背景:苯并[a]芘(B[a]P)是一种致癌的多环芳烃,对人类健康构成重大风险。B[a]P通过复杂的相互作用影响细胞过程;然而,全面了解B[a]P对转录组的影响仍然难以捉摸。本研究旨在进行全面分析,重点是确定受B[a]P暴露影响的相关基因和信号通路及其对人类基因表达的影响。
方法:我们搜索了基因表达综合数据库,并确定了四项涉及人细胞中B[a]P暴露的研究(T淋巴细胞,肝细胞癌细胞,和C3A细胞)。我们利用两种方法进行差异表达分析:LIMMA包和线性回归。使用荟萃分析来组合来自使用随机效应模型的鉴定的研究的对数倍数变化(FC)和p值。我们以0.05的Bonferroni调整的显著性水平鉴定了显著基因,并确定了数据集之间的重叠基因。途径富集分析阐明了B[a]P暴露调节的关键细胞过程。
结果:荟萃分析显示,CYP1B1(logFC=1.15,95%CI:0.51-1.79,P<0.05,I2=82%)和ASB2(logFC=0.44,95%CI:0.20-0.67,P<0.05,I2=40%)对B[a]P暴露有明显的上调。通路分析确定了26条显著调节的通路,顶部包括芳基烃受体信号(P=0.00214)和异种生物代谢信号(P=0.00550)。关键基因CYP1A1,CYP1B1和CDKN1A涉及多个途径,强调它们在外源性生物代谢中的作用,氧化应激反应,和细胞周期调控。
结论:结果提供了对B[a]P毒性机制的见解,强调CYP1B1在B[a]P生物活化中的关键作用。研究结果强调了B[a]P的作用机制的复杂性及其对人类健康的潜在影响。确定的基因和途径为进一步探索提供了基础,并增强了我们对与B[a]P暴露相关的多方面生物活性的理解。
BACKGROUND: Benzo[a]pyrene (B[a]P) is a carcinogenic polycyclic aromatic hydrocarbon that poses significant risks to human health. B[a]P influences cellular processes via intricate interactions; however, a comprehensive understanding of B[a]P\'s effects on the transcriptome remains elusive. This study aimed to conduct a comprehensive analysis focused on identifying relevant genes and signaling pathways affected by B[a]P exposure and their impact on human gene expression.
METHODS: We searched the Gene Expression Omnibus database and identified four studies involving B[a]P exposure in human cells (T lymphocytes, hepatocellular carcinoma cells, and C3A cells). We utilized two approaches for differential expression analysis: the LIMMA package and linear regression. A meta-analysis was utilized to combine log fold changes (FC) and p-values from the identified studies using a random effects model. We identified significant genes at a Bonferroni-adjusted significance level of 0.05 and determined overlapping genes across datasets. Pathway enrichment analysis elucidated key cellular processes modulated by B[a]P exposure.
RESULTS: The meta-analysis revealed significant upregulation of
CYP1B1 (log FC = 1.15, 95% CI: 0.51-1.79, P < 0.05, I2 = 82%) and ASB2 (log FC = 0.44, 95% CI: 0.20-0.67, P < 0.05, I2 = 40%) in response to B[a]P exposure. Pathway analyses identified 26 significantly regulated pathways, with the top including Aryl Hydrocarbon Receptor Signaling (P = 0.00214) and Xenobiotic Metabolism Signaling (P = 0.00550). Key genes CYP1A1,
CYP1B1, and CDKN1A were implicated in multiple pathways, highlighting their roles in xenobiotic metabolism, oxidative stress response, and cell cycle regulation.
CONCLUSIONS: The results provided insights into the mechanisms of B[a]P toxicity, highlighting
CYP1B1\'s key role in B[a]P bioactivation. The findings underscored the complexity of B[a]P\'s mechanisms of action and their potential implications for human health. The identified genes and pathways provided a foundation for further exploration and enhanced our understanding of the multifaceted biological activities associated with B[a]P exposure.