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Lipid and metabolic mechanisms responsible for phosgene and phosphorus trichloride exposure toxicity

Award Number: R01ES035365
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Lipid and metabolic mechanisms responsible for phosgene and phosphorus trichloride exposure toxicity - Exposures to phosgene (COCl2) and phosphorous trichloride (PCl3) are public health threats. COCl2 and PCl3 exposures are the result of industrial accidents or chemical warfare/terrorism acts. Following exposures, acute lung injury presenting as apnea and pulmonary edema are major concerns, which contribute to mortality and morbidity. However, mechanisms responsible for the action of these pulmonary toxic agents have not been elucidated. Both COCl2 and PCl3 rapidly produce HCl in the lung. Plasmalogen phospholipids including plasmenylethanolamine (pPE) in the lung are acid-labile leading to the production of lipidic aldehydes and lysophosphatidylethanolamine containing polyunsaturated fatty acids (PUFA-LPE). In addition to COCl2 and PCl3 reacting with the vinyl ether bond of plasmalogens, other functional groups of lipids may also be targeted. These include primary amines and conjugated dienes suggesting that an array of lipophilic compounds is produced during exposures. Functional groups of proteins and metabolites may also be modified by COCl2 and PCl3 exposures leading to metabolic alterations. Extensive discovery omics analyses following exposures to COCl2 and PCl3 will provide critical insights into mechanisms responsible for their toxicity. We hypothesize that both COCl2 and PCl3 exposures result in lipid and metabolic changes leading to endothelial and epithelial cell dysfunction. Both targeted and untargeted approaches will be performed to identify novel lipidic and metabolic changes following COCl2 and PCl3 exposures. In support of this hypothesis, pilot data show: 1) PUFA-LPE levels are elevated in response to PCl3 exposure to primary human lung microvascular endothelial cells (HLMVEC); 2) PUFA-LPE elicits HLMVEC barrier dysfunction; 3) COCl2 exposure to lung lipids results in the production of a family of lipophilic aldehydes and 4) PCl3 elicits profound changes in HLMVEC metabolites and metabolic pathways following exposure. There are two specific aims for the proposed studies. Specific Aim 1 will identify novel lipid and metabolic products following COCl2 and PCl3 exposures resulting in endothelial and epithelial cell dysfunction. Specific Aim 2 will identify mechanisms by which novel lipid and metabolic species produced following COCl2 and PCl3 exposures elicit endothelial and epithelial cell dysfunction. We will investigate COCl2 and PCl3 exposures to both primary human lung microvascular endothelial cells and primary human small airway epithelial cells. This, together with testing these two distinct toxicants at LD50 levels, meet criteria for this RFA. The proposed studies will examine a potential common mechanism for COCl2 and PCl3 toxicity mediated by PUFA-LPE. Additionally, unique lipid and metabolic changes will be examined following COCl2 and PCl3 exposures using untargeted analytical approaches. Collectively, these studies will provide in- sights into the mechanisms responsible for toxicity and will provide therapeutic targets for the development of countermeasures to COCl2 and PCl3.


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: 2024 ( Subtotal = $303,000 )
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Environmental Health	000	2	7/25/2024	NON-COMPETING CONTINUATION	$303,000
														Subtotal = $303,000

Issue Date FY: 2023 ( Subtotal = $303,000 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Environmental Health	000	1	8/15/2023	NEW	$303,000
														Subtotal = $303,000

Grand Total All Awards = $606,000

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Lipid and metabolic mechanisms responsible for phosgene and phosphorus trichloride exposure toxicity

Award Number: R01ES035365

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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