Benzene is a well-known human carcinogen that is one of the major components of air pollution. Few epidemiological studies suggested an association between adverse health effects of benzene at low doses and the development of insulin resistance. Regardless, a detailed analysis of the metabolic effects of benzene exposure and its target tissues has rarely been done. We assessed the effects of chronic and acute exposure to benzene at 50 ppm in inhalation chambers in mice. We show that exposure to benzene for 4 weeks (5h/day), induced hyperglycemia and hyperinsulinemia, associated with impairment in gluconeogenesis and lipid metabolism in males. Females were completely resistant to the negative metabolic consequences of benzene exposure. Moreover, chronic benzene exposure promoted hypothalamic gliosis, ER stress, and elevation of inflammatory genes in male mice. In support, a global proteome profile has identified inflammatory and ER stress pathways in the hypothalamus of the benzene exposed animals suggesting their role in a benzene-induced metabolic imbalance. In support, benzene exposure triggered alterations in neuron-glia interactions by modulating neuronal sensing under hyperglycemic conditions within hypothalamic glucose-sensing VMH neurons. Mechanistically, acute benzene exposure activated hypothalamic ER stress and neuroinflammatory responses, while pharmacological inhibition of IRE1α-XBP1 pathway alleviated glial inflammatory cytokines production suggesting that this may be the primary mechanism by which benzene causes changes in metabolic status. A diabetes drug, Acarbose that extends animals’ life span in a sex-specific manner, and protected against benzene induced metabolic imbalance, ER stress, and neuroinflammatory responses. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the effect of benzene exposure even at lower levels.
L. Kniess Debarba: None. A. Mulka: None. P.I. Fakhoury: None. O. Didyuk: None. A.A. Awada: None. J. Lima: None. L. Koshko: None. U. Klueh: Research Support; Self; Abbott. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC. M. Sadagurski: None.
American Diabetes Association (1-18-JDF-063 to M.S.)