Acetaminophen-induced liver injury triggers short- and long-term neuroinflammation, blood-brain barrier disruption, and behavioral deficits in a genetic mouse model of autism.
9 affiliations
- 1Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia.
- 2Institute of Medical Physics and Biophysics, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
- 3Central Laboratories, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 813 27, Bratislava, Slovakia.
- 4Institute of Forensic Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
- 5Department of Imaging Methods, Institute of Measurement Science, Slovak Academy of Sciences, Bratislava, Slovakia.
- 6Department of Radiology, Center for Advanced Imaging Innovation and Research (CAI2R) & Bernard and Irene Schwartz Center for Biomedical Imaging, New York University Grossman School of Medicine, New York City, NY, USA.
- 7Institute of Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
- 8Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia. [email protected].
- 9Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. [email protected].
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a strong genetic basis, yet its etiology is not fully understood. Neuroinflammation is emerging as a critical secondary factor. Since peripheral organ injury, such as acute liver failure, can induce neuroinflammation, we aimed to investigate whether liver injury could exacerbate ASD-like phenotypes in a genetically susceptible model. We used adult (12-month-old) Shank3-/- mice, a genetic model of ASD, and their wild-type (WT) counterparts. A single high dose of acetaminophen (APAP; 350 mg/kg) was administered intraperitoneally to induce acute liver injury. We assessed acute (24-h) and long-term (1-month) consequences on liver health, neuroinflammation, blood-brain barrier integrity, and brain edema using plasma biomarkers, immunohistochemistry, and in-vivo MRI, as well as behavioral phenotypes, including sociability, repetitive behaviors and exploration. Acutely, APAP induced severe liver damage, cerebral edema, and neuroinflammation in Shank3-/- mice. One month later, despite liver recovery, both APAP-treated WT and Shank3-/- mice exhibited brain edema, elevated apparent transverse relaxation (R2*) rates, and lasting neuroinflammation, evidenced by microgliosis and reactive astrocytosis. These differences were more extensive in the Shank3-/- group. Behaviorally, this was accompanied by increased social deficits in both genotypes. Critically, only the APAP-treated Shank3-/- mice displayed significantly increased repetitive behaviors, and reduced exploratory activity. Here, we show that transient liver injury is associated with long-term neuroinflammation, markers of blood-brain barrier disruption, and behavioral deficits. These findings demonstrate that while peripheral organ damage can induce lasting behavioral changes in healthy animals, the severity and spectrum of these deficits are exacerbated by ASD-associated genetic predisposition. These findings support a preclinical gene-environment interaction framework relevant to ASD-associated vulnerability.
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BibTeX
@article{szabo2026acetaminopheninduced,
title = {{Acetaminophen-induced liver injury triggers short- and long-term neuroinflammation, blood-brain barrier disruption, and behavioral deficits in a genetic mouse model of autism.}},
author = {Jakub Szabó and Andrej Feješ and Ladislav Bačiak and Gabriela Fujeríková and Emese Renczés and Daniel Gogola and Youssef Zaim Wadghiri and Daniela Ostatníková and Peter Celec},
journal = {Acta neuropathologica communications},
year = {2026},
month = jul,
doi = {10.1186/s40478-026-02385-w},
url = {https://europepmc.org/article/MED/42908025},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Acetaminophen-induced liver injury triggers short- and long-term neuroinflammation, blood-brain barrier disruption, and behavioral deficits in a genetic mouse model of autism.
AU - Jakub Szabó
AU - Andrej Feješ
AU - Ladislav Bačiak
AU - Gabriela Fujeríková
AU - Emese Renczés
AU - Daniel Gogola
AU - Youssef Zaim Wadghiri
AU - Daniela Ostatníková
AU - Peter Celec
PY - 2026
DA - 2026/07/01
JO - Acta neuropathologica communications
DO - 10.1186/s40478-026-02385-w
UR - https://europepmc.org/article/MED/42908025
AB - Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a strong genetic basis, yet its etiology is not fully understood. Neuroinflammation is emerging as a critical secondary factor. Since peripheral organ injury, such as acute liver failure, can induce neuroinflammation, we aimed to investigate whether liver injury could exacerbate ASD-like phenotypes in a genetically susceptible model. We used adult (12-month-old) Shank3-/- mice, a genetic model of ASD, and their wild-type (WT) counterparts. A single high dose of acetaminophen (APAP; 350 mg/kg) was administered intraperitoneally to induce acute liver injury. We assessed acute (24-h) and long-term (1-month) consequences on liver health, neuroinflammation, blood-brain barrier integrity, and brain edema using plasma biomarkers, immunohistochemistry, and in-vivo MRI, as well as behavioral phenotypes, including sociability, repetitive behaviors and exploration. Acutely, APAP induced severe liver damage, cerebral edema, and neuroinflammation in Shank3-/- mice. One month later, despite liver recovery, both APAP-treated WT and Shank3-/- mice exhibited brain edema, elevated apparent transverse relaxation (R2*) rates, and lasting neuroinflammation, evidenced by microgliosis and reactive astrocytosis. These differences were more extensive in the Shank3-/- group. Behaviorally, this was accompanied by increased social deficits in both genotypes. Critically, only the APAP-treated Shank3-/- mice displayed significantly increased repetitive behaviors, and reduced exploratory activity. Here, we show that transient liver injury is associated with long-term neuroinflammation, markers of blood-brain barrier disruption, and behavioral deficits. These findings demonstrate that while peripheral organ damage can induce lasting behavioral changes in healthy animals, the severity and spectrum of these deficits are exacerbated by ASD-associated genetic predisposition. These findings support a preclinical gene-environment interaction framework relevant to ASD-associated vulnerability.
SN - 2051-5960
ER -