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標題: 持久性有機污染物及其醌類代謝物誘發人類乳癌細胞核酸氧化損害之研究
Induction of oxidative DNA damage by persistent organic pollutants (POPs) and their quinonoid metabolites in human breast cancer cells.
作者: 林家驊
Lin, Chia-Hua
關鍵字: Persistent organic pollutants;持久性有機污染物;oxidative DNA damage;oxidative stress;pentachlorophenol;polychlorinated biphenyls;polycyclic aromatic hydrocarbons;核酸氧化損壞;氧化壓力;五氯酚;多氯聯苯;多環芳香族碳氫化合物
出版社: 環境工程學系所
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持久性有機污染物質(persistent organic pollutants, POPs),是指可長時間存在於環境中之化學物質,此類物質因具有較高之親脂性,故可累積於生物體之脂肪中。相關之研究顯示生物體暴露於POPs之環境下,能誘發廣泛之不良健康效應,包括內分泌衡定性之失序、氧化壓力 (oxidative stress)之累積、生殖及生長程序異常及癌症等。目前POPs對生物體作用之機制,初步被認為是經由非直接致基因性途徑 (epigenetic) 所導致。然而,POPs之曝露與核酸氧化損壞 (oxidative DNA damage)、細胞死亡及相關基因表現失序之相連性仍未完全建立,且其作用之機制仍多屬為未知。故本研究主旨在探討POPs之曝露與生物體內核酸結構損壞作用之機制,主要是希冀能運用相關之生物性指標檢測方法(biological markers, biomarkers),來評估生物體內累積之具活性代謝衍生物、活性氧分子、及核酸損壞間之關聯性。本研究之假設為曝露於POPs之環境中,例如多氯聯苯 (polychlorinated biphenyls, PCBs),將會經由易感基因表現之失序,如代謝系統酵素,進而使生物體內產生oxidative stress,並進一步誘發間接致核酸損害作用之機轉。本計畫將針對環境中常見之POPs,包括五氯酚 (pentachlorophenol, PCP)、PCBs及多環芳香族碳氫化合物 (polycyclic aromatic hydrocarbons, PAHs),及其於生物體內衍生之活性代謝物於人類乳癌細胞中進行檢測。
本研究中第一研究主題首先利用不同含氯數之PCP醌類代謝物於小牛胸腺核酸(calf thymus DNA, ct-DNA)及人類乳癌MCF-7與T47D細胞中,進行細胞毒性及核酸氧化損壞之分析。結果顯示,PCP之醌類代謝物可於ct-DNA中誘發醛基氧化損害(aldehydic DNA lesions, ADL),其誘發之程度依序為: catechol (CAT)≧ 4-chlorocatechol (4-ClCAT)> 4,5-dichlorocatechol (4,5-Cl4CAT)> 3,4,5-trichlorocatechol (3,4,5-Cl3CAT)> tetrachlorocatechol (Cl4CAT)。相反的,PCP之醌類代謝物中僅Cl4CAT可於MCF-7 cells誘發明顯之ADL生成,且生成之ADL主要是由氧化壓力所導致。實驗結果顯示Cl4CAT於T47D cells中誘發NAD(P)H下降之程度遠大於4-ClCAT及CAT,且此NAD(P)H下降之現象可因為poly(ADP-ribose) polymerase (PARP) inhibitor之添加而遭到完全之抑制。實驗亦證實Cu (II) 及Fe (III)確實參與PCP之醌類代謝物誘發oxidative DNA damage之機制。綜合以上之實驗結果可推論,減少PCP醌類代謝物之含氯數,應可降低其於生物體中誘發oxidative DNA damage及相關生物毒性之能力。
本研究中第二研究主題為運用不同結構之PCBs,包括2,2’,4,4’,5,5’-hexachlorobiphenyl (PCB153)與3,3’,4,4’,5-pentachlorobiphenyl (PCB126),於人類乳癌T47D (ERα(+))與MDA-MB-231 (ERα(–))細胞中,進行活性氧分子(reactive oxygen species, ROS)、PARP-1活化及細胞毒性之分析。結果顯示,PCB153與PCB126可於人類乳癌細胞中誘發顯著之ROS生成及細胞毒性效應。在無細胞毒性之條件下,PCB153與PCB126之暴露均可導致T47D與MDA-MB-231細胞誘發顯著NAD(P)H之下降,且此下降之現象可完全為PARP inhibitor之添加所抑制。由上述之結果可初步推論,PCBs引發之NAD(P)H下降應為其於細胞中誘發核酸股斷裂(DNA strand breaks)進而導致PARP-1活化所導致。實驗結果顯示PCB153於T47D或MDA-MB-231細胞中誘發ROS生成、細胞毒性及PARP-1活化之程度均大於PCB126。實驗利用不同種類抑制劑之添加後發現,ROS、Cu (II)、Fe (III)及細胞色素P450 (cytochrome P450) 1A與2B均參與PCBs誘發細胞毒性之機制。實驗進行PCBs交互作用之結果顯示,PCB153與PCB126之混合可於T47D與MDA-MB-231細胞中產生ROS生成及細胞毒性之拮抗作用(antagonism)。PCBs混合物亦可於T47D細胞中誘發PARP-1活化之拮抗作用,但相同條件下,PCBs混合物於MDA-MB-231細胞中卻無明顯之交互作用產生。綜合以上之結果可推斷,ROS之生成為PCBs於人類乳癌細胞中誘發細胞毒性及核酸損害之重要因子。實驗結果亦證實雌性激素受體α(estrogen receptor α, ERα)存在之與否也將會影響PCBs誘發之相關效應。
最後本研究中第三個研究主題為利用常見之PAHs,萘(naphthalene),其醌類代謝物於人類乳癌MCF-7細胞中,進行ROS生成、化合物代謝速率、細胞毒性、及核酸氧化損壞之分析。結果顯示,不同取代位置之naphthalene醌類代謝物均可於MCF-7細胞中誘發顯著之細胞毒性效應,其中對位醌類代謝物,如1,4-naphthalenediol (NHQ)與1,4-naphthoquinone (1,4-NQ)所誘發之細胞毒性遠大於鄰位醌類代謝物,如1,2-naphthalenediol (NCAT)與1,2-naphthoquinone (1,2-NQ)。利用西方墨點法來觀察調節細胞凋亡(apoptosis)蛋白之表現發現,NCAT與NHQ之暴露除了明顯提升MCF-7細胞中p53蛋白之表現外,更可改變bax/bcl2蛋白表現量之比例,此結果顯示naphthalene之醌類代謝物可於人類乳癌細胞中誘發p53-dependent之細胞凋亡。此外,實驗亦觀察到naphthalene醌類代謝物之暴露可誘發MCF-7細胞內累積大量之ROS與glutathion(GSH)量之下降,其程度依序為: 1,4-NQ > NHQ > 1,2-NQ ≧ NCAT。實驗進一步測量naphthalene醌類代謝物於MCF-7細胞中之移除效率常數(the constant of overall elimination rates, ke)發現,其值約介於0.280 h-1(T1/2=151 min)與13.8 h-1(T1/2=3.05 min)間,且其移除效率依序為: 1,4-NQ > 1,2-NQ > NHQ > NCAT。由上述之結果顯示,對位之醌類代謝物可於短時間內改變細胞內氧化還原之狀態並誘發大量ROS之生成,此現象可進一步導致細胞大量死亡。在無細胞毒性之條件下,naphthalene醌類代謝物之暴露可導致MCF-7細胞內誘發顯著NAD(P)H與NAD+之下降,其中NCAT與1,2-NQ誘發NAD(P)H下降之現象可完全為PARP inhibitor之添加所抑制,而NHQ與1,4-NQ則否。利用彗星法(comet assay)來觀察naphthalene醌類代謝物於MCF-7細胞中誘發核酸單股斷裂之現象,結果顯示NCAT與1,2-NQ可誘發核酸單股斷裂之增加,而NHQ與1,4-NQ則否。綜合研究結果可推論,相同條件下NHQ與1,4-NQ易誘發細胞之死亡,而NCAT與1,2-NQ易誘發核酸單股股斷裂之生成並導致PARP-1活化進而使細胞內NAD(P)H/NAD+下降。
綜合本研究結果顯示,生物體暴露於POPs環境下會改變POPs於生物體內之氧化還原狀態,進而使生物體內產生oxidative stress,並進一步誘發間接致核酸氧化損害之作用。此現象顯示生物體暴露於POPs之環境下,將增加其基因突變之機率,並可能進一步提高生物體罹患癌症之風險。

Persistent organic pollutants (POPs) are chemicals that resist chemical and biological degradation. POPs often have high lipid solubility that leads to their accumulation in animals, human, and environment. POPs is known to induce a broad-spectrum of adverse biological effects, including disruption of endocrine homeostasis, induction of oxidative stress, and cancer in laboratory animals and human. The mechanisms by which POPs exert their actions are believed to mediate via epigenetic pathways to cellular malignancy. However, the link between POPs exposure and deregulation of specific gene expression involving DNA damage and cell death is not conclusive, and any mechanism responsible remains unknown. The objective of this proposal is to address the issues of whether exposure to specific congeners of POPs is associated with increased levels of reactive metabolites, induction of functional and structural damage to DNA. Specifically, we propose to apply biomarkers to assist in understanding the roles of POPs in modulating expressions of the susceptible genes and induction of the oxidative DNA damage. We hypothesize that exposure to certain types of POPs may induce oxidative stress and DNA damage via the induction of alteration of normal profiles of endogenous metabolism. To uncover the roles of POPs in mediating the gene expression and oxidative DNA damage, human breast cancer cells were exposed to POPs, including the quinonoid derivatives of pentachlorophenol (PCP) and polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs).
The first part of this study is to investigate the degree of chlorination of catechol derivatives of pentachlorophenol (PCP) on the induction of cytotoxicity and DNA damaging effects in calf thymus DNA (ct-DNA) and in two human breast carcinoma cell lines. The DNA lesions induced by various degrees of chlorination of PCP-derived catechols decrease in the rank order catechol (CAT)≧ 4-chlorocatechol (4-ClCAT)> 4,5-dichlorocatechol (4,5-Cl4CAT)> 3,4,5-trichlorocatechol (3,4,5-Cl3CAT)> tetrachlorocatechol (Cl4CAT). In contrast, Cl4CAT was the only congeneric form of PCP-derived catechols that induced a significant increase in the number of ADL in human MCF-7 cells. The data also confirmed that the ADL induced by Cl4CAT in MCF-7 cells was derived from oxidative events. In addition, we demonstrated that the depletion of NAD(P)H in human T47D cells exposed to chlorinated catechols decrease in the rank order Cl4CAT » 4-ClCAT ≧ CAT. Additionally, the depletion of NAD(P)H in T47D cells exposed to Cl4CAT was completely blocked by three types of poly(ADP-ribose) polymerase-1 inhibitors. The evidence suggests that superoxide, hydrogen peroxide, hydroxyl radical, and transition metals, including Fe(II) and Cu(I), are involved in Cl4CAT-mediated DNA damage in cells. Overall, these findings indicate that dechlorination may decrease the potentials of chlorinated catechols to induce oxidative DNA lesions and cytotoxic effects in living cells.
The second part of this research is to investigate whether exposure to polychlorinated biphenyls (PCBs), i.e. PCB153 and PCB126, is associated with induction of reactive oxygen species (ROS), poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cell death in human T47D and MDA-MB-231 breast cancer cells. Results indicated that PCB153 and PCB126 induced concentration- and time-dependent increases in cytotoxic response and ROS formation in both T47D and MDA-MB-231 cells. At non-cytotoxic concentrations both PCB153 and PCB126 induced decreases in intracellular NAD(P)H and NAD+ in T47D and MDA-MB-231 cells where T47D cells were more resistant to PCB-induced reduction in intracellular NAD(P)H than MDA-MB-231 cells. Further investigation indicated that three specific PARP inhibitors completely blocked PCB-induced decreases in intracellular NAD(P)H in both T47D and MDA-MB-231 cells. These results suggest that decreases in intracellular NAD(P)H in PCB-treated cells are primarily due to reduction in intracellular NAD+ pool mediated by PARP-1 activation through formation of DNA strand breaks. Overall, the extent of cytotoxic response, ROS formation, and PARP-1 activation generated in T47D and MDA-MB-231 cells was greater for PCB153 than for PCB126. This evidence also suggests the involvement of ROS, Cu(I), Fe(II), and CYP1A/2B enzymes in mediating the induction of cell death by PCB153 and PCB126. Further, antagonism was observed between PCB126 and PCB153 for effects on cytotoxic response and ROS formation in T47D and MDA-MB-231 cells. Antagonism was also observed between PCB153 and PCB126 in the induction of NAD(P)H depletion at lower concentration (<10 μM) in T47D cells, but not in MDA-MB-231 cells. In conclusions, results from our investigation suggest that ROS formation induced by PCBs is a significant determinant factor in mediating the DNA damage and cell death in human breast cancer cells. The data also suggests that the status of estrogen receptor α may play a role in modulating the PCB-induced oxidative DNA damage and cell death in human breast cancer cells.
The third part of this study is to examine the differences in the induction of cytotoxic effects and poly(ADP-ribose) polymerase-1 activation in human MCF-7 breast cancer cells by quinonoid derivatives of naphthalene. Results from the cytotoxic response analyses in cells indicated that all naphthalene quinonoids induced cell death in MCF-7 cells where NHQ and 1,4-NQ were more efficient than NCAT and 1,2-NQ in the induction of cell death. Results from Western blot analyses confirmed that treatment of cells with NCAT and NHQ resulted in up-regulation of p53 protein expression and a significant shift in bax/bcl2 ratio, suggesting the induction of p53-dependent apoptosis in MCF-7 cells. The induction of ROS formation and GSH depletion in cells by naphthalene quinonoids decreases in the rank order 1,4-NQ > NHQ > 1,2-NQ ≧ NCAT. Further investigation indicated that least-squares estimates of the overall rates of elimination (ke) of naphthalene quinonoids in MCF-7 cells decreased in the rank order 1,4-NQ > 1,2-NQ > NHQ > NCAT. Values of ke were estimated to be between 0.280 h-1 (T1/2 = 151 min) and 13.8 h-1 (T1/2 = 3.05 min). These results provide evidence that the para-isomeric form of naphthalene quinonoids tend to induce acute production of ROS and alterations in intracellular redox status in cells, leading to the subsequent cell death. Further, all naphthalene quinonoids induced decreases in intracellular NAD(P)H and NAD+ in MCF-7 cells at non-cytotoxic concentrations. The reduction of intracellular NAD(P)H in cells exposed to NCAT and 1,2-NQ was blocked by poly(ADP-ribose)polymerase (PARP) inhibitors whereas PARP inhibitors did not prevent the reduction of NAD(P)H in cells exposed to NHQ and 1,4-NQ. Further investigation confirmed that increases in the number of DNA single-strand breaks were detected in MCF-7 cells exposed to NCAT and 1,2-NQ as measured by the Comet assay whereas NHQ and 1,4-NQ did not induce increases in the number of single-strand breaks in MCF-7 cells. Overall, results from our investigation suggest that while NHQ and 1,4-NQ are more efficient in the induction of cell death, NCAT and 1,2-NQ are prone to induce depletion of NAD(P)H and NAD+ mediated by PARP-1 activation through formation of DNA single-strand breaks in human cultured cells.
In conclusions, we demonstrated that ROS formation induced by POPs is a significant determinant factor in mediating the DNA damage, and cell death in human breast cancer cells.
其他識別: U0005-1907200710153100
Appears in Collections:環境工程學系所

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