Cui Fengzhen, Pan Qingfei, Wang Siyi, Zhao Faming, Wang Runxin, Zhang Tingting, Song Yaying, He Jun, Zhang Haolin, Weng Qiang, Jin Yang, Xia Wei, Li Yuanyuan, Yang Guo-Yuan, De Vos Winnok H, Timmermans Jean-Pierre, Xu Shunqing, Tang Yaohui, Sheng Xia
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.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Adv Sci (Weinh). 2021 Dec;8(23):e2102686. doi: 10.1002/advs.202102686. Epub 2021 Oct 28.
Benzophenones are widely supplemented in personal care products, but little is known about its neurodevelopmental toxicity. The previous epidemiological study discovered a negative correlation between maternal exposure to a benzophenone metabolite 4-hydroxybenzophenone (4HBP) and child's neurodevelopment, yet the causal relationship and detailed mechanism remain to be defined. Here, it is reported that prenatal, but not postnatal, exposure to environmentally relevant level of 4HBP impairs hippocampus development and causes cognitive dysfunction in offspring mice. Transcriptomic analyses reveal that 4HBP induces the endoplasmic reticulum stress-induced apoptotic signaling and inflammatory response in hippocampal neural stem cells. Mechanistically, 4HBP exposure activates protein kinase R-like ER kinase (PERK) signaling, which induces CHOP, inhibits IκB translation, and transactivates p65, thereby promoting inflammation and apoptosis on multiple levels. Importantly, genetic or pharmacological inhibition of PERK pathway significantly attenuates 4HBP-induced NFκB signaling and neurodevelopmental abnormalities in mice and in a human brain organoid model. The study uncovers the neurodevelopmental toxicity of BP and cautions its exposure during pregnancy.
二苯甲酮广泛添加于个人护理产品中，但其对神经发育的毒性却知之甚少。此前的流行病学研究发现，母亲接触二苯甲酮代谢物4-羟基二苯甲酮（4HBP）与儿童神经发育之间存在负相关，但因果关系和详细机制仍有待确定。在此，有报道称，产前而非产后暴露于环境相关水平的4HBP会损害子代小鼠的海马体发育并导致认知功能障碍。转录组分析表明，4HBP在海马神经干细胞中诱导内质网应激诱导的凋亡信号和炎症反应。从机制上讲，4HBP暴露激活蛋白激酶R样内质网激酶（PERK）信号，该信号诱导CHOP，抑制IκB翻译，并反式激活p65，从而在多个层面促进炎症和凋亡。重要的是，对PERK通路的基因或药理学抑制可显著减轻4HBP诱导的小鼠和人脑类器官模型中的NFκB信号和神经发育异常。该研究揭示了二苯甲酮的神经发育毒性，并警示孕期接触该物质的风险。
