Department of Neurology, Wuhan Fourth Hospital/Pu'ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China.
Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Toxicol In Vitro. 2022 Aug;82:105367. doi: 10.1016/j.tiv.2022.105367. Epub 2022 Apr 25.
Benzophenones are widely used in industry and commonly added in many personal care products. However, the neurotoxicity, in particular neurodevelopmental toxicity, of benzophenone family chemicals and metabolites has not been fully elucidated. Our recent mechanistic study in mice showed that early life exposure to a major benzophenone metabolite, 4-hydroxybenzophenone (4HBP), disrupted endoplasmic reticulum (ER) proteostasis and evoked inflammatory response in hippocampal neural stem cells (NSCs), leading to cognitive dysfunction. Despite so, detailed inflammatory cytokine(s) that possibly mediate this toxicity remains to be defined and validated. In this study, we confirmed that 4HBP treatment inhibited the viability and sphere growth of mouse NSCs in vitro. Importantly, re-interrogation of the transcriptomic data of NSCs treated with 4HBP identified the top upregulated genes, wherein the chemokine Cxcl1 ranked first. Immunofluorescent staining and qRT-PCR validated the robust induction of Cxcl1 on the protein and mRNA levels upon 4HBP treatment. Furthermore, siRNA-mediated knockdown of Cxcl1 transiently blocked its expression and led to enhanced NSCs viability in the presence of 4HBP. Together, these in vitro results indicated that the adverse effect of benzophenones on NSCs is mediated, at least in part, by induction of the chemokine Cxcl1.
二苯甲酮类广泛应用于工业生产，也普遍添加于多种个人护理产品中。然而，二苯甲酮类化学物质及其代谢物的神经毒性，特别是神经发育毒性，尚未得到充分阐明。我们最近在小鼠身上进行的一项机制研究表明，生命早期接触一种主要的二苯甲酮代谢物 4-羟基二苯甲酮（4HBP），会破坏内质网（ER）的蛋白质平衡，并在海马神经干细胞（NSCs）中引发炎症反应，导致认知功能障碍。尽管如此，可能介导这种毒性的详细炎症细胞因子仍有待确定和验证。在这项研究中，我们证实 4HBP 处理会抑制体外培养的小鼠 NSCs 的活力和球体生长。重要的是，对用 4HBP 处理的 NSCs 的转录组数据进行重新分析，确定了上调最显著的基因，其中趋化因子 Cxcl1 排名第一。免疫荧光染色和 qRT-PCR 验证了 4HBP 处理后 Cxcl1 在蛋白和 mRNA 水平上的强烈诱导。此外，siRNA 介导的 Cxcl1 敲低可暂时阻断其表达，并在存在 4HBP 的情况下增强 NSCs 的活力。这些体外结果表明，二苯甲酮类对 NSCs 的不良影响至少部分是通过诱导趋化因子 Cxcl1 介导的。
