title: Cigarette smoke induces DNA damage and alters base-excision repair and tau levels in the brain of neonatal mice.
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.
authors.affiliation: Department of Health Sciences, University of Genoa, I-16132 Genoa, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: La Maestra
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kisby
authors.forename: Rosanna T
authors.initials: RT
authors.lastname: Micale
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Yoke W
authors.initials: YW
authors.lastname: Kow
authors.forename: Gaobin
authors.initials: G
authors.lastname: Bao
authors.forename: Clayton
authors.initials: C
authors.lastname: Sheppard
authors.forename: Sarah
authors.initials: S
authors.lastname: Stanfield
authors.forename: Huong
authors.initials: H
authors.lastname: Tran
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Agostini
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D019570:Inhalation Exposure; D015227:Lipid Peroxidation / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D012906:Smoke; D016875:tau Proteins; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase