Di-2-ethylhexyl Phthalate Induces Neurotoxicity of Transforming Microglia into M1 Subtype through Targeting α-Syn Dimerization.

Di-2-ethylhexyl phthalate (DEHP) accumulates in the food chain, threatening human and animal health. However, how DEHP induces neurotoxicity by interfering with microglia has not been fully revealed. Our research aims to explore the effects of DEHP on microglia and identify relevant targets that cause neurotoxicity. The results indicated that DEHP damaged neurons, leading to swelling, demyelination, and abnormal autophagy. Inhibition of autophagy resulted in α-Syn misfolding, characterized by an increase in dimers with increasing additive concentrations (P = 0.0096). Dimer formation was promoted by the addition of additives, which increased the electrostatic force, along with interactions between Glu106, Gly51, and Val66. Transmitted from neurons to microglia (Pearson r2 = 0.889), pathological aggregates under DEHP exposure induced microglial M1 subtype switching. This study elucidated a novel mechanism by which DEHP damages the nerves of birds and provided a therapeutic target for the neurotoxic disease risk caused by the transmission of plastic additives through the food chain.