Integrative multi-omics analysis of metabolic dysregulation induced by occupational benzene exposure in mice

Authors: SCOFIELD, SYDNEY - Wayne State University; KOSHKO, LISA - Wayne State University; STILGENBAUER, LUKAS - Wayne State University; BOOMS, ALIX - Van Andel Research Institute; BERUBE, ROXANNE - Wayne State University; KASSOTIS, CHRISTOPHER - Wayne State University; LIN, CHUNG-HO - University Of Missouri; JANG, HYEJEONG - Wayne State University; KIM, SEONGHO - Wayne State University; STEMMER, PAUL - Wayne State University; LEMPRADI, ADELHEID - Van Andel Research Institute; SADAGURSKI, MARIANNA - Wayne State University

Submitted to: Science of the Total Environment
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/4/2025
Publication Date: 3/11/2025
Citation: Scofield, S., Koshko, L., Stilgenbauer, L., Booms, A., Berube, R., Kassotis, C., Lin, C., Jang, H., Kim, S., Stemmer, P., Lempradi, A., Sadagurski, M. 2025. Integrative multi-omics analysis of metabolic dysregulation induced by occupational benzene exposure in mice. Science of the Total Environment. https://doi.org/10.1016/j.scitotenv.2025.179060.
DOI: https://doi.org/10.1016/j.scitotenv.2025.179060

Interpretive Summary: Benzene found in water and industrial and vehicle fumes is known to harm health, but even at levels below sa fety limits, its effects on meta bolism a ren’t well understood . Mice were exposed to lowdose benzene (0.9 ppm for 8 hours daily over 9 weeks), then analyzed across multiple biological scales (RNA, proteins). Results included higher blood sugar and insulin levels, mitochondrial dysfunction, and disrupted immune and metabolic pathways in the liver, muscle, and fat. These findings suggest that current exposure limits may not be safe for metabolic health and could help redefine regulations and protect workers against hidden metabolic disorders.

Technical Abstract: Type 2 Diabetes Mellitus (T2DM) is a significant public health burden. Emerging evidence links volatile organic compounds (VOCs), such as benzene to endocrine disruption and metabolic dysfunction. However, the effects of chronic environmentally relevant VOC exposures on metabolic health are still emerging. Building on our previous findings that benzene exposure at smoking levels (50 ppm) induces metabolic impairments in male mice, we investigated the effects of benzene exposure below OSHA’s Occupational Exposure Limit (OEL) on metabolic health. Adult male C57BL/6 mice were exposed to 0.9 ppm benzene 8 h a day for 9 weeks. We assessed measures of metabolic homeostasis and conducted RNA and proteome sequencing on insulin-sensitive organs (liver, skeletal muscle, adipose tissue). At this dose, exposure caused significant metabolic disruptions, including hyperglycemia, hyperinsulinemia, and insulin resistance. Transcriptomic analysis of liver, muscle, and adipose tissue identified key changes in metabolic and immune pathways especially in liver. Proteomic analysis of the liver revealed mitochondrial dysfunction as a shared feature, with disruptions in oxidative phosphorylation, mitophagy, and immune activation. Comparative analysis with high-dose (50 ppm) exposure showed conserved and dose-specific transcriptomic changes in liver, particularly in metabolic and immune responses. Our study is the first to comprehensively assess the impacts of occupational benzene exposure on metabolic health, highlighting mitochondrial dysfunction as a central mechanism and the dose-dependent molecular pathways in insulin-sensitive organs driving benzene-induced metabolic imbalance. Our data indicate that the current OSHA OEL for benzene is insufficient and needs to be lowered, as they could result in adverse metabolic health in exposed workers, particularly men, following chronic exposure.