Telomere shortening and DNA damage of embryonic stem cells induced by cigarette smoke
ABSTRACT Embryonic stem cells (ESCs) provide a valuable in vitro model for testing toxicity of chemicals and environmental contaminants including cigarette smoke. Mouse ESCs were acutely or chronically exposed to smoke components, cigarette smoke condensate (CSC), or cadmium, an abundant component of CSC, and then evaluated for their self-renewal, apoptosis, DNA damage and telomere function. Acute exposure of ESCs to high dose of CSC or cadmium increased DNA damage and apoptosis. Yet, ESCs exhibited a remarkable capacity to recover following absence of exposure. Chronic exposure of ESCs to low dose of CSC or cadmium resulted in shorter telomeres and DNA damage. Together, acute exposure of ESCs to CSC or cadmium causes immediate cell death and reduces pluripotency, while chronic exposure of ESCs to CSC or cadmium leads to DNA damage and telomere shortening. Notably, a sub-proportion of ESCs during passages is selected to resist to smoke-induced oxidative damage to telomeres.
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ABSTRACT: Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shorten-ing, but no epidemiologic study to date has examined their associations with LTL in the general population. We ex-amined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999– 2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cad-mium were associated with −5.54% (95% CI: −8.70, −2.37) and −4.50% (95% CI: −8.79, −0.20) shorter LTLs, re-spectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks. Cadmium and lead pose a major public health challenge because of their ubiquitous presence in the environment and their established toxicity even at low levels. Although these metals are naturally occurring elements found in the Earth's crust, their widespread occurrence in the environment is largely the result of anthropogenic activity. Lead and cad-mium are global contaminants (1–3) and they accumulate in the body (4, 5), resulting in widespread exposure. The major exposure sources in the general population are diet and tobac-co smoke (1–3). Contaminated dust and air can be important sources of these metals in communities near industrial sites and in certain occupational settings (2, 3). An increasing body of epidemiologic evidence suggests that environmental exposures to lead and cadmium might contribute to the etiology of chronic diseases, such as cardio-vascular disease (6–8) and chronic kidney disease (9–11). Although the mechanisms of these associations are poorly understood, they may be mediated in part through oxidative stress and inflammatory intermediaries. In experimental stud-ies, both metals were found to contribute to oxidative stress (12) and stimulate cytokine production (13, 14). In epidemio-logic studies, cadmium and lead exposure have been positively associated with biological markers of oxidative stress and inflammation, such as γ-glutamyl transferase and C-reactive protein (15–18). Telomeric attrition may also be an important mechanism for metal-induced toxicity. Telomeres are DNA protein structures that function to protect the ends of eukaryotic chromosomes.American journal of epidemiology 12/2014; DOI:10.1093/aje/kwu293 · 4.98 Impact Factor
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ABSTRACT: The complexity of fracture repair makes it an ideal process for studying the interplay between the molecular, cellular, tissue and organ level events involved in tissue regeneration. Additionally, as fracture repair recapitulates many of the processes that occur during embryonic development, investigations of fracture repair provide insights regarding skeletal embryogenesis. Specifically, inflammation, signaling, gene expression, cellular proliferation and differentiation, osteogenesis, chondrogenesis, angiogenesis, and remodeling, represent the complex array of interdependent biological events that occur during fracture repair. Here we review studies of bone regeneration in genetically modified mouse models, during aging, following environmental exposure, and in the setting of disease that provide insights regarding the role of multi-potent cells and their regulation during fracture repair. Complementary animal models and ongoing scientific discoveries define an increasing number of molecular and cellular targets to reduce the morbidity and complications associated with fracture repair. Lastly, some new and exciting areas of stem cell research such as the contribution of mitochondria function, limb regeneration signaling and microRNA (miRNA) post-transcriptional regulation are all likely to further contribute to our understanding of fracture repair as an active branch of regenerative medicine. © 2014 American Society for Bone and Mineral Research.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2014; DOI:10.1002/jbmr.2373 · 6.59 Impact Factor
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ABSTRACT: DNA methylation is the most studied epigenetic modification, capable of controlling gene expression in the contexts of normal traits or diseases. It is highly dynamic during early embryogenesis and remains relatively stable throughout life, and such patterns are intricately related to human development. DNA methylation is a quantitative trait determined by a complex interplay of genetic and environmental factors. Genetic variants at a specific locus can influence both regional and distant DNA methylation. The environment can have varying effects on DNA methylation depending on when the exposure occurs, such as during prenatal life or during adulthood. In particular, cigarette smoking in the context of both current smoking and prenatal exposure is a strong modifier of DNA methylation. Epigenome-wide association studies have uncovered candidate genes associated with cigarette smoking that have biologically relevant functions in the etiology of smoking-related diseases. As such, DNA methylation is a potential mechanistic link between current smoking and cancer, as well as prenatal cigarette-smoke exposure and the development of adult chronic diseases.Frontiers in Genetics 07/2013; 4:132. DOI:10.3389/fgene.2013.00132