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.

Inactivation of a common OGG1 variant by TNF-alpha in mammalian cells

“…From each reaction, 7 μL were resolved in a 12.5% polyacrylamide UreaGel (National Diagnostics), which was then run at 2000V, 100mA, 125W for 90 min. The dried gel was then exposed overnight to a phosphorimager screen (GE Healthcare), which was then scanned using a Typhoon Trio+ device (GE Healthcare) (33). To calculate OGG1 activity, the 3′ product and the uncut substrate band in the autoradiograms as well as OGG1 expression and beta actin levels measured by western blot were quantified by densitometry using ImageQuantTL software (GE Healthcare Life Sciences).…”

Association of XRCC3 and XRCC4 gene polymorphisms, family history of cancer and tobacco smoking with non-small-cell lung cancer in a Chinese population: a case–control study

“…Studies of familial aggregation in lung cancer suggest that inherited genetic susceptibility may contribute to tumorigenesis. 2 Tobacco smoke can induce DNA damage, 3 such as DNA double-strand breaks (DSBs), which are the most detrimental form of DNA damage and can result in gene mutation, cell death or neoplastic transformation. In addition, improperly repaired DSBs can induce a high predisposition to gene translocations and tumorigenesis.…”

Xenobiotic pulmonary exposure and systemic cardiovascular response via neurological links

“…Within neurons, xenobiotic particles have been shown to interact with cytoskeletal elements and intracellular organelles, ultimately affecting their function, possibly resulting in apoptosis (3,49,107,124). Evidence exists of DNA damage, including single-and double-strand breaks and DNA-protein crosslinks (72); altered overall DNA content (11); as well as mitochondrial DNA methylation (18), following exposure to xenobiotic particles. Furthermore, xenobiotic particles may penetrate to the endoplasmic reticulum and trigger the unfolded protein response, a signaling cascade initiated by the intracellular accumulation of misfolded proteins, as well as oxidative stress (129), a response that may also involve the mitochondria (49,78,107,114) (Fig.…”