HIF-1/m⁶A/NF-B/CCL3 axis-mediated immunosurveillance participates in low level benzene-related erythrohematopoietic development toxicity

Defective erythropoiesis is one of the causes of anemia and leukemia. However, the mechanisms underlying defective erythropoiesis under a low-dose environment of benzene are poorly understood. In the present study, multiple omics (transcriptomics and metabolomics) and methods from epidemiology to experimental biology (e. g., benzene-induced (WT and HIF-1 alpha + ) mouse, hiPSC-derived HSPCs) were used. Here, we showed that erythropoiesis is more easily impacted than other blood cells, and the process is reversible, which involves HIF-1 and NF-kB signaling pathways in low-level benzene exposure workers. Decreased HIF-1 alpha expression in benzeneinduced mouse bone marrow resulted in DNA damage, senescence, and apoptosis in BMCs and HSCs, causing disturbances in iron homeostasis and erythropoiesis. We further revealed that HIF-1 alpha mediates CCL3/ macrophage-related immunosurveillance against benzene-induced senescent and damaged cells and contributes to iron homeostasis. Mechanistically, we showed that m6A modification is essential in this process. Benzeneinduced depletion of m6A promotes the mRNA stability of gene NFKBIA and regulates the NF-kappa B/CCL3 pathway, which is regulated by HIF-1 alpha/METTL3/YTHDF2. Overall, our results identified an unidentified role for HIF-1 alpha, m6A, and the NF-kB signaling machinery in erythroid progenitor cells, suggesting that HIF-1 alpha/METTL3/ YTHDF2-m6A/NF-kappa B/CCL3 axis may be a potential prevention and therapeutic target for chronic exposure of humans to benzene-associated anemia and leukemia.