2 3 7 8-四氯二聯苯戴奧辛在NNK誘發肺腫瘤生成作用之促進機轉探討
摘要
TCDD is highly toxic to several rodent species and may have adverse health effects in exposed human populations. Epidemiologic studies indicated that increased risk of lung cancer could be found in populations of TCDD exposure. However, only few experimental studies have been attempted to characterize pulmonary effects of TCDD exposure. The present study was conducted to determine the tumor promoting capability of TCDD in lung tumorigenesis. In in vivo study, following tumor initiation with NNK, A/J mouse were given repeated injections of TCDD and sacrificed at 24 weeks. The result indicated that treatment of TCDD in NNK-initiated animals for 24 weeks led to increase incidence of lung adenoma, which demonstrated the potent tumor promoting capability of TCDD in mouse lung. Inhibition of apoptosis is one of the important mechanisms of tumor promotion. In in vitro study, we applied cell culture model with Beas-2B cells to determine if TCDD may inhibit apoptosis induced by staurosporine. We found that TCDD can attenuate staurosporine-induced early apoptosis determined by Annexin V. These results were corroborated by the increased protein expression of bcl-2, bcl-xl and decreased bad, caspase-3, 9, PARP pretreated with TCDD. Furthermore,TCDD can increase AKT and ERK phosphorylation, and the up-stream signaling. The inhibitors of AKT (Ly294002) and ERK (U0126) can reduce the anti-apoptosis effect of TCDD determined by Annexin V. Take together, the results suggest that one possible mechanism of lung tumor promotion of TCDD could be inhibition of apoptosis through activation of the AKT and ERK signaling pathway.