ToxSci Advance Access published online on January 17, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn012
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Increased pancreatic beta cell apoptosis following fetal and neonatal exposure to nicotine is mediated via the mitochondria.
1 Reproductive Biology Division, Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON., Canada L8N 3Z5 2 Department of Medicine, McMaster University, Hamilton, ON., L8N 3Z5 3 Department of Pediatrics, McMaster University, Hamilton, ON., L8N 3Z5
Correspondence to: Dr. Alison Holloway, Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, L8N 3Z5, Canada, Phone: 905-525-9140 x 22130, FAX: 905-524-2911, Email: hollow{at}mcmaster.ca
Received November 14, 2007; revision received January 8, 2008; accepted January 8, 2008
 |
Abstract |
|---|
In Canada, nicotine replacement therapy is recommended as a safe smoking cessation aid for pregnant women. However, we have shown in an animal model that fetal and neonatal nicotine exposure causes increased beta cell apoptosis and loss of beta cell mass, which leads to the development of postnatal dysglycemia and obesity. The goal of this study was to determine whether the observed beta cell apoptosis is mediated via the mitochondrial and/or death receptor pathway. Female Wistar rats were given saline (control) or nicotine bitartrate (1mg/kg/d) via subcutaneous injection for 2 weeks prior to mating until weaning (postnatal day 21). At weaning, pancreas tissue was collected for Western blotting, electron microscopy (EM) and immunohistochemistry. Key markers of each apoptotic pathway were examined in whole pancreas homogenates and mitochondrial/cytosolic pancreas fractions. In the death receptor pathway, Fas and soluble FasL protein were significantly increased in the nicotine-exposed offspring compared to control animals; there was no difference in the ratio of inactive/active caspase-8 or membrane-bound FasL expression. In the mitochondrial pathway, there was a significant increase in the ratio of Bcl2/Bax, Bax translocation to the mitochondria, cytochrome c release to the cytosol and the ratio of active/inactive caspase-3 in nicotine-exposed offspring relative to control animals. Furthermore, increased mitochondrial swelling was observed by EM in the pancreatic beta cells of nicotine-exposed offspring. Taken together, these data suggest that beta cell apoptosis following developmental nicotine exposure is mediated via the mitochondria.
Key Words: mitochondria; apoptosis; nicotine; fetal programming; beta cells; type 2 diabetes.