2026-11-092026-11-09https://scholars.csmu.edu.tw/handle/123456789/38086Female lung adenocarcinoma (FLAC) is not only unusually abundant, it is also the leading cause of cancer death among women in Taiwan. Among all potential environmental risk factors, cooking-oil fumes (COF) bear the most and strongest epidemiological evidence to be closely associated to the development of FLAC. The most concerning constituents in COF are perhaps BaP, a potent carcinogen, and tt-DDE (trans, trans-2,4-decadienal), a known mutagen. Our preliminary studies have demonstrated that BaP, a Ah receptor (AhR) agonist, induced CYP1A1 and 1B1 expressions in both human lung cells H1355 and immortalized human lung bronchial epithelial cells (BEAS-2B). In the presence of estrogen (E2), BaP enhanced the E2 metabolism with an increased production of E2 metabolites, 2- and 4-hydroxyestradiols (2- and 4-OHE2). We also found that BaP reduced the conversion of the OHE2 to their methylated forms (MeOE2) by inhibiting the conversion enzyme COMT. The result was an accumulation of the 2- and 4-OHE2s which are known to be genotoxic and carcinogenic. Our hypothesis on the interrelationship between AhR activation and FLAC was supported by genomic findings on adenocarcinoma obtained from non-smoking female patients. It was found that both the CYP mRNA levels were significantly elevated in the tumor tissues. We also found that tt-DDE induced cell proliferation, ROS production, and up-regulation of certain inflammatory cytokines (TNFa and IL-1b) which played important roles in tumor initiation and promotion. Our preliminary proteomic study also indicated that tt-DDE uniquely induced profile changes in certain specific proteins associated with drug metabolism, oxidative stress, and cell growth. These preliminary data strongly indicated that activation of AhR and up-regulation of P450 CYP1A1 and 1B1 enzymes by AhR agonist (e.g. BaP), in the presence of E2, play an important role in the development of FLAC. Furthermore, oxidative stress and up-regulation of tumorgenic cytokines by components in COF (e.g. tt-DDE) would also contribute to the development of FLAC. All our past studies were conducted with single chemicals (either BaP or tt-DDE) alone. Therefore, our future studies will explore the combined effects of BaP / tt-DDE and of the standardized COF mixture (which is to be provided via Dr. Dennis Hsieh？HHHHH？HHHHHs project) on AhR activation, CYP1A1 and 1B1 expressions, E2 metabolite profile,, oxidative stress, DNA damage, cytokine inductions, etc. Genomic profile from the treated BEAS-2B cells will be generated and compared with the genomic profile generated from actual patients with FLAC. Proteomic studies will be further conducted to better define the alteration in protein profiles resulted in the exposures. Our present proposed investigation is based on a sound scientific hypothesis and will utilize coordinated molecular, metabolomic, toxicogenomic, and proteomic approaches to explore and elucidate the interrelationship between COF and FLAC development.女性肺腺癌（FLAC）在台灣不僅是發生率高而且也佔婦女癌症死亡率的首位。流行病學上的證據顯示，在所有環境風險因子中，以油煙（COF）與女性肺腺癌的關係最為密切。而油煙的成分中，被最多人認為造成癌症的主要成分為BaP，一種致癌物；及tt-DDE(trans, trans-decadienal )，已知的致突變劑。我們初步的研究顯示BaP是Ah受體的促進劑，使人類肺細胞株H1355及人類肺小支氣管表皮細胞（BEAS-2B）的CYP1A1和1B1表現增加。當有雌激素（E2）存在的時候，BaP促進E2的代謝，進而增加E2代謝物2-及4-hydroxyestradiols的形成。我們也發現BaP經由抑制OHE2甲基化成MeOE2的酵素（COMT）而降低OHE2轉變成MeOE2。這樣的結果造成2-及4-OHE2的累積，而前述這兩者分別為基因毒性物質及致癌物。從非吸煙肺腺癌女性病人的基因體學上的發現，可以支持我們對於Ah受體活化與女性肺腺癌有關連所提出的假設，因為這些腫瘤組織中，CYP1A1與CYP1B1 mRNA的量明顯的增加。而且我們也發現，tt-DDE可增進細胞分裂，增加ROS的量及向上調節某些發炎性的細胞激素（TNFa和IL-1b）。以上這些物質在腫瘤的初始化與促進中都扮演重要的角色。我們初步在蛋白質體上的研究也顯示，tt-DDE獨特地誘發某些與藥物代謝、氧化壓力和細胞生長有關的蛋白質發生變化。這些初期的研究數據強烈的指出，在E2的存在下，經Ah受體促進劑（如BaP）處理後，Ah受體被活化，同時P450 CYP1A1和1B1兩種酵素的表現增加，這些情形在女性肺腺癌的發展有舉足輕重的角色。此外油煙成分（如tt-DDE）會造成氧化壓力及向上調節致癌性細胞激素的表現，因此也會促使女性肺腺癌的發生。我們所有過去的研究都集中在單一化合物（例如BaP或是tt-DDE）暴露下的影響。因此，我們未來的研究方向將朝向探討BaP/ttDDE與標準化油煙混合物(由謝顯堂博士的計劃提供)結合後所產生的各種效應：如Ah受體的活化、CYP1A1及CYP1B1的表現、E2代謝物的圖譜、氧化緊迫、DNA損害和細胞激素的被激化等等。未來在基因體研究會找出處理過的BEAS-2B細胞株的基因變化並拿來與真正女性肺腺癌的病人組織，做基因庫的比對。而藉由定義出暴露後所產生各項相關蛋白質的變化使得蛋白質體的研究能有更好的指標。我們目前的研究計劃植基於科學性的假設，並整合分子生物、代謝、基因毒理及蛋白質體等各項研究方式以期能發現並顯示出女性肺腺癌的發生與油煙的關係。肺癌油煙lung cancercooking oil fumeProject