Early Hippocampal Stress Responses to Short-Term Cigarette Smoke Exposure in Mice
4 affiliations
- 1Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
- 2School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
- 3Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW 2113, Australia
- 4Department of Medical Biochemistry and Microbiology, Uppsala University, 752 37 Uppsala, Sweden
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 IRE1α 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.
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BibTeX
@article{marzagalli2026early,
title = {{Early Hippocampal Stress Responses to Short-Term Cigarette Smoke Exposure in Mice}},
author = {Rubina Marzagalli and Ng Min Zhen and Christabella Winata and Yik Lung Chan and Venkata Sita Rama Raju Allam and Hui Chen and Brian Gregory George Oliver and Alessandro Castorina},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198760},
url = {https://www.mdpi.com/1422-0067/27/19/8760},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Early Hippocampal Stress Responses to Short-Term Cigarette Smoke Exposure in Mice
AU - Rubina Marzagalli
AU - Ng Min Zhen
AU - Christabella Winata
AU - Yik Lung Chan
AU - Venkata Sita Rama Raju Allam
AU - Hui Chen
AU - Brian Gregory George Oliver
AU - Alessandro Castorina
PY - 2026
DA - 2026/09/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198760
UR - https://www.mdpi.com/1422-0067/27/19/8760
AB - 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 IRE1α 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.
SN - 1422-0067
ER -