# Targeted Therapeutic Approaches to Counteract Toxicity from Phosgene Oxime Skin Exposure

> **NIH NIH U01** · MICHIGAN STATE UNIVERSITY · 2020 · $474,397

## Abstract

Project Summary Abstract
Stockpiled during World War II, Phosgene Oxime (CX; dichloroform oxime) is a potent chemical weapon that
poses a threat of exposure; both, alone and with other chemical agents. It is an urticant or nettle agent grouped
with vesicating agents due to similar damaging properties; although, it causes more severe damage than other
vesicants due to its highly reactive nature. Even though it is the most notorious vesicant with special military
and terrorist interests, it is one of the least studied chemical warfare agents with no specific antidote available.
Information on its effect on human dermal tissue and absorption is limited, and its mechanism of action is
unknown. To overcome these limitations, our completed and ongoing studies are directed towards the
development of a relevant cutaneous CX exposure mouse injury model to elucidate the mechanisms of skin
damage by CX and examine systemic toxic effects of CX to identify novel therapeutic targets. The results from
our completed studies demonstrate that mast cells could be important players in CX-induced toxicity. The
toxicity response and skin urticaria from CX resembles anaphylactic reaction and urticaria from allergic
reactions, which involves an inflammatory response mainly due to mast cell activation. Data from our published
and completed studies in SKH-1 hairless mice show that CX cutaneous exposure causes mast cell
degranulation and release of mediators including histamine and tryptase, pro-inflammatory cytokines, and an
inflammatory response in the skin tissue associated with edema, erythema, necrosis, urticaria and blanching.
CX cutaneous exposure in mice also caused vasculature dilation and blood congestion in multiple organs
resulting in systemic toxicity, and decrease in breath and heart rate, temperature drop and mortality. These
symptoms were similar to anaphylaxis (potentially lethal multisystem allergic reaction with acute respiratory
and cardiovascular compromise leading to unconsciousness, shock and mortality), which is a result of sudden
systemic release of mediators from mast cells. Based on our published and recently obtained data under
the current R21 grant, we hypothesize that mast cell activation and associated release of mediators are
the major events following CX cutaneous exposure which cause inflammatory pathway activation as
well as lethal allergic reaction, and that these would be novel targets for therapeutic intervention to
mitigate CX-induced skin morbidity and mortality. To test this hypothesis, the specific aims proposed are:
1. To further establish mast cells as key players and molecular targets in CX toxicity by employing mast cell
deficient mice; and 2. To test the efficacy of FDA approved therapies that can counteract CX-induced morbidity
and mortality from cutaneous exposure in mice, mainly by targeting mast cell activation and release of
histamine. We believe that outcomes from above aims will help establish that mast cell activation ...

## Key facts

- **NIH application ID:** 10013129
- **Project number:** 5U01AR075470-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Neera Tewari-Singh
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,397
- **Award type:** 5
- **Project period:** 2019-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013129

## Citation

> US National Institutes of Health, RePORTER application 10013129, Targeted Therapeutic Approaches to Counteract Toxicity from Phosgene Oxime Skin Exposure (5U01AR075470-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013129. Licensed CC0.

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