6-氯烟酸通过C3ar1信号诱导小鼠神经干细胞毒性

IF 2.7 4区 医学 Q3 TOXICOLOGY
Min He, Yahang Lin, Xiaojing Zhang, Siyi Wang, Xinyu Yang, Fengzhen Cui, Xia Sheng
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引用次数: 0

摘要

神经干细胞(NSCs)由于其增殖和分化为各种神经细胞类型的能力,对大脑发育至关重要。新烟碱类杀虫剂(NNIs)已取代传统农药,在环境和生物样品中被广泛使用和检测。产前暴露于NNIs与后代神经发育障碍的风险增加有关,但其因果关系和基本机制仍有待澄清。6-氯烟酸(6-ClNA)作为氯吡啶类新烟碱的主要代谢物之一,已被确定为一种潜在的神经毒素,但其对神经干细胞的影响尚未得到充分的研究。在这里,我们证明了6-ClNA暴露显著破坏了NSC的体外增殖和分化。转录组学分析显示,6-ClNA改变了与增殖、凋亡和炎症相关的通路的表达,并显著激活了C3ar1/C1qa信号轴。使用siRNA基因消融C3ar1可显著恢复NSC增殖和神经球形成,并减少细胞凋亡,提示C3ar1/C1qa在介导6-ClNA的神经毒性作用中发挥核心作用。这些发现表明,早期暴露于NNIs可能会影响NSCs的适应性和功能,其中C3ar1通路起着不可或缺的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
6-Chloronicotinic Acid Induces Toxicity in Mouse Neural Stem Cells via the C3ar1 Signaling

Neural stem cells (NSCs) are essential for brain development due to their ability to proliferate and differentiate into various neural cell types. Neonicotinoid insecticides (NNIs), which have replaced traditional pesticides, are now widely used and frequently detected in environmental and biological samples. Prenatal exposure to NNIs has been associated with an increased risk of neurodevelopmental disorders in offspring, yet the causal relationship and the underpinning mechanism remain to be clarified. As one of the primary metabolites of chloropyridinyl neonicotinoids, 6-chloronicotinic acid (6-ClNA) has been identified as a potential neurotoxin, though its effects on NSCs have not been fully explored. Here, we demonstrate that 6-ClNA exposure significantly disrupted NSC proliferation and differentiation in vitro. Transcriptomic analyses revealed that 6-ClNA altered the expression of pathways related to proliferation, apoptosis, and inflammation, with notable activation of the C3ar1/C1qa signaling axis. Genetic ablation of C3ar1 using siRNA markedly restored NSC proliferation and neurosphere formation, as well as reduced apoptosis, suggesting a central role of C3ar1/C1qa in mediating 6-ClNA's neurotoxic effects. These findings imply that early-life exposure to NNIs may affect the fitness and function of NSCs, wherein the C3ar1 pathway plays an indispensable role.

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来源期刊
CiteScore
7.00
自引率
6.10%
发文量
145
审稿时长
1 months
期刊介绍: Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.
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