Cigarette smoke induces DNA damage and alters base-excision repair and tau levels in the brain of neonatal mice

Sebastiano La Maestra, Glen E. Kisby, Rosanna T. Micale, Jessica Johnson, Yoke W. Kow, Gaobin Bao, Clayton Sheppard, Sarah Stanfield, Huong Tran, Randall L. Woltjer, Francesco D'agostini, Vernon E. Steele, Silvio De flora

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)471-479
Number of pages9
JournalToxicological Sciences
Volume123
Issue number2
DOIs
StatePublished - Oct 1 2011

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Keywords

  • Base-excision repair
  • Brain
  • Cigarette smoke
  • DNA damage
  • Neonatal mice
  • Neurodegenerative disorders
  • Tau

ASJC Scopus subject areas

  • Toxicology

Cite this

La Maestra, S., Kisby, G. E., Micale, R. T., Johnson, J., Kow, Y. W., Bao, G., Sheppard, C., Stanfield, S., Tran, H., Woltjer, R. L., D'agostini, F., Steele, V. E., & De flora, S. (2011). Cigarette smoke induces DNA damage and alters base-excision repair and tau levels in the brain of neonatal mice. Toxicological Sciences, 123(2), 471-479. https://doi.org/10.1093/toxsci/kfr187