Neurotoxic Effects of Atrazine on Dopaminergic System via miRNAs and Energy-Sensing Pathways

Atrazine (ATR, 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) is a globally prevalent herbicide known to induce dopaminergic neurotoxicity at high concentrations. MicroRNAs (miRNAs), pivotal in regulating gene expression post-transcriptionally, play essential roles in neuronal differentiation, proliferation, and apoptosis. This study investigates the effects of ATR on the dopaminergic system and behavioral responses in rats, with a particular focus on critical dopaminergic proteins such as tyrosine hydroxylase (TH), nuclear receptor related-1 protein (NURR1), and α-synuclein. The results reveal that ATR exposure significantly reduces the expression of TH and NURR1, while elevating levels of α-synuclein. Through miRNA sequencing and proteomic analysis, we identify alterations in miRNA and protein profiles that are intricately linked to the development of the dopaminergic system. Notably, treatment with ATR results in a marked increase in AMPK levels concurrent with a decrease in miR-322-5p. The differentially expressed genes associated with ATR exposure primarily influence the dopaminergic system by engaging in critical pathways such as AMPK, mTOR, autophagy, FoxO, and HIPPO. This study underscores the neurotoxic impact of ATR on the dopaminergic system via miRNA regulatory mechanisms and energy-sensing pathways, including AMPK and SIRT1, providing a molecular foundation for developing strategies to prevent and treat neurotoxicity induced by ATR exposure.