ABSTRACT
The goal of our study was to evaluate whether drugs currently used for smoking cessation (i.e., nicotine replacement therapy, varenicline [a partial agonist at nicotinic acetylcholine receptors (nAChR)] and bupropion [which acts in part as a nAChR antagonist]) can affect beta cell function and determine the mechanism(s) of this effect. INS-1E cells, a rat beta cell line, were treated with nicotine, varenicline and bupropion to determine their effects on beta cell function, mitochondrial electron transport chain enzyme activity and cellular/oxidative stress. Treatment of INS-1E cells with equimolar concentrations (1µM) of three test compounds resulted in an ablation of normal glucose-stimulated insulin secretion by the cells. This disruption of normal beta cell function was associated with mitochondrial dysfunction since all three compounds tested significantly decreased the activity of mitochondrial electron transport chain enzyme activity. These results raise the possibility that the currently available smoking cessation pharmacotherapies may also have adverse effects on beta cell function and thus glycemic control in vivo. Therefore whether or not the use of nicotine replacement therapy, varenicline and bupropion can cause endocrine changes which are consistent with impaired pancreatic function warrants further investigation.
Subject(s)
Insulin-Secreting Cells/drug effects , Smoking Cessation , Smoking/drug therapy , Animals , Benzazepines/toxicity , Bupropion/toxicity , Dopamine Uptake Inhibitors/toxicity , Electron Transport/drug effects , Gene Expression/drug effects , Glucose/pharmacology , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/metabolism , Mitochondria/drug effects , Nicotine/toxicity , Nicotinic Agonists/toxicity , Oxidative Stress/drug effects , Pancreatic Function Tests , Quinoxalines/toxicity , Rats , Signal Transduction/drug effects , VareniclineABSTRACT
BACKGROUND: Fetal and neonatal nicotine exposure causes ß-cell oxidative stress and apoptosis in neonates, leading to adult-onset dysglycemia. The aim of the present study was to determine whether an antioxidant intervention could prevent nicotine-induced ß-cell loss. METHODS: Nulliparous female Wistar rats received daily subcutaneous injections of either saline or nicotine bitartrate (1.0 mg/kg per day) for 2 weeks prior to mating until weaning. Nicotine-exposed dams received either normal chow or diet containing antioxidants (1000 IU/kg vitamin E, 0.25% w/w coenzyme Q10, and 0.1% w/w α-lipoic acid) during mating, pregnancy, and lactation; saline-exposed dams received normal chow. Pancreatic tissue was collected from male offspring at 3 weeks of age to measure ß-cell fraction, apoptosis, proliferation, and the presence of cells coexpressing insulin and glucagon. RESULTS: The birth weight of offspring born to nicotine-exposed dams was significantly reduced in those receiving dietary antioxidants compared with those fed normal chow. Most interestingly, the antioxidant intervention to nicotine-exposed dams prevented the ß-cell loss and apoptosis observed in nicotine-exposed male offspring whose mothers did not receive antioxidants. Male pups born to nicotine-treated mothers receiving antioxidants also had a tendency for increased ß-cell proliferation and a significant increase in islets containing insulin/glucagon bihormonal cells compared with the other two treatment groups. CONCLUSION: The present study demonstrates that exposure to maternal antioxidants protects developing ß-cells from the damaging effects of nicotine, thus preserving ß-cell mass.
Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Insulin-Secreting Cells/drug effects , Islets of Langerhans/drug effects , Nicotine/toxicity , Prenatal Exposure Delayed Effects/prevention & control , Animals , Animals, Newborn , Antioxidants/administration & dosage , Birth Weight/drug effects , Body Weight/drug effects , Cell Proliferation/drug effects , Diet , Female , Ganglionic Stimulants/administration & dosage , Ganglionic Stimulants/toxicity , Glucagon/metabolism , Injections, Subcutaneous , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Islets of Langerhans/cytology , Islets of Langerhans/metabolism , Male , Nicotine/administration & dosage , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Rats , Rats, Wistar , Time Factors , WeaningABSTRACT
The objective of this study was to determine the effect of in utero and lactational exposure to nicotine on the male reproductive tract. Dams were randomly assigned to receive saline or nicotine bitartrate (1mg/kg-d s.c.) daily for two weeks prior to mating until weaning (postnatal day 21). Male offspring were sacrificed at 7 (peri-pubertal) and 26 (adult) weeks of age. Nicotine-exposure resulted in retention of spermatids after stage VIII, tubular vacuolation, degeneration of pachytene and round spermatids at stage VII in the testes; and lymphocyte infiltration, germ cell exfoliation, and hypospermia in epididymides, at 7 weeks of age. Nicotine-exposure had no effect on testis or epididymal morphology, daily sperm production, epididymal sperm reserve, sperm viability at 26 weeks of age, and circulating testosterone levels at either age examined. We conclude that maternal nicotine-exposure during pregnancy and lactation can induce transient structural changes in the testis and epididymis of male offspring.
