Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

Abstract

Abbreviations:CNS, central nervous system; ARC, arcuate nucleus of the hypothalamus; DMH, dorsomedial hypothalamic nucleus; LHA, lateral hypothalamus; PVH, paraventricular hypothalamic nucleus; AbstractBenzene 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 carcinogenic effects of benzene exposure have been well studied, less is known about metabolic effects of benzene exposure.We show that chronic exposure to benzene at low levels induces severe metabolic imbalance in a sex-specific manner, which 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 anti-diabetes drug, protected against benzene induced central and peripheral metabolic imbalance. 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 negative metabolic effect of chronic exposure to benzene for smokers or for people living/working in urban environments with high concentrations of exposure to automobile exhausts.

Metabolic Reprogramming byIn UteroMaternal Benzene Exposure

“…Under these conditions, benzene exposure had no significant effect on litter size or composition and no significant changes in animals white blood cell counts (Debarba et al 2020). Our findings indicate that maternal exposure to benzene induces deleterious effects on energy expenditure, glucose metabolism, and insulin resistance in adult offspring in a sex-specific manner, providing the evidence that gestational benzene exposure is a potential risk factor for metabolic disorders.…”

“…This adapted regimen for benzene inhalation resembles chronic human benzene exposure levels in highly polluted gas stations, or exposure to tobacco smoke (De Donno et al 2018;Lorkiewicz et al 2019;Pankow et al 2017). We have recently demonstrated that under these conditions, benzene exposure has no significant changes in white blood cell counts in benzene exposed animals versus control animals breathing room air (Debarba et al 2020). Maternal exposure to benzene did not significantly affect male and female offspring body mass at weaning and throughout adulthood ( Figure 1B and C).…”

“…Benzene exposure: Pregnant dams in inhalation chambers using FlexStream™ automated Perm Tube System (KIN-TEK Analytical, Inc) were exposed to benzene concentration of 50 ppm for 6h/day, 5 days a week as before (Debarba et al 2020). FlexStream™ automated Perm Tube System allows creating precision gas mixtures.…”

“…We exposed pregnant females to benzene at the concentration of 50 ppm throughout the pregnancy using an exposure chamber for 6 hr/day, 5 days/wk for 21 days (Debarba et al 2020). Figure 1A illustrates a schematic timeline of the experimental design.…”

“…Benzene is known to be carcinogenic at high concentrations, but its association in causing metabolic diseases particularly T2DM is still emerging. Recent studies demonstrated that benzene non-cancerous health effects at environmental levels include impaired glucose homeostasis and insulin resistance (Abplanalp et al 2017;Amin et al 2018;Debarba et al 2020). We have recently shown that chronic exposure of adult mice to benzene at the levels relevant to human exposures associated with cigarette smoke (50 ppm) induces severe metabolic imbalance associated with central hypothalamic inflammation and endoplasmic reticulum (ER) stress in a sex-specific manner (Debarba et al 2020).…”