TY - JOUR
T1 - Cigarette smoke induces DNA damage and alters base-excision repair and tau levels in the brain of neonatal mice
AU - La Maestra, Sebastiano
AU - Kisby, Glen E.
AU - Micale, Rosanna T.
AU - Johnson, Jessica
AU - Kow, Yoke W.
AU - Bao, Gaobin
AU - Sheppard, Clayton
AU - Stanfield, Sarah
AU - Tran, Huong
AU - Woltjer, Randall L.
AU - D'agostini, Francesco
AU - Steele, Vernon E.
AU - De flora, Silvio
N1 - Funding Information:
*Department of Health Sciences, University of Genoa, I-16132 Genoa, Italy; †Center for Research on Occupational and Environmental Toxicology (CROET), Oregon Health & Science University, Portland, Oregon 97239; ‡Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia 30322; §Department of Pathology, Oregon Health & Science University, Portland, Oregon 97239; and {Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland 20892-7322
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
KW - Base-excision repair
KW - Brain
KW - Cigarette smoke
KW - DNA damage
KW - Neonatal mice
KW - Neurodegenerative disorders
KW - Tau
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U2 - 10.1093/toxsci/kfr187
DO - 10.1093/toxsci/kfr187
M3 - Article
C2 - 21778470
AN - SCOPUS:80053442450
SN - 1096-6080
VL - 123
SP - 471
EP - 479
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -