1,2-DCE exposure induces autophagosome accumulation and neuronal death via the ROS-JNK/c-Fos/c-Jun/FoxO1/FoxO3a axis.

As a ubiquitous organic pollutant in industrial settings, 1,2-dichloroethane (1,2-DCE) has been documented to induce cognitive impairment; however, the underlying molecular mechanisms remain poorly understood. In our animal experiments, mice were exposed to 0, 0.225, 0.45, and 0.9 g/m3 of 1,2-DCE via static whole-body inhalation for 3.5 h daily over 56 days. Our results demonstrate that 56-day repeated 1,2-DCE exposure induces oxidative damage, activates autophagy, and promotes apoptosis in mouse hippocampal neural cells. We also observed impaired lysosomal function following 1,2-DCE treatment. On this basis, we hypothesized that 1,2-DCE disrupted autophagic flux, which was verified by blocked p62 degradation and an elevated LC3-II/I ratio, ultimately leading to neuronal apoptosis. These findings were further validated in vitro using the autophagy agonist rapamycin and the inhibitor chloroquine. In addition, 2-chloroethanol (2-CE), the primary metabolite of 1,2-DCE in vivo, increased p62 and LC3-II/I levels in PC12 cells in both dose- and time-dependent manners. Importantly, in vivo studies revealed that the ROS-JNK/c-Fos/c-Jun/FoxO1/FoxO3a axis acts as a critical upstream regulator, modulating transcription of core autophagy-related genes to initiate and enhance autophagy. These results were confirmed in vitro via pharmacological inhibition of ROS and JNK. Furthermore, activated JNK may promote autophagy through Bcl-2 phosphorylation, thereby facilitating subsequent apoptosis. Collectively, our study demonstrates for the first time that 1,2-DCE exposure triggers ROS-mediated and JNK-dependent autophagy, thereby inducing autophagic flux blockade and subsequent neuronal apoptosis.