Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
China National Center for Food Safety Risk Assessment, No. 37, Guangqu Road, Chaoyang District, Beijing 100022, China.
Toxicol Appl Pharmacol. 2024 Oct;491:117050. doi: 10.1016/j.taap.2024.117050. Epub 2024 Aug 5.
Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant posing various toxicity effects on organisms. Previous studies demonstrated that BaP could induce hepatotoxicity, while the underlying mechanism remains incompletely elucidated. In this study, a comprehensive strategy including network toxicology, transcriptomics and gut microbiomics was applied to investigate the hepatotoxicity and the associated mechanism of BaP exposure in mice. The results showed that BaP induced liver damage, liver oxidative stress and hepatic lipid metabolism disorder. Mechanistically, BaP may disrupt hepatic lipid metabolism through increasing the uptake of free fatty acid (FFA), promoting the synthesis of FA and triglyceride (TG) in the liver and suppressing lipid synthesis in white adipose tissue. Moreover, integrated network toxicology and hepatic transcriptomics revealed that BaP induced hepatotoxicity by acting on several core targets, such as signal transducer and activator of transcription 1 (STAT1), C-X-C motif chemokine ligand 10 (CXCL10) and toll-like receptor 2 (TLR2). Further analysis suggested that BaP inhibited JAK2-STAT3 signaling pathway, as supported by molecular docking and western blot. The 16S rRNA sequencing showed that BaP changed the composition of gut microbiota which may link to the hepatotoxicity based on the correlation analysis. Taken together, this study demonstrated that BaP caused liver injury, hepatic lipid metabolism disorder and gut microbiota dysbiosis, providing novel insights into the hepatotoxic mechanism induced by BaP exposure.
苯并[a]芘（BaP）是一种普遍存在的环境污染物，对生物体具有多种毒性作用。先前的研究表明，BaP 可诱导肝毒性，但其潜在机制尚不完全阐明。在这项研究中，采用了包括网络毒理学、转录组学和肠道微生物组学在内的综合策略，来研究 BaP 暴露对小鼠的肝毒性及其相关机制。结果表明，BaP 可诱导肝损伤、肝氧化应激和肝脂代谢紊乱。从机制上讲，BaP 可能通过增加游离脂肪酸（FFA）的摄取、促进肝脏中 FA 和甘油三酯（TG）的合成以及抑制白色脂肪组织中的脂质合成来破坏肝脂代谢。此外，整合的网络毒理学和肝转录组学研究表明，BaP 通过作用于几个核心靶标（如信号转导和转录激活因子 1（STAT1）、C-X-C 基序趋化因子配体 10（CXCL10）和 Toll 样受体 2（TLR2））来诱导肝毒性。进一步的分析表明，BaP 抑制了 JAK2-STAT3 信号通路，这一结果得到了分子对接和 Western blot 的支持。16S rRNA 测序显示，BaP 改变了肠道微生物组的组成，基于相关性分析，这可能与肝毒性有关。综上所述，本研究表明，BaP 可导致肝损伤、肝脂代谢紊乱和肠道微生物组失调，为 BaP 暴露诱导的肝毒性机制提供了新的见解。
