有機磷農藥達馬松對雄性大鼠之系統性毒性

Abstract

有機磷化合物是使用最廣泛的農藥類別，而達馬松（methamidophos）與愛殺松（ethion）為常用的有機磷農藥，但除了已知的急性神經毒性之外，達馬松對其他器官的毒理資料不足，其內分泌干擾作用也尚未清楚。本研究主要在探討達馬松對雄性大鼠的神經行為、生殖及代謝系統引起的毒性，及愛殺松對睪丸和肝臟造成的影響。以0.5、1、2 mg/kg達馬松胃管給予雄性大鼠連續28天後，發現其血清乙醯膽鹼酶活性有顯著劑量效應關係之下降。閃尾、強迫遊泳及明暗穿箱之行為毒性測試結果顯示達馬松增加大鼠疼痛耐受度、憂鬱及焦慮行為；另也發現大腦紋狀體5-HT1A、NR2B、小腦GABAAα2、NR2A、海馬迴5-HT1A、5-HT2A、NR2A、NR2B、MOR之mRNA表現量具上升趨勢，但無統計意義；小腦GABAAα1、5-HT2A mRNA有下降趨勢，但無統計意義。處理2 mg/kg達馬松的大鼠，睪丸與副睪相對重量呈現上升趨勢。在生殖毒性方面，達馬松使睪丸及副睪精子數目有下降趨勢，脂質過氧化程度及穀胱甘肽過氧化酶活性具上升趨勢，另也造成睪丸代謝酶基因CYP2E1 mRNA表現量上升及CYP2E1蛋白表現和氧化壓力基因Nrf-2的mRNA及蛋白表現量有上升趨勢。達馬松造成睪丸類固醇荷爾蒙生成及作用基因androgen receptor、3β-hydroxysteroid dehydrogenase及發炎基因IL-1a、細胞凋亡基因Bax mRNA有增加之趨勢。檢測外來物質代謝酶活性發現，達馬松造成肝臟微粒體7-ethoxycoumarin O-deethylase活性下降及睪丸微粒體aniline hydroxylase活性上升。而以5、10、20 mg/kg愛殺松胃管給予雄性大鼠連續14天後，發現睪丸參與類固醇荷爾蒙合成基因（3β-hydroxysteroid dehydrogenase、CYP19、5α-reductase）、發炎基因IL-1β之mRNA表現量下降。愛殺松另造成肝臟methoxyresorufin代謝活性下降。本研究發現達馬松對雄性大鼠造成神經行為、生殖及代謝之不良影響；愛殺松則對雄性荷爾蒙標的器官睪丸之雄性素合成及代謝活性具有干擾作用，也影響肝臟P450代謝酵素產生抑制作用。達馬松與愛殺松之系統毒性及內分泌干擾作用機制仍有待進一步探討。

Methamidophos and ethion belong to the class of organophosphorus pesticides which are the most widely used agricultural chemicals worldwide. With the exception of acute neurotoxicity, the toxicological profiles of methamidophos and ethion are insufficient and their endocrine-disrupting activities have not been clearly defined. The major objectives of the present study were to explore the behavioral, reproductive, and metabolic effects of methamidophos and the impacts of ethion on testis and liver in rats. After treatment with methamidophos at 0.5, 1, and 2 mg/kg orally once daily for 28 days in male rats, serum acetylcholinerase activity was decreased in a dose-dependent manner. Methamidophos induced depression-, anxiety-, and antinociception-like behaviors in forced swim, light-dark transition, and tail-flick tests, respectively. Striatum 5-HT1A, NR2B, cerebellum GABAAα2, NR2A and hippocampus 5-HT1A, 5-HT2A, NR2A, NR2B, MOR mRNA expression levels showed trends toward increases, but cerebellum GABAAα1 and 5-HT2A mRNA showed trends toward decreases in methamidophos-treated rats. The organophosphate at 2 mg/kg caused increasing trends in testis and epididymis relative organ weights. In reproductive toxicity studies, treatment with methamidophos caused decreasing trends in testicular and cauda epididymal sperm counts and increasing trends in lipid peroxidation and glutathione peroxidase activity in testis. In addition, CYP2E1 mRNA expression was induced by methamidophos, CYP2E1 protein expression and Nrf-2 mRNA and protein expression levels showed trends toward increases. Furthermore, methamidophos resulted in increasing trends in testicular androgen receptor, 3β-hydroxysteroid dehydrogenase, IL-1a, and Bax mRNA expression. The results of monooxygenase activity assays showed that methamidophos decreased cytochrome P450-dependent 7-ethoxycoumarin O-deethylase in the liver and increased aniline hydroxylase activity in the testis. After treatment with ethion at 5, 10, and 20 mg/kg orally once daily for 14 days in male rats, testicular steroidogenesis genes (3β-hydroxysteroid dehydrogenase, CYP19, 5α-reductase) and inflammation gene IL-1β mRNA expression were decreased. Treatment with ethion also reduced methoxyresorufin O-demethylase activity in the liver. These present findings demonstrate that methamidophos can cause behavioral, reproductive, and metabolic effects in male rats. Ethion also has the ability to interfere with testicular steroidogenesis and inhibit hepatic monooxygenase activity. The mechanisms underlying these systemic toxicities and endocrine-disrupting activities of methamidophos and ethion still need further investigation.