ToxSci Advance Access originally published online on January 17, 2008
Toxicological Sciences 2008 103(2):362-370; doi:10.1093/toxsci/kfn012
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Increased Pancreatic Beta-Cell Apoptosis following Fetal and Neonatal Exposure to Nicotine Is Mediated via the Mitochondria
* Reproductive Biology Division, Department of Obstetrics and Gynecology
Department of Medicine
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
1 To whom correspondence should be addressed. Fax: 905-524-2911. E-mail: hollow{at}mcmaster.ca.
Received November 14, 2007; accepted January 8, 2008
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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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 (1 mg/kg/day) via sc 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 Fas ligand (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.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Although cigarette smoking is associated with numerous adverse obstetrical and fetal outcomes (Andres and Day, 2000
; Cnattingius and Lambe, 2002; Faiz and Ananth, 2003; Nordentoft et al., 1996; Robinson et al., 2000; Shiverick and Salafia, 1999), approximately 15–20% of all women smoke during pregnancy (Andres and Day, 2000; Bergmann et al., 2003). Furthermore, recent epidemiologic studies have demonstrated a relationship between maternal smoking and the subsequent development of obesity, hypertension, and type 2 diabetes in adult offspring (Bergmann et al., 2003; Montgomery and Ekbom, 2002; Power and Jefferis, 2002; Toschke et al., 2002; Vik et al., 1996; Von et al., 2002; Wideroe et al., 2003). Our laboratory has previously shown in a rat model that maternal exposure to nicotine, the major addictive component of cigarettes, during pregnancy and lactation results in the development of obesity and impaired glucose homeostasis in adult offspring (Bruin et al., 2007; Holloway et al., 2005). Furthermore, this fetal and neonatal nicotine exposure resulted in elevated pancreatic beta-cell apoptosis and loss of beta-cell mass at weaning, which persisted into adulthood (Bruin et al., 2007). These results may partially explain the increased risk of type 2 diabetes in children born to women who smoked during pregnancy (Montgomery and Ekbom, 2002). However, the cellular pathways which are involved in nicotine-induced beta-cell toxicity during fetal and neonatal development have not yet been identified.
There are two major signaling pathways of programmed cell death, the mitochondrial pathway (intrinsic), and the death receptor pathway (extrinsic) (illustrated in Fig. 1). In the mitochondrial pathway, proapoptotic members of the Bcl2 family (Bax, Bak, or Bid) translocate to the mitochondrial outer membrane and are involved in the formation of a mitochondrial permeability transition pore (mtPTP) (Green and Kroemer, 2004; Gulbins et al., 2003; Gupta, 2003; Jiang and Wang, 2004; Ryter et al., 2007; Wallace, 2005; Zimmermann et al., 2001). Opening of the mtPTP destroys the mitochondrial membrane potential, causing ion equilibration, mitochondrial swelling, and release of proteins, including cytochrome c, from the intermembrane space into the cytosol (Wallace, 2005). Cytochrome c release leads to the formation of an apoptosome, which in turn activates caspase-3 and ultimately induces cell apoptosis (Gulbins et al., 2003; Jiang and Wang, 2004; Wallace, 2005). Antiapoptotic members of the Bcl2 family (Bcl2 and Bcl-XL) sequester Bax, Bak, and/or Bid in the cytosol, thus preventing translocation of these proapoptotic signaling molecules to the mtPTP and inhibiting apoptosis.
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The death receptor pathway involves the binding of a death receptor (e.g., Fas) to a ligand (e.g., FasL), which results in activation of a caspase signaling cascade to induce cell death (Gupta, 2003
; Timmer et al., 2002; Wallace, 2005; Zimmermann et al., 2001). In particular, the Fas-FasL interaction leads to oligomerization of FasL, recruitment of Fas-associated death domain protein, and procaspase-8 to the cytoplasmic death domain of Fas, where a death-inducing signal complex (DISC) is formed (Timmer et al., 2002; Wallace, 2005). DISC formation leads to the activation of caspase-8, which in turn causes cleavage of procaspase-3 to its active form (Timmer et al., 2002; Wallace, 2005). Alternatively, active caspase-8 can induce cleavage of Bid to tBid, which will then translocate to the mitochondrial outer membrane, resulting in release of mitochondrial proteins and amplification of the Fas/FasL apoptosis signal (Timmer et al., 2002; Wallace, 2005). The goal of the current study was to determine whether the beta-cell apoptosis observed in this animal model following fetal and neonatal nicotine exposure is mediated via the mitochondrial and/or death receptor pathway. |
MATERIALS AND METHODS |
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Maintenance and treatment of animals.
All animal experiments were approved by the Animal Research Ethics Board at McMaster University, in accordance with the guidelines of the Canadian Council for Animal Care. Nulliparous 200–250 g female Wistar rats (Harlan, Indianapolis, IN) were maintained under controlled lighting (12:12 light:dark) and temperature (22°C) with ad libitum access to food and water. Dams were randomly assigned (n = 10 per group) to receive saline (vehicle) or nicotine bitartrate (1 mg/kg/day, Sigma-Aldrich, St Louis, MO) via sc injection daily for 2 weeks prior to mating until weaning. At postnatal day 1, litters were culled to eight to assure uniformity of litter size between treated and control litters. To eliminate any confounding effects of the female reproductive cycle, only male offspring were used in this study. After weaning, male offspring (n = 5 per treatment group) were selected randomly for the experiments described below. Immediately following sacrifice, pancreas tissue was excised and either frozen in liquid nitrogen for Western blotting analysis, fixed in 10% neutral buffered formalin for immunohistochemistry, or fixed in 2% glutaraldehyde and 0.1M cacodylate buffer (pH 7.4) for electron microscopy experiments as described below.
Western blotting.
Protein expression was measured in either whole pancreas homogenates (n = 5 per group) or mitochondrial/cytosolic fractions (n = 5 per group) of nicotine- and saline-exposed offspring. Protein was extracted from the whole frozen pancreas using RIPA lysis buffer (15mM Tris-HCl, 1% [vol/vol] Triton X-100, 0.1% [wt/vol] SDS, 167mM NaCl, 0.5% (wt/vol) sodium deoxycholatic acid), with Complete Mini EDTA-free protease inhibitors (Roche Applied Science, Laval, PQ). To separate mitochondrial and cytosolic fractions, the Compartmental Protein Extraction Kit (K3013010; Biochain Institute, Inc., Hayward, CA) was used according to manufacturer's instructions. For Western blots of whole pancreas homogenates, 30 µg of protein was loaded; for Western blots of the mitochondrial/cytosolic fractions, 20 µg of protein was loaded. Protein was subjected to SDS-PAGE and then electrotransferred to polyvinylidene difluoride blotting membrane (BioRad Laboratories, Hercules, CA). Membranes were blocked overnight with 5% (wt/vol) skim milk in TTBS (Tris-buffered saline [TBS], 0.5% [vol/vol] Tween 20) at 4°C and then incubated for 1 h at room temperature in primary antibody on a rocking platform. The membrane was cut horizontally; one half was incubated with the antibody for the protein of interest and the other half with a loading control antibody (
-tubulin or β-actin, depending on which molecular weight was compatible with the primary protein of interest). The following antibodies were used for this study (all rabbit polyclonal except Bcl2): Fas (1:1000; 50 kDa; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), FasL (1:1000; antibody reacts with both the membrane-bound form [40 kDa] and the soluble form [26 kDa]; Santa Cruz Biotechnology), caspase-8 (1:12,000; antibody reacts with both the inactive form [55kDa] and the active form [17 kDa]; AbCam, Cambridge, MA), Bax (1:1000; 23 kDa; Santa Cruz Biotechnology), Bcl2 (1:1000; mouse monoclonal; 26 kDa; Santa Cruz Biotechnology), cytochrome c (1:1500; 11 kDa; Santa Cruz Biotechnology), caspase-3 (1:2000; antibody reacts with both the inactive form [35 kDa] and the active form [17 kDa]; Santa Cruz Biotechnology), β-actin (1:2000; 43 kDa; AbCam), and -tubulin (1:2000; 55 kDa; AbCam). After washing with TTBS, blots were incubated with peroxidase-conjugated secondary anti-rabbit (1:2000; Santa Cruz Biotechnology) or anti-mouse (1:2000; Amersham Biosciences, Piscataway, NJ) antibodies for 1 h at room temperature on a rocking platform. Blots were washed thoroughly in TTBS, followed by TBS after immunoblotting. Reactive protein was detected with ECL Plus chemiluminescence (Amersham Biosciences) and Bioflex X-ray film (Clonex Corporation, Markham, ON). Densitometric analysis of immunoblots was performed using ImageJ 1.37v software; all proteins were quantified relative to the loading control. For antibodies that recognized two forms of the protein at different molecular weights (i.e., caspase-3, caspase-8, and FasL), both bands were quantified from the same sample relative to the loading control from that lane.
Immunohistochemistry.
To determine the cellular localization of the active apoptotic pathways, immunohistochemical staining for active caspase-3 was performed in pancreas sections of nicotine- and saline-exposed offspring. Active caspase-3 was selected because it is the final executioner caspase common to both the extrinsic and intrinsic pathways of programmed cell death. The pancreas from each animal (n = 5 per group) was fixed by immersion in 10% (vol/vol) neutral buffered formalin (EM Science, Gibbstown, NJ) at 4°C overnight, washed in water, and embedded in paraffin. Tissue sections (5 µm) were deparaffinized in xylene, rehydrated, and washed in PBS. Endogenous peroxidase activity was quenched in methanol, followed by antigen retrieval in 10 mmol/l citrate buffer (pH 3.0) at 37°C and blocking with 10% (vol/vol) normal goat serum and 1% (wt/vol) BSA at room temperature. Sections were then incubated with the primary antibody, a polyclonal rabbit anti-active caspase-3 antibody (1:10 dilution; Santa Cruz Biotechnology) overnight at 4°C. Sections were washed in PBS, and immunostaining was identified using the Vectastain kit (Vector Laboratories, Burlingham, CA) with diaminobenzadine as the chromogen. Tissue sections were counterstained with Harris's hematoxylin, destained with acid alcohol, dehydrated, and mounted with Permount (Fisher Scientific, Fair Lawn, NJ). Negative control sections were incubated with 1% (wt/vol) BSA in PBS in place of the primary antibody.
Electron microscopy.
Pancreas tissue from saline- and nicotine-exposed offspring (n = 5 per group) were cut into small pieces and immersed in 2% glutaraldehyde in 0.1M sodium cacodylate buffer (pH 7.4) at 4°C for 1–3 days. Samples were then washed with 0.2M sodium cacodylate buffer (pH 7.4), fixed for 1 h in 1% OsO4 in 0.1M sodium cacodylate buffer (pH 7.4) at room temperature, and dehydrated in an ethanol series followed by 100% propylene oxide (PO). Infiltration was performed at room temperature by immersion of tissues in 50% epon-araldite/50% PO for 30 min, followed by 75% epon-araldite/25% PO for 30 min, and 2 x 60 min in 100% epon-araldite. Tissues were embedded in 100% epon-araldite and polymerized overnight at 65°C. All chemicals used for electron microscopy were purchased from Canemco, Inc. (Montreal, PQ), unless otherwise stated. Thick sections (approximately 1 µm) were cut on an Ultracut E ultramicrotome (Leica Microsystems, Wetzlar, Germany), stained with toluidine blue, and examined under a light microscope to ensure the presence of islets. Thin sections (approximately 70 nm) were then cut from areas of the tissue containing islets, mounted on a Cu/Pd grid (200 mesh), and stained with saturated uranyl acetate and lead citrate. Grids were examined with a JEOL 1200EX transmission electron microscope (JEOL Ltd, Tokyo, Japan), and representative photographs were taken. All photographs were analyzed using Image Pro Plus Version 5.1 software (Media Cybernetics, Inc., Silver Spring, MD). Beta cells were identified within the pancreas sections by the presence of insulin granules. The number of mitochondria was calculated relative to the area of a beta cell in at least four different cells per animal. To assess mitochondrial swelling, the average mitochondrial area and optical intensity were determined by manually circling a minimum of 140 mitochondria within the beta cells of each animal. Higher optical intensity values (a measure of brightness) represent increased empty, white spaces and less tightly formed cristae within a mitochondrion, which is an indication of organelle swelling.
Statistical analysis.
All statistical analyses were performed using SigmaStat (v.3.1; SPSS, Chicago, IL). The results are expressed as mean ± SEM. Data were checked for normality and equal variance and were tested using unpaired Student t-tests ( = 0.05). Where data failed normality or equal variance test, data were reanalyzed using Mann-Whitney rank sum test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Mitochondrial Mediated Apoptosis Pathway
To examine the mitochondrial mediated pathway of apoptosis, protein expression of total Bcl2, Bax, and caspase-3 were measured in whole pancreas homogenates from saline- and nicotine-exposed offspring. In addition, the mitochondrial and cytosolic fractions were isolated from pancreas samples for measurement of Bax translocation to the mitochondrial membrane and cytochrome c release from the mitochondria into the cytosol. Nicotine-exposed offspring had decreased Bcl2 expression (p < 0.05; Fig. 2B) but no change in Bax expression (p > 0.05; Fig. 2A) relative to saline controls. This resulted in a 2.7-fold increase in the ratio of Bax (proapoptotic) to Bcl2 (antiapoptotic) compared to control animals (p < 0.05; Fig. 2C). Although there was no change in total Bax, the ratio of Bax expression in the cytosolic fraction relative to the mitochondrial fraction was reduced (p < 0.05) following nicotine exposure (Fig. 3A), suggesting increased translocation of Bax from the cytosol to the mitochondria. Additionally, nicotine-exposed offspring had an increase (p < 0.05) in the ratio of cytochrome c expression in the cytosolic fraction relative to the mitochondrial fraction compared to saline-exposed animals (Fig. 3B), implying that nicotine exposure increases cytochrome c release from the mitochondria into the cytosol. Finally, caspase-3, the last protein activated in the apoptosis signaling cascade, was examined. There was no change in the inactive 35-kDa form of caspase-3 (Fig. 4A) but an increase in the 17-kDa active form of the protein was observed (Fig. 4B), which translated into a 3.3-fold increase (p < 0.05) in the ratio of active to inactive caspase-3 protein in the nicotine-exposed relative to saline-exposed offspring (Fig. 4C).
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Death Receptor–Mediated Apoptosis Pathway
To examine the death receptor pathway of apoptosis, protein expression of the Fas receptor (Fas), FasL, and caspase-8 were measured in whole pancreas homogenates from saline- and nicotine-exposed offspring. Nicotine exposure caused a significant (p < 0.05) upregulation of Fas and the soluble form of FasL (Figs. 5A and 5B) relative to saline exposure, but no change in expression of the membrane-bound FasL (Fig. 5B). There were no significant differences in expression of either the inactive or active forms of caspase-8 (Fig. 6A) or the ratio of inactive to active caspase-8 (Fig. 6B).
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Immunohistochemical Localization of Active Caspase-3
Immunohistochemical staining of pancreas sections from saline- and nicotine-exposed offspring revealed that all active caspase-3 protein was localized within the islet cells; there was no immunopositive staining in the acinar tissue of these sections (Fig. 7).
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Electron Microscopy
Electron microscopy photographs of pancreatic beta cells from saline- and nicotine-exposed offspring (Figs. 8A and 8B, respectively) were examined to assess changes in mitochondrial number and morphology. The average optical intensity of the mitochondria in nicotine-exposed beta cells was increased by approximately 11% compared to the saline-exposed mitochondria (p < 0.05; Fig. 8E). There was no difference in the number of mitochondria per beta-cell area (p = 0.332; Fig. 8C) or the average mitochondrion area within the beta cells of saline- and nicotine-exposed animals (p = 0.160; Fig. 8D).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Humans with type 2 diabetes are characterized by the inability to produce a sufficient amount of insulin to compensate for peripheral insulin resistance (Butler et al., 2003
; Kahn, 2003; Leahy, 2005). This insulin insufficiency is observed prior to the diagnosis of type 2 diabetes (Kahn, 2003) and is attributed to a reduction in beta-cell mass (Leahy, 2005; Rhodes, 2005). Indeed, recent studies have demonstrated a 40–60% reduction in beta-cell mass from human patients with type 2 diabetes prior to diagnosis compared to weight-matched controls (Butler et al., 2003; Sakuraba et al., 2002; Yoon et al., 2003). Similarly, in our animal model, fetal and neonatal exposure to nicotine results in a permanent loss of beta-cell mass, a defect which precedes the onset of glucose intolerance (Bruin et al., 2007). The nicotine-induced reduction in beta-cell mass in this rodent model has been attributed to elevated levels of beta-cell apoptosis and an impaired capacity for islet cell proliferation (Bruin et al., 2007). However, the specific apoptotic pathways responsible for this toxicity were unknown. Results from the current study suggest that exposure to nicotine during fetal and neonatal development triggers apoptotic signaling in pancreatic beta cells via the mitochondrial mediated pathway.
For this study, markers of both major apoptotic signaling cascades, the death receptor, and mitochondrial mediated pathways were examined. Although nicotine exposure resulted in some alterations to the death receptor–mediated pathway (increased Fas and soluble FasL), apoptosis appears to be mediated primarily through the mitochondrial pathway. Bcl2, which normally sequesters Bax in the cytosol (Wallace, 2005), was significantly reduced in the pancreas following nicotine exposure, thus explaining the observed increase in translocation of Bax to the mitochondria. The presence of Bax on the mitochondrial outer membrane would trigger opening of the mtPTP, causing swelling of the mitochondria and release of proteins such as cytochrome c into the cell cytosol (Wallace, 2005). Indeed, mitochondrial swelling was confirmed by the increased mitochondrial optical intensity in the beta cells of nicotine-exposed offspring observed with electron microscopy. Furthermore, this swelling resulted in increased release of cytochrome c from the mitochondria and triggered activation of caspase-3 in the nicotine-exposed offspring. The apoptotic cysteine protease, caspase-3, is normally expressed as a 32-kDa precursor, but following apoptosome formation by cytochrome c, the protein is cleaved, first into p20 and p12 fragments and then the p20 subunit is further proteolyzed to form the mature 17-kDa fragment (Han et al., 1997). The active form of caspase-3 is classified as an "executioner" caspase and is responsible for the majority of cellular apoptotic events (Zimmermann et al., 2001). For this reason, active caspase-3 was selected as a representative protein for localization of apoptotic signaling within the pancreas. Immunopositive staining of the active executioner caspase was restricted to pancreatic islets, indicating that the observed activation of the mitochondrial mediated apoptotic pathway was specific to the endocrine cells. Furthermore, nicotine-induced mitochondrial swelling observed by electron microscopy was evident in the insulin-secreting beta cells. Therefore, it is likely that the changes to the mitochondrial mediated apoptosis markers observed by Western blotting in the whole pancreas homogenates are localized to the pancreatic islets.
Activation of caspase-3 can also be triggered by the binding of Fas to its ligand FasL, via the death receptor pathway. This interaction triggers either caspase-8–mediated cleavage of procaspase-3 or DISC-mediated translocation of tBid to the mitochondria, leading to release of mitochondrial proteins (Timmer et al., 2002; Wallace, 2005). Results from the current study showed an upregulation of Fas protein, as well as the soluble form of FasL in the pancreas, but no change in activation of caspase-8. Without caspase-8 activation, downstream signaling events in the death receptor cascade such as cleavage of procaspase-3 to its active form, and subsequent apoptosis do not occur. Furthermore, induction of soluble FasL may not have a significant impact on apoptotic signaling since soluble FasL has reduced biological activity compared to the membrane-bound form of the ligand (Date et al., 2003). These data suggest that the death receptor pathway is not activated in the pancreas by nicotine exposure. Instead, this study indicates that nicotine-induced beta-cell toxicity in this animal model is mediated by the mitochondria. Similarly, beta-cell apoptosis in response to high glucose levels has also been shown to be mediated via the mitochondrial apoptosis pathway. Indeed, glucose stimulation resulted in alterations to the mitochondrial apoptotic pathway in beta cells that are similar to those seen in this study, namely an increased Bax/Bcl2 ratio, Bax translocation, cytochrome c release, and caspase-3 activation (Kim et al., 2005).
Taken together, this study overwhelmingly points to the mitochondria as the principal mediator of beta-cell apoptosis resulting from fetal and neonatal exposure to nicotine. However, mitochondria are not only involved in the regulation of apoptosis in beta cells but are also central to the maintenance of beta-cell function (Del Guerra et al., 2005; Lowell and Shulman, 2005; MacDonald et al., 2005). Since we have demonstrated that the mitochondria are affected by nicotine exposure, results from this study may have further consequences for beta-cell function. Transgenic mice with beta-cell–specific mitochondrial defects have decreased glucose-stimulated insulin release (i.e., impaired beta-cell function) (Silva et al., 2000; Silva and Larsson, 2002), suggesting that mitochondrial dysfunction can lead to the development of type 2 diabetes. Indeed, both human and animal studies have observed impaired mitochondrial function in pancreatic islets of subjects with type 2 diabetes (Anello et al., 2005; Simmons et al., 2005). Therefore, the effect of fetal and neonatal nicotine exposure on mitochondria may have implications beyond determining the early fate of beta cells and may in fact be the underlying cause of the observed dysglycemia in nicotine-exposed adult offspring. These results suggest a mechanism by which fetal and neonatal exposure to nicotine as is delivered through maternal smoking or nicotine replacement therapy may result in postnatal glucometabolic abnormalities and suggest that the long-term postnatal health consequences of nicotine exposure warrants further investigation.
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FUNDING |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFUNDINGREFERENCES |
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Canadian Institute of Health Research (MOP 69025) to A.C.H. and K.M.M; a Canadian Institutes of Health Research (CIHR)/Ontario Women's Health Council Doctoral Award Strategic Training Program in Tobacco Research Fellowship, an Ontario Graduate Scholarship, and an Ashley Studentship for Research in Tobacco Control to J.E.B.
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ACKNOWLEDGMENTS |
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H.C.G. holds the Population Health Institute Chair in Diabetes Research (sponsored by Aventis). We thank the staff of the McMaster University Central Animal Facility, Ms Jillian Hyslop and Ms Lisa Kellenberger, for their assistance with the animal work and the staff of the McMaster University Electron Microscopy Facility for their excellent technical support with the EM analysis.
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