Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

Tressler, Caitlin M.; Wadsworth, Benjamin; Carriero, Samantha; Dillman, Natalie; Crawford, Rachel; Hahm, Tae-Hun; Glunde, Kristine; Cadieux, C. Linn

doi:10.3390/ijms25115624

Title: Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

Journal Article · 22 May 2024 · International Journal of Molecular Sciences (Online)

DOI: https://doi.org/10.3390/ijms25115624 · OSTI ID:2471305

Tressler, Caitlin M. ^[1]; Wadsworth, Benjamin ^[2]; Carriero, Samantha ^[3]; Dillman, Natalie ^[1]; Crawford, Rachel ^[1];

^[1]; Glunde, Kristine ^[1];

^[2]

Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD (United States)
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD (United States); Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals’ resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood–brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States); Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine

Sponsoring Organization:: USDOE Office of Science (SC); USDOD; NIH

Grant/Contract Number:: SC0014664

OSTI ID:: 2471305

Journal Information:: International Journal of Molecular Sciences (Online), Journal Name: International Journal of Molecular Sciences (Online) Journal Issue: 11 Vol. 25; ISSN IJMCFK; ISSN 1422-0067

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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Title: Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

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