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  3. Identifying Metabolic Perturbations and Toxic Effects of Rac-Metalaxyl and Metalaxyl-M in Mice Using Integrative NMR and UPLC-MS/MS Based Metabolomics

Identifying Metabolic Perturbations and Toxic Effects of Rac-Metalaxyl and Metalaxyl-M in Mice Using Integrative NMR and UPLC-MS/MS Based Metabolomics

  • Int J Mol Sci. 2019 Nov 1;20(21):5457. doi: 10.3390/ijms20215457.
Ping Zhang 1 2 3,  Sheng Wang 4 5,  Yuhan He 6 7 8,  Yangyang Xu 9 10,  Dongmei Shi 11 12,  Furong Yang 13 14,  Weizhong Yu 15 16,  Wentao Zhu 17,  Lin He 18 19 20
Affiliations

Affiliations

  • 1 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. pingz@swu.edu.cn.
  • 2 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. pingz@swu.edu.cn.
  • 3 State Cultivation Base of Crop Stress Biology for Southern Mountainous Land of Southwest University, Southwest University, Chongqing 400715, China. pingz@swu.edu.cn.
  • 4 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. zpcauz@163.com.
  • 5 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. zpcauz@163.com.
  • 6 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. hm20161027@163.com.
  • 7 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. hm20161027@163.com.
  • 8 State Cultivation Base of Crop Stress Biology for Southern Mountainous Land of Southwest University, Southwest University, Chongqing 400715, China. hm20161027@163.com.
  • 9 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. zp8708@163.com.
  • 10 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. zp8708@163.com.
  • 11 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. shidm48@163.com.
  • 12 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. shidm48@163.com.
  • 13 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. yfr200111@163.com.
  • 14 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. yfr200111@163.com.
  • 15 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. yuweizhong147@163.com.
  • 16 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. yuweizhong147@163.com.
  • 17 Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. pingz028@163.com.
  • 18 Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China. helinok@vip.tom.com.
  • 19 Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China. helinok@vip.tom.com.
  • 20 State Cultivation Base of Crop Stress Biology for Southern Mountainous Land of Southwest University, Southwest University, Chongqing 400715, China. helinok@vip.tom.com.
PMID: 31683916 DOI: 10.3390/ijms20215457
Abstract

Although metabolic perturbations are sensitive indicators for low-dose toxic effects, the metabolic mechanisms affected by rac-metalaxyl and metalaxyl-M in mammals from a metabolic profiling perspective remain unclear. In this study, the metabolic perturbations and toxic effects of rac-metalaxyl and metalaxyl-M in mice were carefully investigated using integrative nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) based metabolomics. Histopathology, NMR-based untargeted urine profile, multivariate pattern recognition, metabolite identification, pathway analysis, UPLC-MS/MS based targeted serum Amino acids, and tryptophan pathway analysis were determined after rac-metalaxyl and metalaxyl-M exposure, individually. Histopathology indicated that metalaxyl-M induced greater hepatocellular inflammatory, necrosis, and vacuolation in mice than rac-metalaxyl at the same exposure dosage. The metabolic perturbations induced by rac-metalaxyl and metalaxyl-M were directly separated using partial least-squares discriminant analysis (PLS-DA). Furthermore, metabolite identification and pathway analysis indicated that rac-metalaxyl mainly induced ten urine metabolite changes and four pathway fluctuations. However, metalaxyl-M induced 19 urine metabolite changes and six pathway fluctuations. Serum Amino acids and tryptophan pathway metabolite changes induced by rac-metalaxyl and metalaxyl-M were also different even at the same exposure level. Such results may provide specific insight into the metabolic perturbations and toxic effects of rac-metalaxyl and metalaxyl-M, and contribute to providing available data for health risk assessments of rac-metalaxyl and metalaxyl-M at a metabolomics level.

Keywords

NMR; UPLC-MS/MS; amino acids; metabolic perturbation; metabolomics; metalaxyl; tryptophan metabolism.

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