Particulate matter induced cognitive impairments via endoplasmic reticulum stress-mediated damage to mitochondria-associated endoplasmic reticulum membranes in immature rats

• Published in: Toxicology (Amsterdam) 2024-12, Vol.509, p.153979, Article 153979
• Main Authors: Wang, Lingman, Gui, Jianxiong, Tian, Bing, Ding, Ran, Wang, Wandi, Jiang, Chunxue, Zhang, Shengxuan, Zhang, Xiaofang, Liu, Jie, Jiang, Li
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Anxiety - chemically induced; Cognitive behavioral impairments; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Female; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Male; Memory, Short-Term - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria-associated endoplasmic reticulum membranes; Particulate matter; Particulate Matter - toxicity; Phenylbutyrates - pharmacology; Rats; Rats, Sprague-Dawley
• ISSN: 0300-483X; 1879-3185; 1879-3185
• DOI: 10.1016/j.tox.2024.153979

Particulate matter (PM) exposure has been increasingly recognized as detrimental to cognitive function and is associated with neurodevelopmental disorders. Mitochondria-associated endoplasmic reticulum membranes (MAMs) form an integrated interface between mitochondria and the endoplasmic reticulum (ER), facilitating crucial cellular functions. Prolonged ER stress (ERS) is implicated in various pathological states in the nervous system. MAMs and ERS may play vital roles in adverse effects of early-life PM exposure on cognitive abilities. This study investigated whether ERS plays a role in PM-induced MAMs dysfunction, leading to neuronal damage and cognitive impairments in early postnatal rats. Using a rat model with PM exposure concentrations of 2 and 10 mg/kg from postnatal Day 3 (PND3) to PND28, we observed that PM exposure resulted in anxiety-like behavior and impaired spatial working memory. The protein levels of ERS markers, including GRP78 and CHOP, were significantly increased in response to PM exposure. Western blot, transmission electron microscopy (TEM), and immunofluorescence analyses revealed decreased MAMs-related proteins and disrupted MAM structure and function caused by PM exposure. Administration of the ERS inhibitor 4-phenylbutyric acid (4-PBA) ameliorated these effects, restoring MAMs integrity and improving cognitive deficits. These findings highlighted the key role of ERS-MAMs dysfunction in PM-induced neurotoxicity and cognitive impairments, providing a new perspective and strategy for the prevention of cognitive deficits in early age with PM exposure. •Early-life PM exposure impairs cognitive function and induces anxiety-like behavior in rats.•PM exposure increases ER stress and disrupts MAMs integrity, leading to neurotoxicity.•4-PBA treatment restores MAMs integrity and improves cognitive function after PM exposure.