現今農業發達，為了提高作物經濟效益，農藥於精緻農業中不可或缺，然而當皮膚接觸到農藥時可能會造成皮膚搔癢、紅腫，而引發過敏性接觸性皮膚炎(ACD)。在ACD的誘發機制涉及先天免疫系統及後天免疫系統，已有許多文獻證實致敏原於後天免疫系統的作用機轉，但於先天免疫系統中的調控機制尚未清晰，因此本研究目的為探討台灣常見農藥Chlorothalonil是否可以誘發ACD，並了解其誘發ACD之先天免疫系統中細胞之間的調控與分子機轉的改變，如在農藥刺激下細胞產生的自噬作用(Autophagy)和細胞凋亡(Apoptosis)，並使用紫檀芪(Pterostilbene)作為預防策略，探討是否可以緩解農藥對皮膚所產生的損傷及ACD發炎症狀。於體內 (in vivo)試驗，本研究使用BALB/c小鼠暴露於農藥Chlorothalonil (0.24%)與農藥Captan (0.24%)，並擇一合併管餵紫檀芪 (100mg/kg)，分別進行局部淋巴結試驗 (Local lymph node assay)和ACD動物模型。而在體外試驗中 (in vitro)，則使用人類角質形成細胞 (HaCaT)與人類單核球細胞 (THP-1)暴露於農藥下，探討農藥誘發ACD之先天免疫系統中細胞的反應與分子機轉的調控。在LLNA動物實驗中，農藥Chlorothalonil與農藥Captan均有潛力作為致敏物質，且Chlorothalonil對皮膚刺激反應強烈；而在ACD動物模型中，更進一步證實農藥Chlorothalonil為致敏物質之一，可以誘導產生過敏性接觸性皮膚炎，使暴露之皮膚產生紅腫及發炎現象，其表皮明顯增厚且淋巴球浸潤嚴重，但給予紫檀芪可有效緩解Chlorothalonil所誘發的ACD。於細胞實驗中，細胞在農藥Chlorothalonil的暴露下其存活率顯著下降並具有劑量效應關係，並可觀察到NLRP3發炎體、發炎作用途徑、細胞凋亡與細胞自噬相關蛋白，以及ROS的表現量上升，表示Chlorothalonil於先天免疫中可藉由活化NLRP3發炎體釋放發炎性細胞因子，造成皮膚發炎，並且誘導產生細胞凋亡及自噬作用來造成皮膚的嚴重損傷。本研究證實Chlorothalonil會誘發ACD，並針對先天免疫系統進行進一步的了解Chlorothalonil的暴露對皮膚造成損傷及產生發炎作用之分子機轉，並證實紫檀芪可以有效減緩ACD發炎的症狀和對皮膚的傷害，提供未來預防ACD的新策略。

Recently, agriculture is developed, and pesticides are essential in precision agriculture. However, there are itching, redness, and swelling of the skin caused by contact with pesticides, which can induce allergic contact dermatitis (ACD). The mechanism of ACD involves the innate immune system and the adaptive immunity system. Many literatures have confirmed that the allergens play a role in the adaptive immune system, but the regulatory mechanism in the innate immune system is not clear. Therefore, the present study is to investigate whether Chlorothalonil, a common pesticide in Taiwan, can induce ACD, and to understand the molecular mechanism of the innate immune system that causing ACD, cells interaction and response (eg, autophagy and apoptosis). And pterostilbene was used as prevention stratagy to study whether it can reverse the skin damage caused by pesticides and the symptoms of ACD inflammation. In in vivo study, BALB/c mice were exposed to the pesticide Chlorothalonil (0.24%) and Captan (0.24%), and choose one combined with Pterostilbene (PT, 100mg/kg) by oral administration in local lymph node assay (LLNA) and ACD animal model. In in vitro experiments, HaCaT and THP-1 cells were exposed to pesticide Chlorthalonil, to study the molecular mechanism of cells response and regulation in the innate immune system during the process of induced-ACD. In LLNA animal experiments, both pesticides Chlorothalonil and Captan have potential as allergens, especially, a strong response to skin irritation by Chlorothalonil treatment. In ACD animal model, the pesticide Chlorothalonil is one of allergens, which induced allergic contact dermatitis, and caused skin swollen and inflammation. The epidermis of the skin was significantly thickened and the lymphocytes were infiltrated heavily, but the administration of pterostilbene effectively alleviated all of them in ACD. In in vitro experiments, HaCaT and THP-1 cells treated with chlorthalonil significantly reduced the cell viability in concentration-dependent. The expression of NLRP3 inflammasome, the protein of the inflammatory pathway, cell apoptosis and aurophagy, and the production of ROS was observed increased. These results indicated that chlorthalonil might cause skin inflammation by releasing inflammatory cytokines from activation of NLRP3 inflammasome in innate immunity, and induce apoptosis and autophagy to cause skin damage.This study confirmed that Chlorothalonil induced ACD, and further explored the molecular mechanism of skin damage and inflammatory effects in the innate immune system. We also confirmed that pterostilbene effectively reduced the symptoms of ACD inflammation and damage in the skin, and provided a new ACD prevention strategy in the future.

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