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Benzene exposure promotes neuroinflammation and metabolic dysregulation

Award Number: R01ES033171
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: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Benzene exposure promotes neuroinflammation and metabolic dysregulation - ABSTRACT Benzene is a prominent volatile organic compound (VOCs) that is present in water, food, paint, detergents, vehicle exhaust, tobacco smoke, and e-cigarette vapors. Exposure to low doses of environmental benzene in urban areas has been implicated in increasing the risk for metabolic dysfunction across all ages. However, a direct link between exposure to low-dose benzene and metabolic homeostasis is not yet established. Using the limited available literature on environmental exposure to benzene and its metabolic outcomes, we performed a preliminary meta-analysis and found a positive association between exposure to benzene and metabolic impairments. Our preliminary studies provide strong evidence that chronic exposure to benzene at varying low doses, modeling human exposure routes, induces significant insulin resistance and hyperglycemia in rodents. Neuroinflammation is increasingly recognized as one of the causal factors in the pathology of metabolic diseases. Glial cells (microglia and astrocytes) have recently garnered specific attention for their role in neuroinflammatory responses in metabolic disorders. Microglia, produce various pro-inflammatory molecules that are critical for the development of peripheral metabolic imbalance and insulin resistance via hypothalamic inflammation. We show that benzene exposure at several low doses relevant to occupational and environmental exposure promotes robust hypothalamic glial activation and elevation in the hypothalamic inflammatory IKKβ/NF-κB signaling pathway followed by the induction of endoplasmic reticulum (ER) stress response. Our central hypothesis is that benzene-induced changes in microglial function and IKKβ/NF-κB signaling underlie changes in whole-body glucose homeostasis and metabolic responses. This hypothesis will be assessed with a novel murine model of air-pollution combining molecular, genetic, and physiological approaches designed to manipulate both the number and the inflammatory activation state of resident microglia in the following Specific Aims: 1) To determine the contribution of exposure to low benzene concentrations to neuroinflammation and metabolic regulation; 2) To determine the role of central IKKβ/NF-κB inflammatory mechanism in a benzene-induced metabolic imbalance: 3) To determine the cellular and molecular interplay between microglia neuroinflammation and ER stress response triggered by benzene exposure. The proposed research will, for the first time, directly assess the role of benzene-induced changes in glial function and inflammatory signaling in regulating whole-body metabolism. Such a study will be of importance for shaping public health policy regarding benzene exposure and its role in predisposition to develop metabolic diseases.


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: 2025 ( Subtotal = $359,423 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	4	1/16/2025	NON-COMPETING CONTINUATION	$359,423
														Subtotal = $359,423

Issue Date FY: 2024 ( Subtotal = $379,518 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	3	1/31/2024	NON-COMPETING CONTINUATION	$379,518
														Subtotal = $379,518

Issue Date FY: 2023 ( Subtotal = $387,581 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	2	1/10/2023	NON-COMPETING CONTINUATION	$387,581
														Subtotal = $387,581

Issue Date FY: 2022 ( Subtotal = $410,165 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Environmental Health	000	1	3/27/2022	NEW	$410,165
														Subtotal = $410,165

Grand Total All Awards = $1,536,687

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Benzene exposure promotes neuroinflammation and metabolic dysregulation

Award Number: R01ES033171

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: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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