Subchronic Acrylamide Exposure Activates PERK-eIF2α Signaling Pathway and Induces Synaptic Impairment in Rat...

Acrylamide (ACR), a well-documented neurotoxicant to humans, is extensively found in starchy foods. More than 30% of the typical daily calorie intake comes from ACR-containing foods. Epidemiological and toxicological studies have found that ACR exposure is associated with mild cognitive change in men and experimental animals. However, there is limited information on the mechanisms by which ACR exposure induces memory deficits. The aberrant activation of the PKR-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) signaling pathway is emerging as a major common theme in cognitive decline. The present study is designed to explore the effect of subchronic ACR exposure on the PERK signaling and the synaptic impairment to elucidate the potential mechanism of ACR-induced cognitive dysfunction in rat. ACR exposure at 5 and 10 (mg/kg)/day by gavage for 14 weeks results in gait abnormality and cognitive impairment in rats, which were accompanied by neuronal loss, glial cell proliferation, and synaptic ultrastructure damage in the hippocampus. ACR reduced the expression of phosphorylated cAMP response element-binding protein (P-CREB), brain-derived neurotrophic factor (BDNF), and synaptic vesicle proteins synapsin-1 and synaptophysin synthesis. ACR also excessively activates the PERK-eIF2α signaling, resulting in overexpression of C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4). This work helps to propose a possible mechanism of subchronic exposure of ACR-induced neurotoxicity.