Long Yun, Wang Yiwei, Song Zijing, He Xin, He Yisheng, Lin Ge
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
School of Medicine, The Chinese University of Hong Kong-Shenzhen, Shenzhen 518172, China.
Toxins (Basel). 2024 Dec 13;16(12):538. doi: 10.3390/toxins16120538.
Pyrrolizidine alkaloids (PAs) are common phytotoxins that are found worldwide. Upon hepatic metabolic activation, the reactive PA metabolites covalently bind to DNAs and form DNA adducts, causing mutagenicity and tumorigenicity in the liver. However, the molecular basis of the formation and removal of PA-derived DNA adducts remains largely unexplored. In the present study, Sprague Dawley (SD) rats were exposed to retrorsine (RTS), a representative PA, at a human-relevant dose of 3.3 mg/kg/day for 28 days. The rats were divided into three groups: control, RTS-28 (sacrificed after continuous RTS exposure), and RTS-161 (sacrificed at 133 days post-RTS-exposure). The multi-omics analyses demonstrated the involvement of homologous recombination (HR) and non-homologous end joining (NHEJ) repair pathways as a response to PA-induced DNA damage. Additionally, the characteristic guanine adducts induced by RTS exposure were in accordance with the higher expression of XPA and XPC, indicating that nucleotide excision repair (NER) and base excision repair (BER) also contributed to repairing RTS-induced DNA damage. Furthermore, we also showed that DNA damage persisted after PA exposure, and mutagenically related repair errors might occur due to the prolonged genotoxic effects. The present study lays the foundation for bridging PA-derived DNA adducts, DNA damage, DNA repair, and the follow-up mutagenesis and carcinogenesis associated with PA exposure.
吡咯里西啶生物碱（PAs）是常见的植物毒素，在全球范围内都有发现。经肝脏代谢激活后，具有反应活性的PA代谢产物与DNA共价结合并形成DNA加合物，从而在肝脏中引起致突变性和致癌性。然而，PA衍生的DNA加合物的形成和清除的分子基础在很大程度上仍未得到探索。在本研究中，将Sprague Dawley（SD）大鼠以与人类相关的剂量3.3 mg/kg/天暴露于代表性PA——倒千里光碱（RTS）中，持续28天。大鼠被分为三组：对照组、RTS - 28组（持续暴露于RTS后处死）和RTS - 161组（在暴露于RTS后133天处死）。多组学分析表明，同源重组（HR）和非同源末端连接（NHEJ）修复途径参与了对PA诱导的DNA损伤的反应。此外，RTS暴露诱导的特征性鸟嘌呤加合物与XPA和XPC的高表达一致，表明核苷酸切除修复（NER）和碱基切除修复（BER）也有助于修复RTS诱导的DNA损伤。此外，我们还表明，PA暴露后DNA损伤持续存在，并且由于长期的基因毒性作用可能会发生与诱变相关的修复错误。本研究为连接PA衍生的DNA加合物、DNA损伤、DNA修复以及与PA暴露相关的后续诱变和致癌作用奠定了基础。
