Chiral pollutants often pose significant differential environmental health risks.In this study,the biotransformation of chiral dinotefuran(DIN)and its enantioselective metabolic toxicity mechanisms have been systemically investigated.Firstly,reversedphase chromatography-high resolution mass spectrometry was developed to quantify the content of DIN R/S chiral enantiomer with pg level sensitivity,revealing a lower elimination rate constant(K_(e))of S-DIN(0.730 h^(-1))than R-DIN(0.746 h^(-1)).Secondly,the interaction mechanism between DIN metabolism and important endogenous bioactive molecules,such as aldehyde oxidase(AOX)and neurotransmitters,was revealed.The DIN nitro-group was converted into a guanidine group by the reducing site of nearby flavin adenine dinucleotide(FAD)in AOX with the preferred higher affinity of S-configuration.Meanwhile,the endogenous tryptophan(Trp)aldehyde metabolic intermediate,5-hydroxyindoleacetaldehyde(5-HIAL),provides a persistent electron donor for DIN reduction via the oxidation-catalyzed site in AOX,resulting in remarkable up-regulation of monoamine neurotransmitters such as serotonin and dopamine.Thirdly,the higher level of neurotransmitters further mediated dysregulation of oxylipin homeostasis via the serotonergic pathway,where S-DIN exhibited more pronounced liver lipid damage and environmental health risk with the accumulated lipid biomarkers,oxidized triglyceride(OxTG)and oxidized sphingomyelin(OxSM).This study elucidates the AOX-mediated enantioselectivity metabolic pathway of DIN,providing a new analytical method for chiral pollutants and paves the way for their health risk assessments.
