結合多種數據資料庫分析國人陶斯松暴露量對人體代謝的影響並利用小鼠模式進行評估

Abstract

陶斯松(Chlorpyrifos, CPF)是一種廣效型的殺蟲劑，常施灑於穀類、水果、蔬菜等作物上，使用層面非常廣泛，因此經常殘留於蔬果中並被消費者攝入。雖根據過去的安全性評估以及現有的農藥管理可避免國人暴露過多CPF，但近年來的流行病學、動物實驗紛紛指出長期暴露CPF於不引發神經毒性的劑量下可能會影響動物的代謝，如肥胖、高血醣、胰島素阻抗等，然而文獻中所使用之劑量又遠高於實際暴露量，且以往的安全性評估皆由健康的動物進行實驗，我們認為這可能會忽略其潛藏的安全問題，因此我們藉由台灣膳食暴露評估模組(Taiwan Dietary Exposure Evaluation Model, TDEEM)串連台灣營養健康狀況變遷調查(Nutrition And Health Survey in Taiwan, NAHSIT)與總膳食調查計畫(Total Diet Survey, TDS)兩大資料庫估計出台灣民眾可能之CPF暴露量，分析國人中健康族群與代謝症候族群在目前的暴露狀態下是否對於各項血液生化數值造成影響，並以上述之估計暴露量管餵一般飲食(Normal diet, ND)與高脂飲食(High fat diet, HFD)誘導之代謝異常小鼠，觀察醣類與脂質的代謝狀況，再以細胞模式確認其結果。在數據分析中我們發現在老年族群中CPF暴露量與血清三酸甘油酯(Triglyceride, TG)呈現正相關 (r=0.1231, P<0.05)，在動物實驗中也觀察到ND組中暴露中劑量(0.002 mg/kg-bw)與高劑量(0.6 mg/kg-bw)CPF會使血清TG分別上升約1.5倍與1.63倍，而高劑量(0.6 mg/kg-bw)也會造成肝臟中TG的上升1.27倍，在肝臟蛋白表現量則觀察到中劑量(0.002 mg/kg-bw)CPF 可使p-ACC/ACC下降0.65倍，但在肝細胞脂肪堆積模式中發現CPF並不會促進肝脂肪堆積，推測CPF可能不是直接作用於肝臟，而是藉由影響其他臟器再間接影響到肝臟脂質的代謝。綜合以上實驗結果，我們認為在安全暴露量下的CPF可能會影響人體脂質代謝。

Chlorpyrifos (CPF) is a broad-spectrum insecticide, and usually used to cereals, fruits, and vegetables. Due to its wide usage, it is easily to be consumed from CPF residues in fruits or vegetables. Although the usage of pesticide has been verified by safety assessments and controlled by pesticide management, recent epidemiological and animal studies reported that CPF could affect human or animal metabolism under doses without neurotoxicity. However, the doses adopted in these studies are still too high when compared with the dose of CPF residues in foods. Besides, conclusions of safety assessments are based on the studies using healthy animals, raising the possibility of ignoring some hidden security issues. In this study, firstly, we used TDEEM to connect Nutrition and Health Survey in Taiwan (NAHSIT) and the Total Diet Study (TDS) data banks and deducted individual CPF exposure. We further analyzed the relationship between the individual CPF exposure and relevant biochemical values. Secondly, we investigated the effects of exposure dose deduced from our analysis on mice fed with either normal diet (ND) or high fat diet (HFD). Our results reveal that the Estimated Daily Intake (EDI) of CPF positively correlates (r=0.1231, P<0.05) with serum triglyceride (TG) in the elderly population. In animal model, we also observed that middle-dose (0.002 mg/kg-bw) and high-dose (0.6 mg/kg-bw) CPF increased 1.5-fold and 1.63-fold serum TG in ND group, respectively. High-dose CPF (0.6 mg/kg-bw) increased hepatic TG to 1.27 folds, while middle- dose (0.002 mg/kg-bw) CPF suppressed hepatic p-ACC/ACC ratio by 0.65 folds. From the results of hepatocyte model, we observed that CPF didn’t affect lipid accumulation, so we proposed that CPF might indirectly act through other tissues to affect liver. Taken together, we claim that the CPF may affect human lipid metabolism under legal exposure.