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Electrophilic Halogenated Fatty Aldehydes Target Erythrocytes to Mediate Halogen Toxicity

Award Number: R01ES036487
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/11/2026
PERIOD OF PERFORMANCE END DATE: 04/10/2029

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Electrophilic Halogenated Fatty Aldehydes Target Erythrocytes to Mediate Halogen Toxicity - Exposures to chlorine (Cl2) and bromine gases (Br2) are public health threats. Cl2 and Br2 exposures occur due to industrial accidents as well as chemical warfare. Although cardiopulmonary failure caused mortality and morbidity is a major concern following exposures, the mechanisms underlying end organ injury after exposure to Cl2 or Br2 remain to be fully elucidated. Coagulopathy occurs following both Cl2 and Br2 exposures and likely leads to organ injury. We discovered that exposure of mice to Cl2 or Br2 gas results in robust levels of both 2- halofatty aldehyde (2-haloFALD) and their glutathione (GSH) adducts (FALD-GSH) in the lungs. Recent pilot data suggest a link between 2-haloFALD production, red blood cell (RBC) fragility and coagulopathy. These pilot data show: 1) FALD-GSH levels are elevated in RBCs following Cl2 and Br2 exposures to mice; 2) the 2- haloFALD, 2-ClFALD, modifies spectrin; 3) platelets metabolize 2-ClFALD to FALD-GSH; 4) FALD-GSH is an agonist for the cysteinyl leukotriene receptor, CysLT2; and 5) FALD-GSH causes CysLT2 receptor-dependent thrombus formation in blood. Since spectrin is responsible for RBC structural integrity and since CysLT2 receptor agonists cause platelet activation, we propose that halolipid metabolism is central in halogen gas toxicity and FALD-GSH is a major mediator of coagulation. We will investigate two mechanisms, direct FALD-GSH activation of platelets and indirect FALD-GSH activation of platelets following RBC hemolysis and release of stored FALD- GSH. We will then determine how FALD-GSH mediates platelet activation via the CysLT2 receptor. This hypothesis will test a unifying mechanism mediating both Cl2 and Br2 gas toxicity resulting in the production of novel agonists of platelet activation which may provide a common therapeutic target for a countermeasure against halogen exposure. Furthermore, while Cl2 and Br2 are similar, the 25-fold greater reactivity of 2-BrFALD reactivity with nucleophiles (glutathione and proteins) compared to that of 2-ClFALD may evoke differences in mechanisms by which each cause injury. There are two specific aims to test this hypothesis. Specific Aim 1 will identify FALD-GSH activation of the CysLT2 receptor as a mechanism responsible for coagulation and lung injury following Cl2 and Br2 exposure. Specific Aim 2 will identify the direct and indirect mechanisms by which FALD-GSH mediates platelet activation via the CysLT2 receptor in primary human cells. We will employ both mouse and rat models of Cl2 and Br2 gas exposure in both males and females. This, together with testing two distinct toxicants meet criteria for this RFA. Collectively, the proposed studies will delineate a common mechanism for Cl2 and Br2 toxicity mediated by 2-haloFALD modification of GSH and RBC spectrin leading to CysLT2 receptor-dependent platelet activation and organ failure. This mechanism could lead to a common treatment for these Chemical Countermeasures Research Program concerns in the future.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,377,000 )
2026	2026	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Environmental Health	000	1	4/8/2026	NEW	$1,377,000
														Subtotal = $1,377,000

Grand Total All Awards = $1,377,000

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Electrophilic Halogenated Fatty Aldehydes Target Erythrocytes to Mediate Halogen Toxicity

Award Number: R01ES036487

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/11/2026

PERIOD OF PERFORMANCE END DATE: 04/10/2029

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