Benzene-induced pulmonary dysfunction in diabetic mice

Benzene is among the most produced chemicals in the United States, and epidemiological evidence links benzene exposure to impaired pulmonary function; yet, the influence of pre-existing metabolic disease on susceptibility remains poorly defined. We investigated the effects of inhaled benzene on pulmonary mechanics and surfactant homeostasis in diabetic mice with varying glycemic severity. Mildly hyperglycemic KK and severely hyperglycemic, insulin-resistant KK-Ay mice were exposed to filtered air or 50 ppm benzene (6 h/d, 5 d/wk) for 2 wk. Pulmonary function was assessed by the forced-oscillation technique, and bronchoalveolar lavage fluid was analyzed for surfactant proteins and lipid composition by lipidomics; whole-lung transcriptomes were profiled by RNA sequencing. Benzene increased respiratory system resistance and Newtonian resistance in KK-Ay mice without altering tissue elastance or compliance in either strain. Methacholine challenge revealed exaggerated bronchoconstriction in benzene-exposed KK-Ay mice, with significant increases in Rn and tissue damping absent in benzene-exposed KK controls. Surfactant protein B was reduced by benzene in both strains, whereas SP-C was diminished in benzene-exposed KK-Ay mice compared with benzene-exposed KK controls. Lipidomic profiling demonstrated benzene-induced surfactant lipid remodeling characterized by elevated triradylglycerols, increased phosphatidylcholine-to-phosphatidylethanolamine ratio, and reduced phosphatidylserine, with specific lipid classes correlating with airway resistance. Transcriptomic analysis identified enrichment of neurotransmitter transport, ion-channel, and calcium-regulated exocytosis pathways, alongside upregulation of phase II detoxification enzymes. These findings demonstrate that in severe hyperglycemic KK-Ay mice, benzene induced airway hyperresponsiveness through convergent disruption of surfactant protein/lipid homeostasis, identifying poorly controlled diabetes as a risk factor for benzene-related respiratory toxicity.