Abstract
Benzo(a)pyrene (BaP) is a prevalent food and environmental carcinogen. Chronic low-dose BaP exposure can promote the migratory and invasive capacities of human hepatocellular carcinoma (HCC) cells, yet its intricate molecular mechanisms remain elusive. Utilizing the established BaP-exposed HCC cell model, we analyzed the gene expression alteration, exosomal RNA cargo, and genetic variants induced by BaP through transcriptomic and whole-genome sequencing. Transcriptomic analysis revealed significant dysregulation in genes and pathways associated with tumor metastasis, particularly those involved in steroidal lipid metabolism and cell migration. BaP exposure enriched PI3K-AKT, mTOR, and NF-κB signaling pathways and disrupted genes implicated in cellular secretory processes, suggesting the potential involvement of exosomes in metastasis. Exosome analysis depicted the RNA profiling in exosomes of HCC cells altered by BaP, and the exosomal circRNA-miRNA-mRNA interaction network was constructed. Finally, whole-genome sequencing delineated BaP-induced gene mutations and genomic instability in HCC cells. In summary, prolonged low-dose BaP exposure induces intricate molecular alterations in gene mutation and expression profiles in HCC cells, notably those secreted in exosomes, which may potentially remodel the tumor microenvironment and foster HCC metastasis. Our findings offer new insights into the molecular underpinnings of BaP-induced HCC metastasis, thereby advancing the comprehensive understanding of BaP toxicity.