| Summary: | 碩士 === 國立成功大學 === 環境醫學研究所 === 97 === 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is an ubiquitous environment- al contaminant and highly toxic to several rodent species. During the 20-year period following the Seveso showed TCDD could increase risk of lung cancer, notably among women (RR = 1.3, 95% CI: 1.2-4.6). In animal studies, TCDD-induced lung lesions appeared to be gender dependent, with predominant increase of the incidence of respiratory tract cancers in female but not in male rat. In TCDD studies, hepatic tumor incidence was lower in TCDD-treated ovariectomized (OVX) female rats compared to TCDD-treated sham-operated rats. Thus, we predict that ovarian hormones (estradiol) may be involved in the process of TCDD-induced lung tumorigenesis. The object of this study is to test the hypothesis that whether ovarian hormones (estradiol) is involved in the two-stage lung tumorigenesis promoted by TCDD in female rodent. For this proposal, a two-stage model for lung tumorigenesis sham-operated or OVX- female A/J mice were applied to investigate the effect of ovarian hormones. In in vivo study, OVX- or sham-operated mice were given tumor initiator NNK at week-1 of experiment, received subcutaneous (s.c.) injections of estradiol or corn oil every two days start from week-2 until the end of experiment, given 4 times weekly of TCDD at week-3 and sacrificed at 7 weeks and 24 weeks of experiment. Treatment of female and male mice with NNK alone or combination with TCDD resulted in increased lung tumor incidence compared with female and male control mice. In addition, lung tumor incidence was lower in OVX female mice compared to female mice treated with NNK and TCDD. Whereas, treatment of OVX female mice with NNK and estradiol resulted in a significant increased lung tumor incidence compared with treatment of female mice with combination of NNK, TCDD and estradiol.Hence, TCDD and estradiol both play important role in tumor promotion, nevertheless, inhibition of estradiol promoted tumor incidence by TCDD in NNK-initiated lung tumorigenesis.Short-term mechanistic studies indicated that TCDD and estradiol affect inflammation and cell proliferation by activatin of Mitogen-activated protein kinases (MAPK) pathways and NF-κB pathways at 7 weeks.Thus, we concluded that TCDD and estradiol promote NNK-initiated lung tumorigenesiscould be through enhanced inflammmation and cell proliferation.
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