Kondakala Sandeep, Lee Jung Hwa, Ross Matthew K, Howell George E
Mississippi State University College of Veterinary Medicine, Department of Basic Sciences, MS 39762, United States.
Mississippi State University College of Veterinary Medicine, Department of Basic Sciences, MS 39762, United States.
Toxicol Appl Pharmacol. 2017 Dec 15;337:67-75. doi: 10.1016/j.taap.2017.10.019. Epub 2017 Oct 31.
The prevalence of obesity is increasing at an alarming rate in the United States with 36.5% of adults being classified as obese. Compared to normal individuals, obese individuals have noted pathophysiological alterations which may alter the toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity on the toxicity of many widely utilized pesticides has not been established. Therefore, the present study was designed to determine if the obese phenotype altered the toxicity of the most widely used organophosphate (OP) insecticide, chlorpyrifos (CPS). Male C57BL/6J mice were fed normal or high-fat diet for 4weeks and administered a single dose of vehicle or CPS (2.0mg/kg; oral gavage) to assess cholinergic (acetylcholinesterase activities) and non-cholinergic (carboxylesterase and endocannabinoid hydrolysis) endpoints. Exposure to CPS significantly decreased red blood cell acetylcholinesterase (AChE) activity, but not brain AChE activity, in both diet groups. Further, CPS exposure decreased hepatic carboxylesterase activity and hepatic hydrolysis of a major endocannabinoid, anandamide, in a diet-dependent manner with high-fat diet fed animals being more sensitive to CPS-mediated inhibition. These in vivo studies were corroborated by in vitro studies using rat primary hepatocytes, which demonstrated that fatty acid amide hydrolase and CES activities were more sensitive to CPS-mediated inhibition than 2-arachidonoylglycerol hydrolase activity. These data demonstrate hepatic CES and FAAH activities in high-fat diet fed mice were more potently inhibited than those in normal diet fed mice following CPS exposure, which suggests that the obese phenotype may exacerbate some of the non-cholinergic effects of CPS exposure.
在美国，肥胖症的患病率正以惊人的速度上升，36.5%的成年人被归类为肥胖。与正常个体相比，肥胖个体存在已被注意到的病理生理改变，这可能会改变外源性物质的毒代动力学，从而改变其毒性。然而，肥胖对许多广泛使用的杀虫剂毒性的影响尚未明确。因此，本研究旨在确定肥胖表型是否会改变最广泛使用的有机磷（OP）杀虫剂毒死蜱（CPS）的毒性。雄性C57BL/6J小鼠分别喂食正常或高脂饮食4周，然后单次给予赋形剂或CPS（2.0mg/kg；经口灌胃），以评估胆碱能（乙酰胆碱酯酶活性）和非胆碱能（羧酸酯酶和内源性大麻素水解）终点。在两个饮食组中，暴露于CPS均显著降低了红细胞乙酰胆碱酯酶（AChE）活性，但未降低脑AChE活性。此外，CPS暴露以饮食依赖的方式降低了肝脏羧酸酯酶活性以及主要内源性大麻素花生四烯酸乙醇胺的肝脏水解，高脂饮食喂养的动物对CPS介导的抑制更敏感。这些体内研究得到了使用大鼠原代肝细胞的体外研究的证实，该研究表明脂肪酸酰胺水解酶和羧酸酯酶活性比2-花生四烯酸甘油水解酶活性对CPS介导的抑制更敏感。这些数据表明，CPS暴露后，高脂饮食喂养小鼠的肝脏羧酸酯酶和脂肪酸酰胺水解酶活性比正常饮食喂养小鼠更易受到有效抑制，这表明肥胖表型可能会加剧CPS暴露的一些非胆碱能效应。
