High susceptibility of neonatal mice to molecular, biochemical and cytogenetic alterations induced by environmental cigarette smoke and light.
ABSTRACT Our recent studies have shown that both cigarette smoke and UV-containing light, which are the most widespread and ubiquitous mutagens and carcinogens in the world, cause systemic genotoxic damage in hairless mice. Further studies were designed with the aim of evaluating the induction of genotoxic and carcinogenic effects in Swiss albino mice exposed to smoke and/or light since birth. We observed that a 4-month whole-body exposure of mice to mainstream cigarette smoke, starting at birth, caused an early and potent carcinogenic response in the lung and other organs. Our further experiments showed that exposure of mice to environmental cigarette smoke, during the first 5 weeks of life, resulted in a variety of significant alterations of intermediate biomarkers, including cytogenetic damage in bone marrow and peripheral blood, formation of lipid peroxidation products, increase of bulky DNA adduct levels, induction of oxidative DNA damage, and overexpression of OGG1 gene in lung, stimulation of apoptosis, hyperproliferation and loss of Fhit protein in pulmonary alveolar macrophages and/or bronchial epithelial cells, and early histopathological alterations in the respiratory tract. Moreover, exposure of mice to UV-containing light, mimicking solar irradiation, significantly enhanced oxidative DNA damage and bulky DNA adduct levels in lung, and synergized with smoke in inducing molecular alterations in the respiratory tract. The baseline OGG1 expression in lung was particularly high at birth and decreased in post-weanling mice. Oxidative DNA damage and other investigated end-points exhibited differential patterns in post-weanling mice and adult mice. The findings of these studies provide a mechanistic clue to the general concept that the neonatal period and early stages of life are critical in affecting susceptibility to carcinogens.
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ABSTRACT: Although the adverse effects of active smoking on sperm quality and fertilization ability are well established, little is known about possible effects of involuntary exposures to cigarette smoke (CS). We designed an experimental study aimed at evaluating the induction of possible noxious effects on testicular morphology and functions in A/J mice exposed whole-body to CS during the first 70 days of life, from birth to early adulthood. Twenty-five sham-exposed neonatal mice and 23 CS-exposed neonatal mice were used. Exposure to CS caused a variety of interconnected alterations in male gonads, including loss of weight and histomorphological alterations of testis, accompanied by a significant increase in abnormalities affecting epidydimal spermatozoa. Induction of oxidative stress was demonstrated by significantly increased concentrations of both reactive oxygen species and lipid peroxidation products in sperm cells. Occurrence of DNA damage in the same cells was documented by using the single cell gel electrophoresis (comet) assay, which showed a remarkable increase in DNA single- and double-strand breaks in CS-exposed mice, as compared with sham-exposed mice. Since biochemical and molecular alterations of sperm cells are known to be associated with impaired sperm quality, our findings suggest that involuntary smoking is potentially able to impair fertility in subjects exposed early in life.International Journal of Hygiene and Environmental Health 09/2014; 218(1). DOI:10.1016/j.ijheh.2014.08.006 · 3.28 Impact Factor
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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.Toxicological Sciences 07/2011; 123(2):471-9. DOI:10.1093/toxsci/kfr187 · 4.48 Impact Factor
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ABSTRACT: Cigarette smoke (CS) is a major risk factor for cardiovascular diseases, cancer, and other chronic degenerative diseases. UV-containing light is the most ubiquitous DNA-damaging agent existing in nature, but its possible role in cardiovascular diseases had never been suspected before, although it is known that mortality for cardiovascular diseases is increased during periods with high temperature and solar irradiation. We evaluated whether exposure of Swiss CD-1 mice to environmental CS (ECS) and UV-C-covered halogen quartz lamps, either individually or in combination, can cause DNA damage in heart and aorta cells. Nucleotide alterations were evaluated by (32)P postlabeling methods and by HPLC-electrochemical detection. The whole-body exposure of mice to ECS considerably increased the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and of bulky DNA adducts in both heart and aorta. Surprisingly, even exposure to a light that simulated solar irradiation induced oxidatively generated damage in both tissues. The genotoxic effects of UV light in internal organs is tentatively amenable to formation of unidentified long-lived mutagenic products in the skin of irradiated mice. Nucleotide alterations were even more pronounced when the mice were exposed to smoke and/or light during the first 5 weeks of life rather than during adulthood for an equivalent period of time. Although the pathogenetic meaning is uncertain, DNA damage in heart and aorta may tentatively be related to cardiomyopathies and to the atherogenesis process, respectively.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 09/2008; 644(1-2):38-42. DOI:10.1016/j.mrfmmm.2008.06.012 · 4.44 Impact Factor