Prenatal exposure to nicotine, tobacco’s major addictive constituent, has been shown to reduce birth weight and increases apoptosis, oxidative stress, and mitochondrial dysfunction in the postnatal pancreas. Given that upregulated levels of the pro-oxidative adapter protein
p66shcis observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shcexpression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shcexpression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shcexpression in INS-1E pancreatic beta cells. Increased p66shcexpression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shcthrough posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function.