Abstract
Nicotine replacement therapy (NRT) is currently recommended as a safe smoking cessation aid for pregnant women. However, fetal and neonatal nicotine exposure in rats causes mitochondrial-mediated beta cell apoptosis at weaning, and adult-onset dysglycemia, which we hypothesize is related to progressive mitochondrial dysfunction in the pancreas. Therefore in this study we examined the effect of fetal and neonatal exposure to nicotine on pancreatic mitochondrial structure and function during postnatal development. Female Wistar rats were given saline (vehicle control) or nicotine bitartrate (1 mg/kg/d) via subcutaneous injection for 2 weeks prior to mating until weaning. At 3–4, 15 and 26 weeks of age, oral glucose tolerance tests were performed, and pancreas tissue was collected for electron microscopy, enzyme activity assays and islet isolation. Following nicotine exposure mitochondrial structural abnormalities were observed beginning at 3 weeks and worsened with advancing age. Importantly the appearance of these structural defects in nicotine-exposed animals preceded the onset of glucose intolerance. Nicotine exposure also resulted in significantly reduced pancreatic respiratory chain enzyme activity, degranulation of beta cells, elevated islet oxidative stress and impaired glucose-stimulated insulin secretion compared to saline controls at 26 weeks of age. Taken together, these data suggest that maternal nicotine use during pregnancy results in postnatal mitochondrial dysfunction that may explain, in part, the dysglycemia observed in the offspring from this animal model. These results clearly indicate that further investigation into the safety of NRT use during pregnancy is warranted.
Highlights
Cigarette smoking is associated with numerous adverse obstetrical and fetal outcomes [1,2,3,4,5,6], yet 15–20% of women reportedly smoke during pregnancy [1,7]
Oral glucose tolerance tests At 4 weeks of age there was no effect of nicotine exposure (p.0.05) on the total glucose response to the oral glucose load
By 15 weeks of age nearly 20% of the mitochondria in beta cells of nicotine-exposed offspring were classified as either stages 3, 4 or 5 and by 26 weeks this proportion had increased to 57% (Figure 2C–E)
Summary
Cigarette smoking is associated with numerous adverse obstetrical and fetal outcomes [1,2,3,4,5,6], yet 15–20% of women reportedly smoke during pregnancy [1,7]. Mounting epidemiologic evidence indicates that maternal smoking is associated with an increased risk of obesity, hypertension and type 2 diabetes in the offspring [7,8,9,10,11,12,13], the mechanisms underlying this relationship are unknown. Postnatal dysglycemia following fetal and neonatal nicotine exposure was associated with a loss of beta cell mass, beginning at birth and persisting into adulthood [14]. This reduction in beta cell mass following developmental nicotine exposure may partially explain the increased risk of type 2 diabetes in the offspring of women who smoked during pregnancy [8]
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