Intergenerational neurotoxicity mediated by maternal plasma metabolite profile remodeling following maternal atrazine exposure.

As a widely used triazine herbicide, atrazine (ATR) has been demonstrated to exert neurotoxicity and induce metabolic disorders in organisms. Our previous studies have further revealed that maternal exposure to ATR during pregnancy and lactation can damage dopaminergic neurons in the midbrain of offspring. Current mechanistic investigations into the intergenerational neurotoxic effects of ATR and other environmental factors have mostly focused on regulatory mechanisms at the genetic material level, which present significant limitations. However, there is a lack of relevant experimental evidence to verify whether maternal ATR exposure during these special periods can induce dopaminergic neuronal damage in offspring through alternative pathways, such as altering maternal plasma metabolite levels, and the specific underlying mechanisms remain to be further explored. This study integrated multiple approaches including neurobehavioral assays, plasma metabolomics, bioinformatics, and molecular biology, systematically elucidated the mechanism by which maternal ATR exposure induces intergenerational dopaminergic neurotoxicity in offspring by remodeling the maternal plasma metabolic profile. Furthermore, by combining the analysis of single-cell transcriptomic data from Parkinson's disease patients with molecular docking and molecular dynamics simulation analyses, we revealed for the first time, from the novel perspective of the metabolite-single cell axis, the potential mechanism by which serotonin may mediate dopaminergic neuronal damage in offspring induced by maternal ATR exposure during pregnancy and lactation-specifically by regulating the AKT1/SRC pathway and intercellular crosstalk across multiple cell types. This finding provides new research strategies and directions for understanding the intergenerational neurotoxicity of environmental pollutants and their early prevention.