RESUMEN
Metabolic activation of many carcinogens leads to formation of reactive intermediates that form DNA adducts. These adducts are cytotoxic when they interfere with cell division. They can also cause mutations by miscoding during DNA replication. Therefore, an individual's risk of developing cancer will depend on the balance between these processes as well as their ability to repair the DNA damage. Our hypothesis is that variations of genes participating in DNA damage repair and response pathways play significant roles in an individual's risk of developing tobacco-related cancers. To test this hypothesis, 61 human B-lymphocyte cell lines from the International HapMap project were phenotyped for their sensitivity to the cytotoxic and genotoxic properties of a model methylating agent, N-nitroso-N-methylurethane (NMUr). Cell viability was measured using a luciferase-based assay. Repair of the mutagenic and toxic DNA adduct, O6-methylguanine (O6-mG), was monitored by LC-MS/MS analysis. Genotoxic potential of NMUr was assessed employing a flow-cytometry based in vitro mutagenesis assay in the phosphatidylinositol-glycan biosynthesis class-A (PIG-A) gene. A wide distribution of responses to NMUr was observed with no correlation to gender or ethnicity. While the rate of O6-mG repair partially influenced the toxicity of NMUr, it did not appear to be the major factor affecting individual susceptibility to the mutagenic effects of NMUr. Genome-wide analysis identified several novel single nucleotide polymorphisms to be explored in future functional validation studies for a number of the toxicological end points.
Asunto(s)
Alquilantes/toxicidad , Linfocitos B/efectos de los fármacos , Carcinógenos/toxicidad , Nitrosometiluretano/toxicidad , Linfocitos B/metabolismo , Línea Celular , Daño del ADN , Metilación de ADN , Reparación del ADN , Humanos , MutagénesisRESUMEN
Parvovirus B19 (B19V) is a small non-enveloped DNA virus of the Parvoviridae family. It is an obligate human pathogen that preferentially replicates in erythroid progenitor cells. B19V is the causative agent of multiple erythroid-related diseases due to replication-induced cytotoxicity. Despite its strong erythroid tropism and related acute disease association, B19V has been determined to persist in many other non-erythroid tissues. This review summarizes and appraises what is known about concomitant B19V DNA persistence and non-acute viral gene expression in various, particularly non-erythroid, tissue types. The methods utilized for B19V detection are described, focusing on the discrepancies in outcomes among the employed assays. The studies where investigations focused on the impact of persistent B19V expression on cellular signaling pathways are also summarized. These studies demonstrate the expanse of the types of cells capable of in vivo B19V expression as well as the possible effect of persistent viral infection on the cellular microenvironment. Overall, these reports indicate that B19V commonly persists in a wide range of both erythroid and non-erythroid tissues, and that low-level viral gene expression can be detected in some persistently infected cells. B19V capsid RNA or proteins have been reported in bone marrow, colon, heart, liver, lymphoid, synovial, testicular, and thyroid tissues. In a sub-set of these cases, B19V capsid mRNA or proteins have been associated with increased inflammatory-related gene expression. The development of standard protocols to assay for B19V infection and expression in the context of non-erythroid, non-acute disease is warranted, and with further targeted studies, may begin to elucidate the impact of persistent B19V infection in vivo. These studies may determine the most conducive cellular environment for persistent gene expression and possible impact on disease pathogenesis.
Asunto(s)
Infecciones por Parvoviridae/inmunología , Infecciones por Parvoviridae/virología , Parvovirus B19 Humano/fisiología , Progresión de la Enfermedad , Células Precursoras Eritroides/inmunología , Células Precursoras Eritroides/virología , Humanos , Especificidad de Órganos , Infecciones por Parvoviridae/patología , Parvovirus B19 Humano/genética , Replicación ViralRESUMEN
Erythrovirus B19 (B19V) is a member of the family Parvoviridae. Infection with B19V has been linked to a variety of diseases including erythroid, thyroid, neurological and autoimmune diseases. Here we show that infection of primary CD36+ cells with B19V coincides with downregulation of thyroid, retinoid, and estrogen hormone receptors. In addition we show changes in expression of a variety of related downstream signaling genes participating in cancer and cardiac-related diseases in B19V-infected erythroid primary cells.