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      Genetic Polymorphisms Associated with Environmental Exposure to Polycyclic Derivatives in African Children

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          Abstract

          Background

          The nonracial leukopenia may be a result of exposure to polycyclic derivatives (benzene-toluene-xylene (BTX)) and may arise from a possible change in the bone marrow microenvironment. The present study sought to evaluate the association of genetic polymorphisms in xenobiotic-metabolizing enzymes with hematological and biochemical profiles.

          Methods

          We evaluated 89 African descendant children, exposed indirectly to benzene derivatives. Laboratory parameters were investigated by automated methods and genetic polymorphisms by PCR-RFLP and PCR multiplex.

          Results

          Children with leukopenia had significantly decreased white blood cells (WBCs) and platelet counts, which is not consistent with benign leukopenia. In the same group, we have found that carriers of the CYP2E1 variant allele had decreased WBC and lymphocytes. Those with NQO1 variant allele had decreased WBC, neutrophil, eosinophil, monocyte, and lymphocyte counts. Carriers of the MPO variant allele had decreased WBC, neutrophil, eosinophil, basophil, monocyte, lymphocyte, and platelet counts and an elevated free iron level. Children with GSTT and GSTM null exhibited decreased WBC, neutrophil, basophil, and lymphocyte counts. Our multivariate analysis model reveals that females were independently associated with leukopenia.

          Conclusion

          Our results suggest that the polymorphisms investigated were associated with hematological changes in the studied population. These alterations could be heightened by exposure to benzene derivatives.

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          Most cited references29

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          Animal models for acquired bone marrow failure syndromes.

          Bone marrow failure is a disease characterized by a drastic decline in the marrow's functional ability to produce mature blood cells. Aplastic anemia, a disease in which patients have essentially empty bone marrow accompanied by severe anemia, neutropenia, and thrombocytopenia, presents a paradigm for bone marrow failure. Damage to the marrow may first result from exposure to toxic chemicals, drug overdose, radiation, and viral infection; however, it is the extended immune-mediated reaction that causes massive destruction of hematopoietic cells and leads to marrow hypoplasia and peripheral pancytopenia. In recent years, animal models of acquired bone marrow failure syndromes have helped to strengthen our understanding of the mechanisms causing bone marrow failure. In this review, animal models for bone marrow failure are summarized by two groups: 1) bone marrow failure induced by toxic chemicals and drugs such as benzene, busulfan, and chloramphenicol, and radiation, and 2) models developed by an immune-related mechanism such as viral infection or foreign lymphocyte infusion.
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            Genetic Polymorphisms of CYP2E1, GSTP1, NQO1 and MPO and the Risk of Nasopharyngeal Carcinoma in a Han Chinese Population of Southern China

            Background Southern China is a major area for endemic nasopharyngeal carcinoma (NPC). Genetic factors as well as environmental factors play a role in development of NPC. To investigate the roles of previously described carcinogen metabolism gene variants for NPC susceptibility in a Han Chinese population, we conducted a case-control study in two independent study population groups afflicted with NPC in Guangdong and Guangxi Provinces of southern China. Methods Five single nucleotide polymorphisms (SNPs) of CYP2E1-rs2031920, CYP2E1-rs6413432, GSTP1-rs947894, MPO-rs2333227 and NQO1-rs1800566 were genotyped by PCR-based RFLP, sequencing and TaqMan assay in 358 NPC cases and 629 controls (phase I cohort). Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI). To confirm our results, sixteen tag SNPs for GSTP1, MPO, NQO1 (which 100% covered these genes), and 4 functional SNPs of CYP2E1 were genotyped in another cohort of 213 NPC cases and 230 controls (phase II cohort). Results No significant associations in NPC risk were observed for the five polymorphisms tested in the phase I cohort. In an additional stratified analysis for phase I, there was no significant association between cases and controls in NPC high risk population (EBV/IgA/VCA positive population). Analysis of 14 tagging SNPs within the same genes in an independent phase II cohort were in agreement with no SNPs significantly associated with NPC. Conclusions Our results suggest that polymorphism of CYP2E1, GSTP1, MPO and NQO1 genes does not contribute to overall NPC risk in a Han Chinese in southern China.
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              Upregulation of NAD(P)H:quinone oxidoreductase by radiation potentiates the effect of bioreductive beta-lapachone on cancer cells.

              We found that beta-lapachone (beta-lap), a novel bioreductive drug, caused rapid apoptosis and clonogenic cell death in A549 human lung epithelial cancer cells in vitro in a dose-dependent manner. The clonogenic cell death caused by beta-lap could be significantly inhibited by dicoumarol, an inhibitor of NAD(P)H:quinone oxido-reductase (NQO1), and also by siRNA for NQO1, demonstrating that NQO1-induced bioreduction of beta-lap is an essential step in beta-lap-induced cell death. Irradiation of A549 cells with 4 Gy caused a long-lasting upregulation of NQO1, thereby increasing NQO1-mediated beta-lap-induced cell deaths. Although the direct cause of beta-lap-induced apoptosis is not yet clear, beta-lap treatment reduced the expression of p53 and NF-kappaB, whereas it increased cytochrome C release, caspase-3 activity, and gammaH2AX foci formation. Importantly, beta-lap treatment immediately after irradiation enhanced radiation-induced cell death, indicating that beta-lap sensitizes cancer cells to radiation, in addition to directly killing some of the cells. The growth of A549 tumors induced in immunocompromised mice could be markedly suppressed by local radiation therapy when followed by beta-lap treatment. This is the first study to demonstrate that combined radiotherapy and beta-lap treatment can have a significant effect on human tumor xenografts.
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                Author and article information

                Contributors
                Journal
                Dis Markers
                Dis. Markers
                DM
                Disease Markers
                Hindawi
                0278-0240
                1875-8630
                2018
                1 August 2018
                : 2018
                : 9078939
                Affiliations
                1Laboratório de Pesquisa em Anemia (LPA), Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão do Jeremoabo, no. 147, Ondina, 40.170-115 Salvador, BA, Brazil
                2Laboratório de Investigação em Genética e Hematologia Translacional (LIGHT), Instituto Gonçalo Moniz (IGM), FIOCRUZ, Rua Waldemar Falcão, 121 Candeal, 40.296-710 Salvador, BA, Brazil
                Author notes

                Academic Editor: Silvia Angeletti

                Author information
                http://orcid.org/0000-0003-3000-1437
                Article
                10.1155/2018/9078939
                6092976
                74bf4780-d812-415a-829c-ecad1f819543
                Copyright © 2018 Rodrigo Mota de Oliveira et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 February 2018
                : 29 April 2018
                : 17 May 2018
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado da Bahia
                Award ID: PET0018/2010
                Categories
                Research Article

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