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Benzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes vaping, and evaporation of benzene containing petrol processes. While the carcinogenic effects of benzene exposure have been well studied, less is known about the metabolic effects of benzene exposure. We show that chronic exposure to benzene at low levels induces a severe metabolic imbalance in a sex-specific manner, and is associated with hypothalamic inflammation and endoplasmic reticulum (ER) stress. Benzene exposure rapidly activates hypothalamic ER stress and neuroinflammatory responses in male mice, while pharmacological inhibition of ER stress response by inhibiting IRE1α-XBP1 pathway significantly alleviates benzene-induced glial inflammatory responses. Additionally, feeding mice with Acarbose, a clinically available …