Early Hippocampal Stress Responses to Short-Term Cigarette Smoke Exposure in Mice

Abstract

Cigarette smoke (CS) is a major environmental toxicant associated with cognitive impairment and neurodegenerative disease, yet the earliest hippocampal responses to short-term exposure remain poorly understood. Here, we investigated the effects of short-term CS exposure on hippocampal neuropeptide signalling, endoplasmic reticulum (ER) stress, mitochondrial homeostasis, neuroplasticity and astroglial activation. Mice were exposed to the equivalent of 0, 2, 4 or 6 cigarettes per exposure session, twice daily for four consecutive days, using a whole-body exposure paradigm. Hippocampal tissue was analysed by reverse transcription quantitative PCR, ELISA, immunofluorescence and histology. Short-term CS exposure disrupted hippocampal PACAP/VIP signalling, characterised by reduced Vip, Adcyap1r1 and Vipr1 expression, decreased VIP protein levels and increased Vipr2 expression across all smoke-exposed groups, while PACAP remained unaffected. CS also activated ER stress, evidenced by increased phosphorylated IRE1alpha immunoreactivity and increasing exposure-related trends in Ern1, Ppp1r15a and Eif2ak3 expression. Mitochondrial and stress-associated transcriptional responses included increased Dnm1l, Opa1 and Mmp9 and reduced Sod1 expression; however, associations among these genes did not remain significant after adjustment for exposure and false-discovery rate. Both Bdnf and Adnp expression showed a decreasing linear trend without significant individual treatment-versus-control comparisons. Neuronal BDNF immunoreactivity increased in CA1 and CA2/3 without detectable changes in CREB phosphorylation. CS further induced an increasing trend in Gfap expression and selective astroglial response within CA2/3. These molecular and cellular responses occurred without overt hippocampal histopathological abnormalities, indicating that brief CS exposure initiates hippocampal stress responses before structural damage is detectable.

The authors' abstract, as published at the source. International Journal of Molecular Sciences, 2026 · DOI ↗