Development of human cell models for assessing the carcinogenic potential of chemicals |
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Authors: | Pang Yaqin Li Wenxue Ma Rulin Ji Weidong Wang Qing Li Daochuan Xiao Yongmei Wei Qing Lai Yandong Yang Ping Chen Liping Tang Shifu Lin Yuchun Zhuang Zhixiong Zheng Yuxin Chen Wen |
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Affiliation: | a Department of Toxicology, Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou, 510080, P.R. China b The Laboratory of Toxicology Research, Shenzhen Center for Disease Control and Prevention, 1 Tianbei, Shenzhen, Guangdong, 518020, P.R. China c National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nanwei Road, Beijing, 100050, P.R. China |
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Abstract: | To develop human cell models for assessing the carcinogenic potential of chemicals, we established transgenic human cell lines and tested the sensitivity of known carcinogens using a cell transformation assay. A retroviral vector encoding an oncogenic allele of H-Ras (HBER) or c-Myc (HBEM) was introduced into human bronchial epithelial cells (HBE) immortalized by SV40 large T (LT) antigen, leading to increased cell proliferation but failing to confer a transformed phenotype characterized by anchorage-independent cell growth and tumor formation of immunodeficient mice. When these pre-transformed cells were treated with nickel sulfate (NiSO4), we found that it shortened the latency of malignant transformation at least by 19 wk in HBER cells or 16 wk in HBEM cells compared to vector control cells. Similarly, the latency of cell transformation was shorter by 15 wk in HBER cells or 9 wk in HBEM cells when cells were treated with benzo(a)pyrenediol epoxide (BPDE). HBER cells appeared to be more sensitive to TPA, NiSO4 or BPDE-induced cell transformation compared to human embryonic kidney cells expressing H-Ras (HEKR), implying that cell-type specificity is one of important factors determining the effectiveness of the assay. Using AFB1 and BaP as the representative pro-carcinogens, we also compared the efficiency of three different metabolic conditions in mediating cell transformation. Low dose chemical induction seems to be a prospective system used for metabolic activation of pro-carcinogens. Our findings provided direct evidence that a genetically modified human cell transformation model can be applied to the assessment of potent carcinogens. |
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Keywords: | HBE, human bronchial epithelial cells HBER, HBE cells expressing H-Ras HBEM, HBE cells expressing c-Myc HBERST, HBE cells expressing H-Ras and SV40 small T (ST) HBEMST, HBE cells expressing c-Myc and SV40 ST HEK, human embryonic kidney cells HEKR, human embryonic kidney cells expressing H-Ras L02, human hepatocytes L02R, L02 cells expressing H-Ras L02-1A2, L02 cells expressing CYP1A2 HBER-1A1, HBER cells expressing CYP1A1 L02-IN, L02 cells treated with 0.1  μM AFB1 HBER-IN, HBER cells treated with 1  μM BaP BPDE, benzo(a)pyrenediol epoxide MNNG, N-methyl-N'-nitro-N-nitrosoguanidine NiSO4, nickel sulfate TPA, 12-o-tetradecanoyl-phorbol-13-acetate. |
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