Kondakala Sandeep, Ross Matthew K, Chambers Janice E, Howell George E
Department of Comparative Biomedical Sciences, Mississippi State University College of Veterinary Medicine, Center for Environmental Health Sciences, Mississippi State University, Starkville, Mississippi, USA.
J Biochem Mol Toxicol. 2022 Jun;36(6):e23028. doi: 10.1002/jbt.23028. Epub 2022 Feb 28.
Chlorpyrifos (CPS) is one of the most widely used organophosphate (OP) insecticides. The acute neurotoxicity of OPs results from the inhibition of acetylcholinesterase (AChE). However, some OPs also inhibit noncholinergic targets including monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and carboxylesterase (CES). Data have shown that highly lipophilic OPs, including CPS, have a persistent toxic effect in obese patients. Therefore, the present study was designed to determine the effect of high fat diet (HFD) induced obesity on the disposition of CPS and its detoxified metabolite 3,5,6-trichloro-2-pyridinol (TCP) following acute exposure as well as effects on cholinergic and noncholinergic CPS targets. Male C57BL/6J mice were fed a standard diet (STD) or HFD for 4 weeks, then treated with vehicle or CPS (25 mg/kg) via oral gavage and euthanized postdosing at 0, 3, 6, and 12 h. Following exposure, CPS levels in adipose tissue of HFD fed animals were increased to a greater extent than in STD fed animals, whereas overall hepatic TCP levels were decreased in HFD fed animals. Red blood cell (RBC) AChE and plasma cholinesterase activities were inhibited regardless of diet intake, but inhibition of RBC AChE activity was significantly lower after 3 h in HFD animals. Hepatic CES and FAAH activities were also significantly decreased following CPS exposure regardless of diet. In conclusion, increased time-integrated CPS levels in adipose tissue indicate CPS may possibly form a depot there and may be retained longer in obese animals than in normal animals.
毒死蜱（CPS）是使用最广泛的有机磷酸酯（OP）杀虫剂之一。OP的急性神经毒性源于对乙酰胆碱酯酶（AChE）的抑制。然而，一些OP还会抑制非胆碱能靶点，包括单酰甘油脂肪酶（MAGL）、脂肪酸酰胺水解酶（FAAH）和羧酸酯酶（CES）。数据表明，包括CPS在内的高亲脂性OP对肥胖患者具有持续的毒性作用。因此，本研究旨在确定高脂饮食（HFD）诱导的肥胖对急性暴露后CPS及其解毒代谢物3,5,6-三氯-2-吡啶醇（TCP）处置的影响，以及对CPS胆碱能和非胆碱能靶点的影响。雄性C57BL/6J小鼠喂食标准饮食（STD）或HFD 4周，然后通过口服灌胃给予溶剂或CPS（25 mg/kg），并在给药后0、3、6和12小时处死。暴露后，HFD喂养动物脂肪组织中的CPS水平比STD喂养动物升高幅度更大，而HFD喂养动物的肝脏总体TCP水平降低。无论饮食摄入情况如何，红细胞（RBC）AChE和血浆胆碱酯酶活性均受到抑制，但HFD动物在3小时后RBC AChE活性的抑制作用明显较低。无论饮食如何，CPS暴露后肝脏CES和FAAH活性也显著降低。总之，脂肪组织中CPS时间积分水平的增加表明CPS可能在那里形成储存库，并且在肥胖动物中可能比正常动物保留更长时间。
