fungicides, algicides, sheep dips, wood preservatives, dyestuffs, and medicines for the eradication of tapeworms in sheep and cattle. Arsenical drugs are still used in treating certain tropical diseases such as African sleeping sickness and amoebic dysentery, and in veterinary medicine to treat parasitic diseases, including filariasis in dogs and black head in turkeys and chickens [2]. Arsenic-containing compounds such as monosodium methanearsonate (MSMA) and disodium metahanearsonate (DMSA) have been and are still being used as to control unwanted weeds in several agricultural areas of the Mississippi Delta. MSMA is currently used by the Mississippi Department of Transportation to control vegetation along highways and rights of way
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