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Journal Article 
Polymorphisms In BRCA2 And WRN, Genomic Instability And Benzene Hematotoxicity 
Galvan, N; Shen, M; Lan, Q; Zhang, L; Chanock, S; Li, G; Vermeulen, R; Guo, W; Grosovsky, AJ; Yin, S; Et al 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
Benzene causes toxicity to the blood-forming system and leukemia. We recently reported that benzene caused a significant decrease of white blood cells, especially granulocytes and B-lymphocytes, among workers with low-level occupational exposure to benzene in China (Science 306:1774, 2004). We explored whether genetic polymorphisms in DNA repair genes conferred susceptibility to benzene hematotoxicity in this same population. Linear regression was used in a cross-sectional study of 250 workers exposed to benzene and 140 frequency-matched unexposed workers to analyze the relationship between polymorphisms in DNA repair genes and granulocyte and B lymphocyte counts. Positive associations were found between polymorphisms in BRCA2 (Ex2 +14 G and gt;A, rs1799943; Ex11 +1487 A and gt;G, rs1801406 and Ex14 -194 A and gt;G, rs1799955 ) and WRN (Ex4 -16 G and gt;A, rs4987236; Ex6 +9 T and gt;C, rs2725349; Ex20 -88 T and gt;G, rs1800392 and Ex26 -12 T and gt;G, rs2725362 ) and decreased granulocyte and/or B-lymphocyte counts among benzene- exposed workers. In contrast, these SNPs were not significantly associated with blood cell counts among controls. BRCA2 and WRN play key roles in double strand break repair and the maintenance of genomic instability, thus the genotyping data indicates that genomic instability may be involved in benzene toxicity. Exposure of TK6 lymphoblastoid cells to the benzene metabolite hydroquinone at 5 and 10 uM induced genomic instability, as measured by increased karyotype heterogeneity and the formation of complex aberrations, further supporting a role for genomic instability in benzene hematotoxicity. RNAi is being used to selectively inhibit mRNA expression and provide a transient knockdown of BRCA2 and WRN so that their roles in benzene metabolite toxicity can be further examined.