Cigarette Smoke Induces DNA Damage and Alters Base-Excision Repair and Tau Levels in the Brain of Neonatal Mice

Department of Health Sciences, University of Genoa, I-16132 Genoa, Italy.
Toxicological Sciences (Impact Factor: 3.85). 07/2011; 123(2):471-9. DOI: 10.1093/toxsci/kfr187
Source: PubMed


The prenatal and perinatal periods of brain development are especially vulnerable to insults by environmental agents. Early life exposure to cigarette smoke (CS), which contains both genotoxicants and oxidants, is considered an important risk factor for both neurodevelopmental and neurodegenerative disorders. Yet, little is known regarding the underlying pathogenetic mechanisms. In the present study, neonatal Swiss ICR (CD-1) albino mice were exposed to various concentrations of CS for 4 weeks and the brain examined for lipid peroxides, DNA damage, base-excision repair (BER) enzymes, apoptosis, and levels of the microtubule protein tau. CS induced a dose-dependent increase in both malondialdehyde and various types of DNA damage, including single-strand breaks, double-strand breaks, and DNA-protein cross-links. However, the CS-induced DNA damage in the brain returned to basal levels 1 week after smoking cessation. CS also modulated the activity and distribution of the BER enzymes 8-oxoguanine-DNA-glycosylase (OGG1) and apyrimidinic/apurinic endonuclease (APE1) in several brain regions. Normal tau (i.e., three-repeat tau, 3R tau) and various pathological forms of tau were also measured in the brain of CS-exposed neonatal mice, but only 3R tau and tau phosphorylated at serine 199 were significantly elevated. The oxidative stress, genomic dysregulation, and alterations in tau metabolism caused by CS during a critical period of brain development could explain why CS is an important risk factor for both neurodevelopmental and neurodegenerative disorders appearing in later life.

Download full-text


Available from: Glen Kisby
  • Source
    • "The central nervous system develops rapidly during fetal and early postnatal life. Given the dynamic and vulnerable nature of developmental processes, this period of morphogenesis is likely to be exquisitely sensitive to environmental insults (Slotkin et al., 2002; Dwyer et al., 2009; La Maestra et al., 2011; Amos-Kroohs et al., 2013; Balsevich et al., 2014). Although little is known about how prenatal and early postnatal smoking exposure influences brain development, emerging studies have shown that neurotransmitters are changed in nicotine and cigarette smoking animals (Slotkin et al., 2002, 2006; Parameshwaran et al., 2012). "

    Preview · Article · Oct 2015 · The International Journal of Neuropsychopharmacology
  • Source
    • ", and single-and double-strand DNA breaks in the neonatal mouse brain returned to basal levels when cigarette smoke exposure was discontinued for 1 week [38]. As smoking has many adverse effects, smoking cessation as early as possible is most beneficial and always preferable [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the adverse effects of smoking, many pregnancies are exposed to tobacco smoke. Recent studies have investigated whether smoking damages placental DNA by measuring DNA adducts. This study investigated whether a more severe lesion, double-strand DNA breaks, was also present in the tobacco smoking-exposed placenta. Term placentae from women who smoked during their entire pregnancies (n = 52), from those who had ceased smoking for at least 4 weeks before delivery (previous smokers, n = 34), and from nonsmoking women (n = 150) were examined using the DNA double-strand break marker phosphorylated γ H2AX. The extent of DNA damage was assessed according to cell type and additional markers were applied for cell fate (apoptosis and DNA repair), and function (human chorionic gonadotropin, human placental lactogen, and glucose transporter 1), to characterize the effect of the DNA damage on placental integrity. Marked phosphorylated γ H2AX-positive cells occurred in the villous syncytiotrophoblast and syncytial knot nuclei in placentae from smokers (P < .001). Phosphorylated γ H2AX foci did not colocalize with the DNA repair protein 53BP1, and damaged nuclei had a marked reduction in expression of human chorionic gonadotropin, human placental lactogen, and glucose transporter 1. Minimal DNA damage, similar to nonsmokers, was present in previous smokers including those that had ceased smoking for just over 4 weeks before delivery. In summary, smoking during pregnancy was associated with marked double-strand DNA break damage to the syncytiotrophoblast. We suggest that smoking cessation is important to prevent additional DNA damage and to facilitate DNA repair.
    Full-text · Article · Oct 2013 · Human pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The HOGG1 gene catalyzes the excision of modified bases and removal of DNA damage adducts. It may play an important role in the prevention of carcinogenesis. Ser³²⁶Cys polymorphism localizes in exon 7 of the hOGG1 gene. It takes the form of an amino acid substitution, from serine to cysteine, in codon 326. Several epidemiological association studies have been conducted on this polymorphism and its relationship with the risk of prostate cancer. However, results have been conflicting. To resolve this conflict, we conducted a meta-analysis on the association between this polymorphism and prostate cancer, taking into account race, country, sources of controls, and smoking status. A total of nine studies covering 2779 cases and 3484 controls were included in the current meta-analysis. Although no significant association was found between hOGG1 Ser³²⁶Cys polymorphism and prostate cancer susceptibility in the pooled analysis, individuals with Ser/Cys+Cys/Cys genotypes were found to have greater risk of prostate cancer if they were also smokers (OR = 2.66, 95% CI = 1.58-4.47) rather than non-smokers (OR = 2.18, 95% CI = 1.13-4.19), compared with those with Ser/Ser genotype. In conclusion, our meta-analysis demonstrates that hOGG1 Ser³²⁶Cys polymorphism is a risk factor for prostate cancer in smokers. Further studies are needed to confirm this relationship.
    Preview · Article · Jan 2012 · PLoS ONE
Show more