鎘化合物是普遍的環境污染物，且被歸類為人類致癌物，但目前對於鎘致毒機制仍未完全明瞭。本研究利用中國倉鼠卵巢細胞研究鎘造成的細胞毒性，以細胞計數和BrdU嵌入法分析細胞生長，結果發現當處理低於0.4 μM鎘24小時對細胞增生無影響，超過0.4 μM鎘則隨著劑量增加抑制細胞生長。以MTT試驗分析細胞存活率發現，鎘造成50%致死率的劑量約為4.6 μM鎘24小時。流式細胞儀分析發現，0.8到2 μM鎘造成細胞G2/M 停滯，而大於2 μM鎘造成細胞壞死，加入細胞壞死抑制劑 (necrostatin-1, Nec-1) 可以抑制死亡。有絲分裂指數分析發現，1 μM鎘造成約6.5%細胞位於M期，且細胞中Cdk1活性有明顯增加。當以1 μM鎘處理同步化在G1/S交界期之細胞，S期進行受到延遲，之後停滯在G2/M期；而以1 μM鎘處理同步化在G2期之細胞，細胞會通過G2/M與G1期，接著逐漸停滯在S期。以原子吸收光譜儀分析細胞中鎘含量，發現只有當細胞內鎘累積量在7.5-17.5 ng/106 cells時，才會造成細胞停滯在G2/M期。
由於活性氧物質對於鎘毒性有很大的關連，我們研究鎘造成細胞中活性氧物質增加與G2/M停滯或細胞壞死之間的關係。處理1或4 μM鎘不同時間後，分析細胞中活性氧物質，結果發現1 μM鎘處理到24小時，而4 μM鎘處理到8小時之後，細胞中活性氧物質逐漸增加。處理抗氧化劑 (BHA) 可以抑制活性氧物質的增加與細胞壞死，但無法降低G2/M比例，代表鎘透過活性氧物質產生造成細胞壞死，而非G2/M停滯。但處理另一種抗氧化劑 (EUK-8，是一種SOD/catalase模仿劑) 則發現，可以抑制鎘造成G2/M停滯與細胞壞死。分析細胞中金屬含量後發現，EUK-8可以抑制鎘進入細胞，但並非透過促進鎘從細胞中釋放。EUK-8是錳與salen形成的金屬複合物，其中錳同樣有效抑制鎘進入細胞及其造成之毒性，但salen卻會使細胞膜通透性增加，而促進鎘進入細胞及其毒性，以電子順磁共振光譜分析EUK-8中所含的自由錳離子只有約0.09%，此劑量錳離子並無法抑制鎘造成G2/M停滯，代表是EUK-8本身抑制鎘毒性。
由於鎘造成細胞壞死是較顯著的毒性效應，因此我們進一步探討其機制。分析細胞中鈣離子濃度後發現4 μM鎘會造成鈣離子濃度的增加。處理細胞中鈣離子螯合劑 (BAPTA-AM) 可以完全抑制鈣離子增加與細胞壞死的現象，代表鎘造成細胞壞死主要是透過鈣離子增加的作用。Calpain是一種需鈣型蛋白酶，分析calpain活性後發現鎘會造成calpain的活化。處理calpain抑制劑 (calpeptin) 或表現抑制蛋白 (calpastatin)可以部分抑制鎘造成細胞壞死。其中，處理BAPTA-AM可以抑制鎘造成活性氧物質產生，但calpeptin則不能，代表calpain與活性氧物質是鈣離子下游獨立平行的訊息途徑。已知粒線體通透性轉換與細胞壞死有關，其發生會造成粒線體膜電位下降，測量粒線體膜電位後發現鎘會造成粒線體膜電位的下降，處理粒線體通透性轉換抑制劑 (cyclosporin A, CsA) 可以抑制此現象以及細胞壞死，而處理BAPTA-AM與calpeptin也可以抑制鎘造成粒線體膜電位下降。NF-κB是促進細胞存活的轉錄因子，利用報導基因分析發現，鎘會導致NF-κB基礎活性下降，而此現象可以被BAPTA-AM與BHA所抑制。因此，鎘造成細胞壞死可以分別透過calpain活化造成粒線體通透性轉換，以及活性氧物質產生而抑制NF-κB活性。此外，Nec-1除了可以阻斷calpain與粒線體通透性轉換之訊息途徑，也可以活化NF-κB，以降低細胞壞死的比例。

Cadmium (Cd) compounds are ubiquitous environmental contaminants that have been classified as human carcinogens. However, the toxicological mechanisms of Cd are not well understood. In this study, we investigated the cytotoxicity of Cd toward Chinese hamster ovary (CHO) K1 cells. Analysis of cell growth using cell counting and BrdU incorporation indicated that there was no difference in growth rate when less than 0.4 μM Cd was given within 24 h. A dose-dependent reduction of cell proliferation was observed when more than 0.4 μM Cd was added. Flow cytometric analysis indicated that cells were arrested at G2/M phase when 0.8 to 2 μM Cd was given for 24 h. However, necrosis were induced when more than 2 μM Cd was administered. This effect can be efficiently inhibited by a programmed necrosis inhibitor, necrostatin-1 (Nec-1). Despite the fact that Cd treatment arrested cells mainly in the G2 but not M phase, an elevation in the cyclin-dependent kinase 1 (Cdk1) activity was found. Analysis of intracellular Cd content showed that only cells received 7.5 to 17.5 ng/106 cells progressed and retarded at G2/M phase. When synchronized cells at G1/S border were treated with 1 μM Cd, cells were delayed at the S phase progression and then arrested at G2/M phase; When synchronized G2 cells were treated, cells passed through G2/M and G1 phase, and then accumulated at S phase.
Since Cd stimulated the production of reactive oxygen species (ROS) and leads to cell damage, we investigated the involvement of ROS with necrosis. Intracellular ROS level increased after treatment with 1 μM for 24 h or 4 μM for 8 h. Antioxidants (BHA) that effectively reduced ROS production did not alter the G2/M arrest but inhibit necrosis after Cd treatment. This finding suggests that the Cd-induced ROS leads to cell necrosis but not G2/M arrest. Interestingly, we found that EUK-8, a SOD/catalase mimics, could rescue cells from G2/M arrest and necrosis. Analysis of intracellular Cd content indicated that EUK-8 reduced cellular Cd accumulation via blockage of Cd uptake into cells rather than promotion of Cd release from cells. EUK-8 is a Mn-salen complex. Mn decreased the uptake and cytotoxicity of Cd, while salen perturbed the membrane integrity and increased the uptake and cytotoxicity of Cd. Electronic paramagnetic resonance (EPR) spectrophotometric analysis indicated that only 0.09% of free manganese (Mn2+) dissolved in EUK-8 solution, which did not inhibit Cd-induced G2/M arrest. This finding indicates that it is EUK-8 itself that reduces Cd toxicity.
Because Cd-induced necrosis was a predominantly toxic effect in CHO cells, we further studied the mechanisms involved. Analysis of intracellular calcium (Ca2+) level indicated that 4 μM Cd caused Ca2+-overload. Intracellular Ca2+ chelator (BAPTA-AM) completely inhibited Cd-induced Ca2+-overload and necrosis. These findings suggests that Ca2+-overload played the most dominant role on Cd-induced necrosis. Calpain is a Ca2+-dependent protease. Analysis of calpain activity indicated that Cd activated calpain. Treatment with calpain inhibitors (calpeptin) or overexpression of endogenous calpain inhibitors (calpastatin) partially inhibited Cd-induced necrosis. BAPTA-AM but not calpeptin reduced Cd-induced ROS, suggesting that calpain activation and ROS production are two independent downstream signalings of Cd-induced Ca2+-overload. It has been known that mitochondrial membrane permeability (MPT) is critical for necrosis induction. Induction of MPT causes collapse of mitochondrial membrane potential (MMP). The MMP level dropped when cells received Cd treatment. MPT inhibitor (cyclospron A, CsA) rescued cells from MMP reduction and necrosis. Cd-induced MPT was also inhibited by BAPTA-AM and calpeptin, which indicating that alternation of MPT is a downstream signal of calpain. NF-κB is a transcription factor that promotes cell survival. Reporter gene analysis indicated that Cd reduced basal NK-κB activity, which was recovered by BAPTA-AM and BHA. Thus, Cd induced necrosis through calpain-triggered MPT and ROS-dependent basal NF-κB inhibition. We also showed in this study that Nec-1 protected cells from Cd-induced necrosis via inhibition of calpain/MPT pathway and activation of NF-κB activity.

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