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As2O3 toxicity in rat hepatocytes: manifestation of caspase-mediated apoptosis

Environmental Toxicology Laboratory, Department of Zoology, School of Life Science, Visva Bharati University, Santiniketan, India

S Roy

Ocean Research Institute, University of Tokyo, Japan

S Agarwal

Environmental Toxicology Laboratory, Department of Zoology, School of Life Science, Visva Bharati University, Santiniketan, India

S Bhattacharya

Environmental Toxicology Laboratory, Department of Zoology, School of Life Science, Visva Bharati University, Santiniketan, India bhattacharyashelley{at}rediffmail.com

In India, arsenic contamination in ground water is of immediate environmental concern affecting a large number of inhabitants in Kolkata. Arsenic is known to be one of the most toxic metalloids naturally occurring in the environment giving rise to severe toxic manifestations including cancer. Because arsenic is also used in chemotherapy of leukemia, it was considered worthwhile to concentrate on the mechanism of toxic action in normal hepatocytes which has not been addressed earlier. Rat hepatocytes were isolated and incubated in As₂O₃ at concentrations of 10, 20, and 40 µM in a time-dependent manner (0, 15, 30 min and 1, 2, and 4 h). The expression of the common stress proteins HSP 70 and 90 throughout the experimental duration confirmed the magnitude of toxic effect imposed by arsenic. Microscopic observations showed clear apoptotic changes in hepatocytes, which were further characterized by DNA ladder formation in time- and concentration-dependent manners. Apoptosis was triggered by caspase activation and over expression of bax at 10 µM As₂O₃ and at 20 and 40 µM concentrations of As₂O₃, MAP kinases were found to mediate the apoptotic pathway. Co-treatment of cells with arsenic and caspase inhibitor (Ac-DEVD-Cho) led to over expression of bcl-2, suppression of bax, and cytosolic sequestration of Bid and Bad. It is therefore concluded that caspase activation has a direct role in arsenic-induced apoptosis mediated by mitochondrial factors at 10 µM As₂O₃, and JUN N-terminal kinase (JNK) and P38 activation are the major mediators of apoptosis at the higher test concentrations (20 and 40 µM) of As₂O₃.

Key Words: apoptosis • As2O3 • Bcl-2 family • caspase • hepatocyte • HSP 70 and 90

Toxicology and Industrial Health, Vol. 24, No. 10, 643-653 (2008)
DOI: 10.1177/0748233708100370


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