Enantioselective Effects of Metalaxyl Enantiomers in Adolescent Rat Metabolic Profiles Using NMR-Based Metabolomics

Abstract

More than 30% of the registered pesticides are chiral with one or more chiral centers and exist as two or more enantiomers. The frequency of chiral chemicals and their environmental safety has been considered in their risk assessment in recent decades. Despite the fact that metabolic disturbance is an important sensitive molecular initiating event of toxicology effects, the potential mechanisms of how chiral compounds affect metabolism phenotypes in organisms remain unclear. As a typical chiral pesticide, metalaxyl is an acylalanine fungicide with systemic function. Although the fungicidal activity almost comes from the R-enantiomer, the toxicity of both enantiomers in animals and human beings is not yet clear. In this study, a nuclear magnetic resonance (NMR)-based metabolomics approach was adopted to evaluate the enantioselectivity in metabolic perturbations in adolescent rats. On the basis of multivariate statistical results, stable and evident metabolic profiles of the enantiomers were obtained. When rats were exposed to R-metalaxyl, the significantly perturbed metabolic pathways were biosynthesis of valine, leucine, and isoleucine, synthesis and degradation of ketone bodies, and metabolism of glycerolipid. In contrast, more significantly perturbed metabolic pathways were obtained when the rats were exposed to S-metalaxyl, including glycolysis, biosynthesis of valine, leucine, and isoleucine, metabolism of glycine, serine, and threonine, synthesis and degradation of ketone bodies, metabolism of glycerophospholipid and glycerolipid. These abnormal metabolic pathways were closely related to liver metabolism. These results offer more detailed information about the enantioselective metabolic effects of metalaxyl in adolescent development and provide data for the health risk assessment of metalaxyl at molecular level.

Effects of the Chiral Fungicides Metalaxyl and Metalaxyl-M on the Earthworm Eisenia fetida as Determined by 1H-NMR-Based Untargeted Metabolomics

“…Metalaxyl proper is a racemic mixture [1], while metalaxyl-M is solely (97%) the R-enantiomer [2]. Some studies indicate that the two enantiomers have different effects on the metabolomes of rats [3,4] and human cells [5]. Toxicological evaluations on earthworms found LC50 values for metalaxyl and metalaxyl-M of 0.022 and 0.052 mg cm −2 , respectively [1], but the underlying mechanism of this toxicity and the lower toxicity of the R-enantiomer is not well understood.…”

Analysis of metabolome changes in the HepG2 cells of apatinib treatment by using the NMR‐based metabolomics

“…The differential metabolites were analyzed in the orthogonal partial least squares discriminant analysis (OPLS‐DA) models by using two criteria . One is the correlation coefficients ( r ) of the variables which related with the first predictive component (tp1) in the OPLS‐DA model, and the other is the variable importance in the projection (VIP)…”

“…The differential metabolites were analyzed in the orthogonal partial least squares discriminant analysis (OPLS-DA) models by using two criteria. 13 One is the correlation coefficients (r) of the variables which related with the first predictive component (tp1) in the OPLS-DA model, 22 and the other is the variable importance in the projection (VIP). 23 For further comparing the relative concentrations of metabolites between different classifications, the relative integral areas of metabolites were calculated.…”

“…By contrast with MS technique, NMR analysis does not damage the sample structure and has excellent spectral reproducibility and a short time . Meanwhile, NMR combined with multivariate statistics is an effective tool in drug screening . With the popularity of NMR and automated accessory, more and more NMR instruments were used in the screening and designing of potential drug active molecules .…”

“…10,11 Meanwhile, NMR combined with multivariate statistics is an effective tool in drug screening. 12,13 With the popularity of NMR and automated accessory, more and more NMR instruments were used in the screening and designing of potential drug active molecules. 14 In addition, high throughput selection extend the NMR experiments to the field of life science in the search for drugs.…”