ToxSci Advance Access originally published online on November 10, 2006
Toxicological Sciences 2007 95(2):391-400; doi:10.1093/toxsci/kfl164
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The Effect of 3-Methyladenine DNA Glycosylase–Mediated DNA Repair on the Induction of Toxicity and Diabetes by the ß-Cell Toxicant Streptozotocin
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* Eppley Institute for Research in Cancer and Allied Diseases
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198–6805
1 To whom correspondence should be addressed at Department of Pharmaceutical Sciences, 512 Salk Hall, University of Pittsburgh, Pittsburgh, PA 15261. Fax: (412) 383-7436. E-mail: goldbi{at}pitt.edu.
Received July 26, 2006; accepted October 25, 2006
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Abstract |
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Type 1 diabetes in humans arises from the autoimmune destruction of pancreatic ß-cells and typically presents in childhood. Genetic susceptibility is an underlying cause, but environmental agents, that is, toxins and viruses, are postulated to be initiating factors. The underlying role of ß-cell death in response to environmental or physiologic events has been investigated as a critical event in diabetes onset. A well-studied rodent model for type 1 diabetes utilizes streptozotocin (STZ) to induce ß-cell death. STZ is a selective ß-cell genotoxicant, and when administered in a single high dose it induces rapid onset of diabetes by generating DNA adducts, including N3-methyladenine and O6-methylguanine adducts, and subsequently ß-cell death by necrosis. In the present work, we have extended previous studies in which mice deficient in the repair of N3-methyladenine adducts, 3-methyladenine DNA glycosylase (alkyladenine DNA glycosylase [Aag]) null mice, were reported to be resistant to the direct cytotoxic effect of STZ, but later developed autoimmune diabetes (J. W. Cardinal et al., 2001, Mol. Cell. Biol. 231, 5605–5613). We found that Aag–/– mice treated with a single high dose of STZ were protected from widespread ß-cell necrosis and diabetes. However, moderate levels of ß-cell apoptosis were observed in the Aag–/– STZ-treated mice. While mice became glucose impaired for the duration of study (14 months after STZ injection), overt diabetes did not develop. We conclude that an autoimmune response is not initiated in Aag–/– mice in response to ß-cell apoptosis. Furthermore, tumor development is not observed in Aag–/– treated mice, suggesting that N3-methyladenine adducts that accumulate in the genome may not be promutagenic in ß-cells.
Key Words: type 1 diabetes; streptozotocin; apoptosis; 3-methyladenine; base excision repair.