Dey Koushik Kumar, Kamila Sreejata, Das Tanmoy, Chattopadhyay Ansuman
Department of Zoology, Toxicology and Cancer Biology Laboratory, Visva-Bharati, Santiniketan, West Bengal, 731235, India.
Biol Trace Elem Res. 2025 Jan 31. doi: 10.1007/s12011-025-04534-z.
Toxicity of lead (Pb) causes several health problems in human beings. The present study reveals the potential effects of Pb on adult zebrafish (Danio rerio) brain at an environmentally relevant concentration. Pb generated reactive oxygen species-mediated oxidative stress, as evidenced by alterations of GSH, MDA levels, and CAT activity. The Nrf2-Keap1 pathway counteracted this stress as a part of cytoprotection. The gene expression and immunolocalization studies confirmed the augmentation of Nrf2 in the brain. Activation of the Nrf2-Keap1 pathway influenced downstream nqo1 and ho1 gene expressions. The alterations in histopathology and mRNA expressions of biomarker genes like hsp70 and ache revealed the toxic insults of Pb in the brain. DNA damage assay verified the genotoxic potential of Pb. The expression pattern of the candidate genes of two critical repair pathways (base excision and mismatch repair) was studied to assess the DNA damage responses. The damages in DNA caused by 15 days of Pb exposure were sufficient to trigger the expression of BER (ogg1, apex1, polβ, and creb1) and MMR (msh2, msh6, and mlh1) genes to protect cells. Chronic exposure for 30 days suppressed both the machinery, predisposing mutations. The overexpression of crucial tumor suppressor genes p53 and brca2 indicated their protective role against cancer progression. Understanding the molecular mechanisms underlying Pb-induced neurotoxicity and the DNA damage response may help to improve our current knowledge for the prevention of Pb poisoning.
铅（Pb）的毒性会给人类带来多种健康问题。本研究揭示了在环境相关浓度下铅对成年斑马鱼（Danio rerio）大脑的潜在影响。铅产生的活性氧介导了氧化应激，谷胱甘肽（GSH）、丙二醛（MDA）水平及过氧化氢酶（CAT）活性的改变证明了这一点。核因子E2相关因子2（Nrf2）- Kelch样环氧氯丙烷相关蛋白1（Keap1）通路作为细胞保护的一部分抵消了这种应激。基因表达和免疫定位研究证实了大脑中Nrf2的增加。Nrf2 - Keap1通路的激活影响了下游醌氧化还原酶1（nqo1）和血红素加氧酶1（ho1）基因的表达。热休克蛋白70（hsp70）和乙酰胆碱酯酶（ache）等生物标志物基因的组织病理学和mRNA表达变化揭示了铅对大脑的毒性损伤。DNA损伤检测验证了铅的遗传毒性潜力。研究了两条关键修复途径（碱基切除修复和错配修复）候选基因的表达模式，以评估DNA损伤反应。暴露于铅15天导致的DNA损伤足以触发碱基切除修复（ogg1、apex1、polβ和creb1）和错配修复（msh2、msh6和mlh1）基因的表达以保护细胞。30天的慢性暴露抑制了这两种机制，增加了突变的易感性。关键肿瘤抑制基因p53和乳腺癌2号基因（brca2）的过表达表明它们对癌症进展具有保护作用。了解铅诱导神经毒性和DNA损伤反应的分子机制可能有助于增进我们目前对预防铅中毒的认识。
