稀土掺杂上转换纳米颗粒（Ln-UCNP）被认为是生物医学和工业应用等各个领域有前景的材料。然而，有关其毒性和环境风险的数据和报告很少。在这些情况下，必须获得数据以充分了解潜在的毒性和不良结果途径。在本研究中，系统评估了早期发育阶段斑马鱼胚胎中未包被的 Ln-UCNP 核（NaYF4:Yb、Er）的毒性。研究发现 Ln-UCNP 具有多种毒性作用，例如对存活率的影响、延迟孵化时间、缩短体长、改变心率和血液循环（显着减少）以及响应光周期刺激的神经行为损伤。生物成像显示，72 hpf 时，Ln-UCNP 分布在绒毛膜、眼睛和皮肤上。然而，口服后会在咽、食道和肠道中蓄积。 Ln-UCNP 会破坏宿主相关微生物（肠道微生物群）的多样性和丰度，导致斑马鱼中有害细菌的流行率增加。转录组学和独创性通路分析 (IPA) 预测白细胞介素 8 (IL-8) 信号传导、神经炎症、心脏肥大信号传导通路、免疫和炎症相关反应干扰素-γ (ifnγ) 和 miR-155 作为调节作用的关键介质。在此基础上，建立了一个因果网络，显示差异表达基因（DEG）的诱导基因表达之间存在密切联系，例如 Ln-UCNPs 处理后的一氧化氮合酶 2（nos2）和肿瘤坏死因子（tnf）下游不良后果，特别是促进细胞凋亡、肝损伤和炎症反应。最后，RT-qPCR 分析证实了暴露幼虫中 nos2 和 tnf 的表达上调，这与 lyz: DsRed 转基因斑马鱼暴露 120 hpf 时荧光标记的中性粒细胞和巨噬细胞数量增加的观察结果一致，这共同证明了Ln-UCNPs 对生物体的促炎作用。总之，我们说明了 Ln-UCNP 核心对斑马鱼的发育毒性、肠道微生物组破坏和促炎作用，IPA 分析的因果网络可能有助于进一步阐明 Ln-UCNP 的不良后果途径。版权所有 © 2024作者。由爱思唯尔公司出版。保留所有权利。

Lanthanide-doped upconversion nanoparticles (Ln-UCNPs) have been considered promising materials for various fields, such as biomedical and industrial applications. However, data and reports regarding its toxicity and environmental risks are scarce. Under these circumstances, data must be obtained to fully understand potential toxicity and adverse outcome pathways. In the present study, the toxicity of uncoated Ln-UCNP cores (NaYF4:Yb, Er) was systematically assessed in zebrafish embryos during early developmental stages. Ln-UCNPs were found to have multiple toxic effects, such as effects on survival rates, delayed hatching times, shorter body lengths, altered heart rates and blood circulation (significantly reduced), and neurobehavioral impairments in response to photoperiod stimulation. Bioimaging showed that Ln-UCNPs were distributed on the chorion, eyes, and skin at 72 hpf. However, it accumulates in the pharynx, esophagus, and intestine after oral administration. Ln-UCNPs disrupt the diversity and abundance of host-associated microorganisms (gut microbiota) leading to an increase in the prevalence of harmful bacteria in zebrafish. Transcriptomic and Ingenuity Pathway Analysis (IPA) predicted Interleukin-8 (IL-8) signaling, neuroinflammation, cardiac hypertrophy signaling pathways, immune and inflammation-related response interferon-gamma (ifnγ), and miR-155 as key mediators in regulatory effects. Based on this, a causal network was built showing the strong links between the induced gene expression of differentially expressed genes (DEGs), such as nitric oxide synthase 2 (nos2) and tumor necrosis factor (tnf) upon Ln-UCNPs treatment, and with the downstream adverse outcomes, in particular, the promotion of apoptosis, liver damage, and inflammatory response. Finally, RT-qPCR analysis confirmed the up-regulated expression of nos2 and tnf in the exposed larvae, consistent with the observation of an increased number of fluorescence-labelled neutrophils and macrophages in lyz: DsRed transgenic zebrafish until 120 hpf exposure, which together demonstrated the proinflammatory effects of Ln-UCNPs on organisms. In conclusion, we illustrated the developmental toxicity, disruption of gut-microbiome, and proinflammatory effects of Ln-UCNP cores on zebrafish, and the causal network from IPA analysis may help further elucidate the adverse outcome pathway of Ln-UCNPs.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.