Benzene exposure promotes neuroinflammation and metabolic dysregulation

接触苯会促进神经炎症和代谢失调

• 批准号: 10445653
• 负责人: Marianna Sadagurski
• 金额: $ 41.02万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445653
• 关键词: Ablation; Affect; Age; Air Pollution; Astrocytes; Attention; Benzene; Benzene Exposure; Cells; Chronic; Detergents; Development; Dose; Energy Metabolism; Environment; Environmental Exposure; Environmental and Occupational Exposure; Etiology; Exposure to; Food; Future; General Population; Genetic; Glucose; Goals; Health; Health Policy; Histology; Homeostasis; Human; Hyperglycemia; Hypothalamic structure; Immune; Impairment; In Situ Hybridization; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intervention; Knockout Mice; Leptin; Link; Literature; Mediating; Meta-Analysis; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Microglia; Modeling; Modernization; Molecular; Molecular Genetics; Morphology; Mus; Neuroglia; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Occupational; Outcome; Oxidative Stress; Paint; Pathology; Pathway interactions; Peripheral; Physiological; Predisposition; Pregnant Women; Public Health; Publishing; Regulation; Research; Risk; Rodent; Role; Shapes; Signal Pathway; Signal Transduction; Societies; System; Testing; Time; Tissues; Tobacco smoke; Underrepresented Minority; Water; Work; biological adaptation to stress; blood glucose regulation; conditional knockout; cost; design; e-cigarette aerosols; endoplasmic reticulum stress; exhaust; exposure route; exposure to cigarette smoke; glial activation; glucose metabolism; glucose monitor; human model; immunological status; in vivo; insight; insulin signaling; insulin tolerance; male; mouse model; neuroinflammation; new therapeutic target; novel; prevent; response; systemic inflammatory response; urban area; urinary; volatile organic compound; young adult

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.

抽象的 苯是一种突出的挥发性有机化合物（VOC），在水，食物，油漆， 洗涤剂，车辆排气，烟草烟雾和电子烟蒸气。暴露于低剂量 在城市地区的环境苯已暗示增加了代谢的风险 各个年龄段的功能障碍。但是，暴露于低剂量苯和 尚未建立代谢稳态。使用有限的可用文献 环境暴露于苯及其代谢结果，我们进行了初步 荟萃分析，发现暴露于苯和代谢之间存在正相关 障碍。我们的初步研究提供了有力的证据表明长期暴露于苯 在不同剂量不同的情况下，建模人类暴露途径，诱导明显的胰岛素抵抗 和啮齿动物中的高血糖。神经炎症越来越被认为是因果关系之一 代谢疾病病理学的因素。神经胶质细胞（小胶质细胞和星形胶质细胞）最近具有 由于其在代谢性疾病中的神经炎症反应中的作用而引起了特定的关注。 小胶质细胞产生各种促炎分子，这对于发展至关重要 通过下丘脑炎症，外周代谢失衡和胰岛素抵抗。我们显示 与占领和环境有关的几种低剂量的苯暴露 暴露会促进下丘脑中强大的下丘脑神经胶质激活和升高 炎症IKKβ/NF-κB信号通路，然后诱导内质网 （ER）应力反应。我们的中心假设是苯诱导的小胶质细胞变化 功能和IKKβ/NF-κB信号传导是全身葡萄糖稳态的变化和 代谢反应。该假设将通过一种新型的空气污染鼠模型进行评估 结合旨在操纵两者的分子，遗传和物理方法 居民小胶质细胞的数量和炎症激活状态在以下特定中 目的：1）确定暴露于低苯浓度的贡献 神经炎症和代谢调节； 2）确定中央IKKβ/NF-κB的作用 苯诱导的代谢失衡中的炎症机制：3）确定细胞 触发的小胶质细胞神经炎症和ER应力反应之间的分子相互作用 通过苯暴露。拟议的研究将首次直接评估 苯诱导的胶质功能变化和调节全身的炎症信号传导 代谢。这样的研究对于制定公共卫生政策至关重要 苯暴露及其在发展代谢疾病的易感性中的作用。