T-2 toxin-induced neurotoxicity in juvenile rats involves hippocampal oxidative stress-ER stress-mediated neuronal apoptosis and potential gut-brain axis involvement.

T-2 toxin, a common Fusarium-derived mycotoxin, poses severe threats to livestock production and public health and exhibits potent neurotoxicity by disrupting blood-brain barrier integrity and neuronal function. However, the detailed mechanisms responsible for its developmental neurotoxicity remain poorly elucidated. This study investigated cognitive impairment and associated central and peripheral alterations in juvenile rats following subchronic T-2 toxin exposure. Juvenile male Wistar rats were orally exposed to T-2 toxin for 28 days. Behavioral, histopathological, microbiome, biochemical, and molecular analyses were performed to evaluate cognitive function, hippocampal injury, intestinal barrier integrity, and gut microbial alterations. T-2 toxin exposure significantly impaired learning, memory, recognition ability, and exploratory behavior. Hippocampal neuronal loss, Nissl body reduction, and endoplasmic reticulum dilation were observed following exposure. T-2 toxin disrupted hippocampal redox homeostasis, as evidenced by increased ROS and MDA levels and decreased SOD activity and GSH content. These changes were accompanied by activation of the PERK-eIF2α-ATF4-CHOP signaling pathway and enhanced neuronal apoptosis. In parallel, T-2 toxin altered gut microbial composition, induced colonic injury, reduced ZO-1 and Occludin expression, and triggered systemic inflammatory imbalance. Collectively, these findings indicate that T-2 toxin-induced cognitive impairment in juvenile rats is associated with oxidative stress-triggered ER stress and neuronal apoptosis in the hippocampus. Concurrent gut microbiota dysbiosis, intestinal barrier dysfunction, and inflammatory alterations suggest a potential contribution of gut-brain interactions to developmental T-2 toxin neurotoxicity. These findings expand current understanding of developmental T-2 toxin neurotoxicity by integrating hippocampal oxidative stress-ER stress signaling with gut microbial and intestinal alterations.