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发布于:2019-12-27 10:29:15  访问:137 次 回复:0 篇
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We consider the following perturbation of
In mouse lung, arsenite enhances the formation of cigarette smoke-induced 8-oxodeoxyguanine (Hays et al., 2006) and BaP-induced DNA adducts (Evans et al., 2004). Moreover, arsenite inhibits the repair of BaP-induced DNA adducts in human lung carcinoma A549 Cycloheximide (Schwerdtle et al., 2003), indicating that inhibition of the DNA repair machinery by arsenite may be responsible for potentiation of carcinogenesis. Although evidence of arsenic acting as a co-carcinogen in humans is strong, the molecular mechanisms by which it causes tumorigenesis are poorly understood.
Hypoxia-inducible factors, which are involved in carcinogenesis and tumor progression, consist of α and β subunits. Both are members of the family of basic helix–loop–helix (bHLH) and PER–ARNT–SIM (PAS) domain-containing transcription factors (Gordan and Simon, 2007). Hypoxia is linked to genetic instability in cells and to tumor progression (Kumareswaran et al., 2012), and HIFs are associated with DNA damage and repair (Bertout et al., 2009). In our previous studies, we established that HIF-2α is involved in the arsenite-induced malignant transformation of cells (Xu et al., 2012). Nevertheless, little is known about the relationship between HIF-2α and the genetic instability in cells exposed to BaP and arsenite.

Materials and methods


Inorganic arsenic is a widely distributed, naturally occurring environmental contaminant affecting tens of millions of people worldwide (Smith et al., 2000). Arsenite itself is not a potent mutagen, but it functions as a co-carcinogen and potentiates the genotoxicity of BaP (Evans et al., 2004, Fischer et al., 2005, Maier et al., 2002). BaP is a potent mutagen found in many environmental matrices, including cigarette smoke and lampblack. Epidemiological studies have revealed the association of cigarette smoke/arsenic co-exposure with increased risk of lung cancer (Chen et al., 2004). In the present study, we found that the arsenite accelerates BaP-induced neoplastic transformation of HBE cells. The finding that exposure of cells to arsenite and BaP together generated a neoplastic phenotype, that is, cells with the capacity of anchorage-independent growth, with increased motility and migration, is an indication that fundamental genetic alterations occurred during treatment. These results are in agreement with the established effects seen in cells exposed to arsenite and BaP. Long-term exposure to low levels of arsenite or to BaP alone damages normal cell functions, which can lead to disease due to dsyregulated molecular programs (Andrew et al., 2006, Wester et al., 2012). Since arsenite and BaP co-exposure may alter the lung tissue biochemistry, physiology, and morphology, it is essential to determine if the combined effects of such exposures induce genetic/biochemical alterations that trigger formation of lung tumors (Evans et al., 2004, Hays et al., 2006). For example, some industrial workers are exposed to arsenite as well as to cigarette smoke/BaP, and the combined effect of these two environmental stresses places these populations at an increased risk of developing cancer (Chen et al., 2004). Such considerations led us to study the action of the combined environmental genotoxic stresses of arsenite and BaP on HBE cells. Our results provide new evidence for arsenite and BaP co-exposure on development of lung cancers.
DNA damage is associated with the initiation step of carcinogenesis. Our results reveal that arsenite and BaP co-exposure decreases the number of γ-H2AX foci. γ-H2AX is involved in the recruitment and accumulation of DNA repair proteins to sites of damage (Fernandez-Capetillo et al., 2003, Fillingham et al., 2006, Paull et al., 2000), including sites of replication fork collapse (Furuta et al., 2003). Although the number of γ-H2AX foci reflects the extent of DNA damage, contradictory reports point to a link between disappearance of the H2AX signal and repair of DNA damage. It is reported that γ-H2AX loss correlates with repair of DNA damage only at low cytotoxic doses (Bouquet et al., 2006).
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