06034nas a2200469 a 4500 20260818112538.0 130214s2011 th uu|m rtt 0| a1eng d .b12114972 AIT Diss. no.EV-11-04 Prisna Pianjing Estrogenic activities of sesame lignans and their metabolites : interactive effect with cadmium in human breast cancer cell lines Pathum Thani, Thailand : Asian Institute of Technology, 2011 91 leaves : ill. (some col.) Dissertation ; no. EV-11-04 A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Environmental Engineering and Management Inter-University Program on Environmental Toxicology, Technology and Management, School of Environment, Resources and Development Thesis (Ph.D.) - Asian Institute of Technology - Chulabhorn Research Institute - Mahidol University, 2011 The estrogenic activities of sesame lignans and their metabolites were investigated by using a viability assay and estrogen response elements (ERE) rep01ier system on the different levels of estrogen in cultured media. Hormone-dependent human breast cancer T47D cells and the cells stably transfected with ERE-luciferase reporter system T47DKBluc cells were utilized. Depending on levels of E2, sesame lignans and their metabolites exhibited different effects on the viability of T47D-KBluc cells. In the absence of estrogen, the trend of induction of cell growth was observed, whereas in the presence of estrogen, cytotoxic effect was evidenced. The ERE luciferase rep01ier assay in T47DKB1uc cells shows that, sesame lignans and their metabolites induced ERE activation. Among tested compounds, sesamol possessed the highest ERE activation prope1iy while ED showed no effect. All tested compounds exhibited lower levels of ERE activation than that of estradiol (E2) activation, suggesting that the tested compounds possess weak estrogenic effect. The antiestogen ICI 182 780 significantly decreased ERE activation induced by the te<ited compounds indicating the involvement of ER in their ERE activations. When 10 æM of tested compounds were co-incubated with various concentrations of E2 (10" 12-10"6 M), all tested compounds decreased the maximum responses of E2-ERE activations indicating that the tested compounds exhibit antiestrogenic effects in the presence of E2. Interestingly, tested compounds inhibited E2- ERE induction by a downward-shift of the E2-ERE dose-response curve. This was different from the inhibitory effects of tamoxifen and ICI 182 780 which showed the parallel-shift of E2-ERE dose-response curves without decreasing the maximum responses of E2-ERE induction. These results suggested that sesame lignans and their metabolites exhibited a non-competitive antagonistic property on E2-ERE activation. Real-time RTPCR studies showed that sesame lignans and their metabolites can induce estrogen targeted pS2 and progesterone receptor gene, suggesting their ERE induction abilities were functional. Cadmium at concentration 5 æM enhanced E2-ERE activation while sesamol, the most prominent ERE activator, could attenuate this response. When T47D cells were treated with cadmium, sesamol, or cadmium plus sesamol in the presence of E2, the results showed that cadmium increased expression of ERa while sesamol or sesamol plus cadmium decreased this expression, suggesting that sesamol may decrease cadmiuminduced estrogenic activity by modulating through ER. In particular, cadmium and sesamol induced alteration of ER expression in cytoplasm; whereas the expression of ERa in nucleus did not change when compared to control. Cadmium induced ERa expression in cytoplasm without the alteration of ERP expression when compared to control. Sesamol or sesamol plus cadmium decreased the expression of ERa while sesamol alone increased the expression of ERP in cytoplasm suggesting that in the presence of E2, sesamol preferentially interacted with ERa and ERP in cytoplasm. Sesamol may decrease cadmium-induced estrogenic activity by modulating ERa in cytoplasm. Fmihermore, these results indicate that sesame lignans and their metabolites possess estrogenic/antiestrogenic effect on ERE activation in human breast cancer cells in accordance with the E2 levels. In the presence of E2, sesamol, a metabolite form of sesamolin, may have the potential for prevention of cadmium- induced estrogenic effect in human breast cancer cells. Seseme Estrogen Breast Cancer Jutamaad Satayavivad, Chairperson Apinya Thiantanawat, Co-Chairperson Preeda Pakpian, Examination Committee Nuchanart Rangkadilok, Examination committee Bung-om SripanidkulchaiIeExamination committee Chulabhorn Research Institute/Mahidol University/ AIT Fellowship (CRI-MU-AIT), Scholarship donor Asian Institute of Technology. Dissertation ; no. 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