Integrated metabolomic and transcriptomic analysis identifies benzo[a] pyrene-induced characteristic metabolic reprogramming during accumulation of lipids and reactive oxygen species in macrophages

Polycyclic aromatic hydrocarbon exposure is a major risk factor for cardiovascular diseases. Macrophage lipid accumulation is a characteristic molecular event in the pathophysiology of cardiovascular diseases. Metabolic reprogramming is an intervention target for diseases and toxic effects of environmental pollutants. However, comprehensive metabolic reprogramming related to BaP-induced macrophage lipid accumulation is currently unexplored. Therefore, metabolomics and transcriptomics were conducted to unveil relevant metabolic reprogramming in BaP-exposed macrophages, and to discover potential intervention targets. Metabolomics revealed that most amino acids, nucleotides, monosaccharides, and organic acids were significantly decreased, while most fatty acids and steroids accumulated in BaPexposed macrophages. Transcriptomics showed that fatty acid synthesis and oxidation, and steroid synthesis and export were decreased, while import of fatty acids and steroids was increased, indicating potential roles of lipid transport in macrophage lipid accumulation following BaP exposure. Meanwhile, alanine, aspartate and glutamate metabolism, branched-chain amino acid degradation, nucleotide synthesis, monosaccharide import, pentose phosphate pathway, citrate synthesis, and glycolysis were decreased, while nucleotide degradation was increased, thus inducing decreases in most amino acids, nucleotides, monosaccharides, and organic acids in BaP-exposed macrophages. Additionally, increases in oxidative stress and the activation of antioxidant systems were observed in BaP-exposed macrophages, which was evinced by increases in reactive oxygen species, and the activation of Fenton reaction, Vdac2/3, Sod2, and Nrf2. Moreover, BaP-induced accumulation of reactive oxygen species and lipids in macrophages could be abolished by epigallocatechin-3-gallate. Quantitative PCR showed that BaP exposure activated aryl hydrocarbon re- ceptor signaling and promoted the proinflammatory phenotype in macrophages, and these effects were inhibited or even abolished by the separate treatment with epigallocatechin-3-gallate or CH-223191, suggesting the regulatory role of aryl hydrocarbon receptor signaling in BaP-induced toxic effects. This study provides novel insights into the toxic effects of polycyclic aromatic hydrocarbons on macrophage metabolism and potential intervention targets.

Automated summary

Polycyclic aromatic hydrocarbon (PAH) exposure is a major risk factor for cardiovascular diseases, and macrophage lipid accumulation is a characteristic event in the pathophysiology of these diseases. Metabolic reprogramming offers potential intervention targets for diseases and toxic effects of environmental pollutants. This study used metabolomics and transcriptomics to uncover metabolic reprogramming in BAPEXPOSED macrophages and identify potential intervention targets. The findings suggest that lipid transport, as well as changes in the metabolism of amino acids, nucleotides, monosaccharides, and organic acids, may play a role in the macrophage lipid accumulation induced by PAH exposure. The study also observed oxidative stress and the activation of antioxidant systems in PAH-exposed macrophages and identified epigallocatechin-3-gallate as a potential inhibitor of reactive oxygen species and lipid accumulation.