Metabolomic Analysis Of The Toxic Effects Of Chronic Exposure To Low-level Dichlorvos On Rats Using Ultra-performance Liquid Chromatography-mass Spectrometry

Objective: The purpose of the current study was to assess the effects oflong-term exposure to low-levels of DDVP on the biochemical parameters andmetabolic profiles of rats，as well as related histopathological outcomes. Moreover,the study also investigated the systemic toxic processes induced by DDVP at differentdoses.Methods: Wistar male adult rats(180－220g) were randomly assigned to fourgroups: the low dose group, oral treatment at2.4mg/kg·bw/day (NOAEL); the middledose group, oral treatment at7.2mg/kg·bw/day (three times NOAEL); the high dosegroup, oral treatment at21.6mg/kg·bw/day (nine times NOAEL); and the controlgroup, oral treatment with approximately the same volume of distilled water. Theurine、serum and liver tissues were collected at different time points to analysis theclinical biochemical indicators and the histopathology of livers, the plasma and urinesamples of rats were collected at different time points to measure metabonomicprofiles by ultra-performance liquid chromatography-mass spectrometry.Results: Significant changes in blood cholinesterase, creatinine, urea nitrogen,aspartate aminotransferase, alanine aminotransferase, and albumin concentrationswere observed in the middle and high dose groups. The histopathological finding wasconsistent with the results of clinical chemical analysis. Fatty degeneration, vacuolardegeneration of liver cytoplasm and liver cell necrosis were found at the level of7.2mg/kg and21.6mg/kg DDVP, no significant histopathological changes were foundin the liver tissues at the level of2.4mg/kg. DDVP treatment resulted in an increasein the lactobionic acid, estrone sulfate, and indoxyl sulfic concentrations(p＜0.05), and a decrease in citric acid, suberic acid, gulonic acid, urea, creatinine, and uricacid(p＜0.05). Significant changes in some of the metabolites were found in thetreated groups as compared with the control group. LysoPC(15:0/0:0),LysoPC(16:0/0:0) LysoPC(17:0/0:0), LysoPC(0:0/18:0), sphingosine, sphinganine,C16sphinganine,C17sphinganine and arachidonic acid were decreased in the treatedgroups(p＜0.05), LysoPE(16:0/0:0) was increased after dosing with DDVP(p＜0.05).Conclusions: DMP, the urine metabolite of DDVP, is sensitive to DDVPexposure and can be used as a biomarker. No significant change was detected in ratsexposed to DDVP at a dose of2.4mg/kg body weight. Chronic exposure to low-level DDVPcan cause a disturbance in carbohydrate and fatty acid metabolism, the antioxidantsystem, etc. Abnormal changes of some lipids in the plasma were closely related tothe liver dysfunction, such as LysoPC (0:0/18:0); Metabolomics analysisprovides unique advantages on mechanisms of action about dichlorvos.