Zhejiang Police College, Zhejiang Key Laboratory of Drug Prevention and Control Technology, Hangzhou 310053, PR China.
College of Environment, Zhejiang University of Technology, Hangzhou 310014, PR China.
Ecotoxicol Environ Saf. 2024 Sep 15;283:116969. doi: 10.1016/j.ecoenv.2024.116969. Epub 2024 Aug 30.
Novel Psychoactive Substances (NPS) derived from tryptamines has been detected in aquatic environments, leading to environmental toxicology concerns. However, the specific toxicological mechanism, underlying these NPS, remains unclear. In our previous work, we used 5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT) as the representative drug for NPS, and found that, 5-MeO-MiPT led to obvious behavioral inhibition and oxidative stress responses in zebrafishes model. In this study, Zebrafish were injected with varying concentrations of 5-MeO-MiPT for 30 days. RNA-seq, qPCR, metabolomics, and histopathological analyses were conducted to assess gene expression and tissue integrity. This study confirms that 5-MeO-MiPT substantially influences the transcription and expression of 13 selected genes, including ucp1, pet100, grik3, and grik4, mediated by the Gα-PLC signaling pathway. We elucidate the molecular mechanism that 5-MeO-MiPT can inhibit DAG-Ca/Pkc/Erk, Pkc/Pla2/PLCs and Ca/Camk Ⅱ/NMDA, while enhance Ca/Creb. Those secondary signaling pathways may be the mechanisms mediating 5-MeO-MiPT inhibiting normal behavior in zebrafish. These findings offer novel insights into the toxicological effects and addiction mechanisms of 5-MeO-MiPT. Moreover, it presents promising avenues for investigating other tryptamine-based NPS and offers a new direction for diagnosing and treating liver-brain pathway-related diseases.
新型精神活性物质（NPS）来源于色胺，已在水生环境中被检测到，引发了环境毒理学方面的担忧。然而，这些 NPS 的具体毒理学机制仍不清楚。在我们之前的工作中，我们使用 5-甲氧基-N-异丙基-N-甲基色胺（5-MeO-MiPT）作为 NPS 的代表性药物，发现 5-MeO-MiPT 会导致斑马鱼模型出现明显的行为抑制和氧化应激反应。在这项研究中，我们用不同浓度的 5-MeO-MiPT 对斑马鱼进行了 30 天的注射。进行了 RNA-seq、qPCR、代谢组学和组织病理学分析，以评估基因表达和组织完整性。这项研究证实，5-MeO-MiPT 通过 Gα-PLC 信号通路，显著影响了 13 个选定基因的转录和表达，包括 ucp1、pet100、grik3 和 grik4。我们阐明了 5-MeO-MiPT 抑制 DAG-Ca/Pkc/Erk、Pkc/Pla2/PLCs 和 Ca/Camk Ⅱ/NMDA，同时增强 Ca/Creb 的分子机制。这些次级信号通路可能是介导 5-MeO-MiPT 抑制斑马鱼正常行为的机制。这些发现为 5-MeO-MiPT 的毒理学效应和成瘾机制提供了新的见解。此外，它为研究其他基于色胺的 NPS 提供了有前景的途径，并为诊断和治疗与肝脑途径相关的疾病提供了新的方向。
