Page 17 - 南京医科大学自然版

第46卷第7期 南京医科大学学报（自然科学版）
2026年7月 Journal of Nanjing Medical University（Natural Sciences） ·963 ·

·专题研究：神经精神疾病·

3⁃HK介导双酚F致小鼠抑郁的机制及亮氨酸的干预作用

吴宇轩 ，袁闻婕 ，卫一敏 ，范蕴文 ，刘见佳 ，王 军 1*
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南京医科大学公共卫生学院，第一临床医学院，江苏 南京 211166
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［摘 要］ 目的：探究犬尿氨酸（kynurenine，Kyn）代谢通路中的关键神经毒性代谢物3⁃羟基犬尿氨酸（3⁃hydroxy⁃kynurenine，
3⁃HK）在双酚F（bisphenol F，BPF）暴露引起小鼠抑郁样行为中的作用及机制，并评估亮氨酸干预该通路所产生的神经保护效
应，从而为寻找潜在干预靶点提供实验依据。方法：构建BPF暴露小鼠模型，通过悬尾实验、强迫游泳、旷场实验等行为学实验
观察小鼠抑郁样行为改变，检测小鼠海马体和前额皮层中3⁃HK、5⁃羟色胺（5⁃hydroxytryptamine，5⁃HT）、Kyn等抑郁相关神经递
质水平的改变以及干扰素⁃γ（interferon gamma，IFN⁃γ）、白介素⁃1β（interleukin⁃1β，IL⁃1β）等促炎因子和犬尿氨酸单加氧酶
（kynurenine⁃3⁃monooxygenase，KMO）表达水平的改变；设置亮氨酸联合干预组，观察BPF诱导的小鼠抑郁样行为是否改善，并检
测神经递质水平、促炎因子和KMO表达水平的变化；采用荧光探针法观察3⁃HK在BPF引起原代神经元活性氧（reactive oxygen
species，ROS）生成中的作用。结果：BPF暴露引起小鼠明显的抑郁样行为，小鼠海马和皮层中5⁃HT含量无明显变化，而Kyn含
量显著减少；BPF显著上调海马和皮层中KMO表达水平，促进3⁃HK的累积同时引发IFN⁃γ、IL⁃1β等促炎因子增加，加剧神经
损伤；亮氨酸干预后BPF诱导的小鼠抑郁样行为得到改善，显著逆转了BPF诱导的KMO及促炎因子的异常表达，3⁃HK水平显
著降低，其余神经递质水平变化不明显；同时，竞争性抑制3⁃HK转运或抑制KMO明显逆转BPF引起的ROS。结论：BPF暴露
可上调海马和皮层KMO表达，引起3⁃HK异常蓄积，继而触发ROS过度生成和神经炎症，这些病理变化可能协同参与神经损伤
和抑郁样行为。亮氨酸则能抑制该代谢偏移，减轻氧化应激与炎症，从而缓解抑郁样行为。
［关键词］ 双酚F；3⁃羟基犬尿氨酸；亮氨酸；抑郁；海马体；大脑皮层
［中图分类号］ R749 ［文献标志码］ A ［文章编号］ 1007⁃4368（2026）07⁃963⁃11
doi：10.7655/NYDXBNSN260263

The mechanism of 3 ⁃ hydroxykynurenine in the depression ⁃ like changes induced by
bisphenol F in mice and the intervention effect of leucine
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WU Yuxuan ，YUAN Wenjie ，WEI Yimin ，FAN Yunwen ，LIU Jianjia ，WANG Jun
School of Public Health，the First Clinical Medical College，Nanjing Medical University，Nanjing 211166，China
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［Abstract］ Objective：To explore the role and mechanism of 3⁃hydroxy⁃kynurenine（3⁃HK），a key neurotoxic metabolite in the
kynurenine pathway，in bisphenol F（BPF）⁃induced depressive⁃like changes in mice and evaluate the intervention effect of leucine by
intervening this pathway，thereby providing experimental evidence for identifying potential intervention targets. Methods：The BPF
exposure mouse model was established to investigate its neurotoxic effects，and the depression⁃like behaviors were assessed through
behavioral tests such as the tail⁃suspension test，forced swimming test，and open⁃field test. Concurrently，the levels of depression⁃
related neurotransmitters，including 3⁃HK，5⁃hydroxytryptamine（5⁃HT），and kynurenine were measured in the hippocampus and
prefrontalcortex.Alterationsintheexpressionlevelsofpro⁃inflammatorycytokines，includinginterferon⁃gamma（IFN⁃γ）and interleukin⁃1β
（IL⁃1β），as well as kynurenine 3⁃monooxygenase（KMO），were also detected. Furthermore，a leucine combined intervention group was
established to assess whether BPF ⁃ induced depression ⁃ like behaviors improved，with additional measurements of neurotransmitter
levels，pro⁃inflammatory factors，and KMO expression. The role of 3⁃HK in BPF⁃induced reactive oxygen species（ROS）generation in
primary neurons was investigated using a fluorescent probe assay. Results：BPF exposure induced depressive⁃like behaviors in mice.
While 5⁃HT levels in the hippocampus and cortex showed no significant change，the content of kynurenine was markedly reduced. BPF
exposure significantly increased the expression levels of KMO in the hippocampus and cortex，and promoted the accumulation of 3⁃HK，

［基金项目］ 国家自然科学基金（82473684）；国家级大学生创新训练计划（202310312025Z，202410312069Z）
通信作者（Corresponding author），E⁃mail：wangjun@njmu.edu.cn（ORCID：0000⁃0002⁃6120⁃6075）
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