Long-Term Anxiety-like Behavior and Microbiota Changes Induced in Mice by Sublethal Doses of Acute Sarin Surrogate Exposure

• Published in: Biomedicines Vol. 10; no. 5; pp. 1167 - 21
• Main Authors: François, Sabine, Mondot, Stanislas, Gerard, Quentin, Bel, Rosalie, Knoertzer, Julie, Berriche, Asma, Cavallero, Sophie, Baati, Rachid, Orset, Cyrille, Dal Bo, Gregory, Thibault, Karine
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.05.2022; MDPI
• Subjects: 4-nitrophenyl isopropyl methylphosphonate; Amygdala; Animal cognition; Anxiety; Anxiety disorders; Behavior; dysbiosis; Homeostasis; Immune system; Inflammation; Intestinal microflora; Intoxication; Lethal dose; Life Sciences; Magnetic resonance imaging; Microbiota; mood disorder; Nerve agents; Pesticides; Sarin; sarin surrogate; sublethal exposure; France; microbiota; anxiety; mood disorder; sarin surrogate; 4-nitrophenyl isopropyl methylphosphonate; sublethal exposure; dysbiosis
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines10051167

Anxiety disorder is one of the most reported complications following organophosphorus (OP) nerve agent (NA) exposure. The goal of this study was to characterize the long-term behavioral impact of a single low dose exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. We chose two different sublethal doses of NIMP, each corresponding to a fraction of the median lethal dose (one mild and one convulsive), and evaluated behavioral changes over a 6-month period following exposure. Mice exposed to both doses showed anxious behavior which persisted for six-months post-exposure. A longitudinal magnetic resonance imaging examination did not reveal any anatomical changes in the amygdala throughout the 6-month period. While no cholinesterase activity change or neuroinflammation could be observed at the latest timepoint in the amygdala of NIMP-exposed mice, important modifications in white blood cell counts were noted, reflecting a perturbation of the systemic immune system. Furthermore, intestinal inflammation and microbiota changes were observed at 6-months in NIMP-exposed animals regardless of the dose received. This is the first study to identify long-term behavioral impairment, systemic homeostasis disorganization and gut microbiota alterations following OP sublethal exposure. Our findings highlight the importance of long-term care for victims of NA exposure, even in asymptomatic cases.