Chang Tzu-Ting, Chang Chun-Han, Hsiu-Chuan Liao Vivian
Department of Bioenvironmental Systems Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, 106, Taiwan.
Department of Bioenvironmental Systems Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, 106, Taiwan.
Chem Biol Interact. 2025 Jan 25;406:111349. doi: 10.1016/j.cbi.2024.111349. Epub 2024 Dec 13.
Aflatoxin B1 (AFB1), a known human carcinogen, represents the most toxic aflatoxin metabolite. Exposure to AFB1 causes increased oxidative stress and immunotoxicity, which are important factors contributing to aging. However, the role of AFB1-induced toxicity in altered innate immunity and aging remains largely unclear. The nematode Caenorhabditis elegans is a suitable model organism for studying aging and toxicology due to its well-studied molecular mechanisms and short life cycle. Effects of AFB1 at 1, 2.5, and 5 μM (312, 781, and 1561 μg/L) on growth, reproduction, and lifespan were examined. The Pseudomonas aeruginosa PA14 slow-killing assay was performed to investigate innate immunity, followed by studying the possible mechanisms using transgenic strains and qPCR analysis. The results showed that early life long-term AFB1 exposure (2.5 and 5 μM) delayed development, reduced reproduction, and shortened lifespan in C. elegans. Furthermore, in aged worms, AFB1 exposure caused a dose-dependent decrease in survival of C. elegans against P. aeruginosa PA14 infection. At adulthood day 4 in the presence of live Escherichia coli OP50, AFB1 (2.5 μM) significantly increased lipofuscin levels (a hallmark of aging) compared to adult day 0, whereas no increase in lipofuscin was observed in nematodes (adulthood day 4) fed with dead E. coli OP50. Additionally, the increased lipofuscin was abolished in the skn-1 mutant with either live or dead E. coli OP50. Furthermore, AFB1 suppressed intestinal SKN-1::GFP translocation. Two-way ANOVA analysis revealed that the activity of E. coli OP50 and AFB1 interactively affected the expression of genes: skn-1, gst-4, hsp-16.1, hsp-16.49, and hsp-70. Our findings highlight the role of AFB1-induced toxicity in altered innate immunity and aging through the involvement of the transcription factor SKN-1/Nrf2.
黄曲霉毒素B1（AFB1）是一种已知的人类致癌物，是毒性最强的黄曲霉毒素代谢产物。接触AFB1会导致氧化应激增加和免疫毒性，而这是导致衰老的重要因素。然而，AFB1诱导的毒性在改变固有免疫和衰老过程中的作用仍不清楚。秀丽隐杆线虫因其分子机制研究深入且生命周期短，是研究衰老和毒理学的合适模式生物。研究了1、2.5和5 μM（312、781和1561 μg/L）的AFB1对秀丽隐杆线虫生长、繁殖和寿命的影响。进行铜绿假单胞菌PA14慢杀试验以研究固有免疫，随后使用转基因菌株和qPCR分析研究可能的机制。结果表明，早期长期接触AFB1（2.5和5 μM）会延迟秀丽隐杆线虫的发育、减少繁殖并缩短寿命。此外，在老龄线虫中，接触AFB1会导致秀丽隐杆线虫抵抗铜绿假单胞菌PA14感染的存活率呈剂量依赖性下降。在成年第4天，存在活的大肠杆菌OP50时，与成年第0天相比，AFB1（2.5 μM）显著增加了脂褐素水平（衰老的一个标志），而在喂食死大肠杆菌OP50的线虫（成年第4天）中未观察到脂褐素增加。此外，在skn-1突变体中，无论喂食活的还是死的大肠杆菌OP50，增加的脂褐素都被消除。此外，AFB1抑制肠道SKN-1::GFP易位。双向方差分析显示，大肠杆菌OP50的活性和AFB1相互作用影响基因skn-1、gst-4、hsp-16.1、hsp-16.49和hsp-70的表达。我们的研究结果突出了AFB1诱导的毒性通过转录因子SKN-1/Nrf2参与改变固有免疫和衰老过程中的作用。
