Although DDE (dichlorodiphenyldichloroethylene), which is an environmental metabolite of the pesticide DDT, it is still present in the environment, and its insecticidal properties are used to fight malaria and the Zika virus disease. We showed for the first time that the neurotoxic effects of DDE involve autophagy, as demonstrated by elevated levels of Becn1, Map1lc3a/MAP1LC3A, Map1lc3b, and Nup62/NUP62 and an increase in autophagosome formation. The suggestion that the aryl hydrocarbon receptor (AHR) and the constitutive androstane receptor (CAR) are involved in the neurotoxic effect of DDE was supported by increases in the mRNA and protein expression of these receptors, as detected by qPCR, ELISA, immunofluorescence labeling and confocal microscopy. Selective antagonists of the receptors, including alpha-naphthoflavone, CH223191, and CINPA 1, inhibited p,p’-DDE- and o,p’-DDE-induced LDH release and caspase-3 activity, while specific siRNAs (Ahr and Car siRNA) reduced the levels of p,p’-DDE- and o,p’-DDE-induced autophagosome formation. Although the neurotoxic effects of DDE were isomer independent, the mechanisms of p,p’- and o,p’-DDE were isomer specific. Therefore, we identified previously unknown mechanisms of the neurotoxic actions of DDE that, in addition to inducing apoptosis, stimulate autophagy in mouse neocortical cultures and induce AHR and CAR signaling.

尽管DDE（二氯二苯基二氯乙烯）是农药DDT的一种环境代谢产物，但它仍存在于环境中，其杀虫特性可用于对抗疟疾和寨卡病毒病。我们首次表明DDE的神经毒性作用涉及自噬，如Becn1，Map1lc3a / MAP1LC3A，Map1lc3b和Nup62水平升高所证明/ NUP62和自噬体形成的增加。通过qPCR，ELISA，免疫荧光标记法和免疫印迹法检测到，这些受体的mRNA和蛋白表达增加支持了芳烃受体（AHR）和组成型雄烷受体（CAR）参与DDE的神经毒性作用。共聚焦显微镜。受体的选择性拮抗剂，包括α-萘黄酮，CH223191和CINPA 1，可抑制p， p'- DDE-和o， p'-DDE诱导的LDH释放和caspase-3活性，而特异性siRNA（Ahr和Car siRNA ）降低了p，p'- DDE-和o，p'的水平-DDE诱导的自噬体形成。尽管DDE的神经毒性作用与异构体无关，但是p，p'-和o， p'-DDE的机制是异构体特异性的。因此，我们确定DDE的神经毒性作用的以前未知的机制，除了诱导细胞凋亡外，还可以刺激小鼠新皮层培养物中的自噬并诱导AHR和CAR信号传导。