Benzene exposure promotes neuroinflammation and metabolic dysregulation

摘要 苯是一种重要的挥发性有机化合物(VOCs)，存在于水、食品、油漆、 洗涤剂、汽车尾气、烟草烟雾和电子烟蒸气。暴露于低剂量的 城市地区的环境苯已被认为与增加新陈代谢风险有关 各个年龄段都有功能障碍。然而，接触低剂量苯和 代谢动态平衡尚未建立。使用有限的可用文献 环境中暴露于苯及其代谢结果，我们进行了初步的 Meta分析发现，接触苯与代谢之间存在正相关 减损。我们的初步研究提供了强有力的证据表明，长期接触苯 在不同的低剂量下，模拟人类暴露途径，诱导显著的胰岛素抵抗 以及啮齿类动物的高血糖。神经炎被越来越多地认为是原因之一。 代谢性疾病的病理因素。神经胶质细胞(小胶质细胞和星形胶质细胞)最近 由于它们在代谢紊乱的神经炎性反应中的作用而引起了特别的关注。 小胶质细胞，产生各种促炎分子，这些分子对肿瘤的发展至关重要 外周代谢失衡和下丘脑炎症引起的胰岛素抵抗。我们展示了 与职业和环境有关的几个低剂量的苯暴露 暴露促进下丘脑神经胶质细胞的激活和升高 炎性IKKβ/NF-κB信号通路与内质网的诱导 (呃)应激反应。我们的中心假设是苯诱导的小胶质细胞的变化 功能和IKKβ/NF-κB信号通路是全身葡萄糖动态平衡变化的基础 代谢反应。这一假设将通过一种新的空气污染小鼠模型进行评估。 将分子、遗传和生理方法结合起来，旨在操纵 小脑胶质细胞的数量和炎性激活状态 目的：1)确定接触低浓度苯对 神经炎症和代谢调节；2)确定中枢IKKβ/NF-κB的作用 苯致代谢失衡的炎症机制：3)确定细胞 小胶质细胞神经炎症和内质网应激反应之间的分子相互作用 因接触苯而死亡。这项拟议的研究将首次直接评估 苯诱导的神经胶质功能和炎症信号在全身调节中的变化 新陈代谢。这项研究将对以下方面的公共卫生政策的制定具有重要意义 苯暴露及其在发展代谢性疾病易感性中的作用。

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.