2. Academic Validation
  3. 3-hydroxykynurenine increase in kynurenine pathway driven bisphenol F induced anxiety- and depression-like behaviors

3-hydroxykynurenine increase in kynurenine pathway driven bisphenol F induced anxiety- and depression-like behaviors

  • Sci Total Environ. 2025 Sep 15:995:180073. doi: 10.1016/j.scitotenv.2025.180073.
Yuxin Lin 1,  Luyao Wang 1,  Sining Meng 2,  Jianjia Liu 3,  Xinyu Li 1,  Wenjuan Wang 4,  Miaoyang Hu 1,  Xi Wang 1,  Weixia Duan 5,  Shangcheng Xu 6,  Jun Wang 7,  Rong Gao 8
Affiliations

Affiliations

  • 1 Center for Global Health, the Key Laboratory of Modern Toxicology, Ministry of Education, Department of Hygienic Analysis and Detection, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 2 Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
  • 3 Department of Medical Laboratory, the First Clinical School of Nanjing Medical University, Nanjing 211166, China.
  • 4 The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, China.
  • 5 Center of Laboratory Medicine, Chongqing Prevention and Treatment Center for Occupational Diseases, Chongqing 400060, China.
  • 6 Center of Laboratory Medicine, Chongqing Prevention and Treatment Center for Occupational Diseases, Chongqing 400060, China. Electronic address: xushangchengmito@163.com.
  • 7 Center for Global Health, the Key Laboratory of Modern Toxicology, Ministry of Education, Department of Toxicology, School of Public Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: wangjun@njmu.edu.cn.
  • 8 Center for Global Health, the Key Laboratory of Modern Toxicology, Ministry of Education, Department of Hygienic Analysis and Detection, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: gaorong@njmu.edu.cn.
PMID: 40695220 DOI: 10.1016/j.scitotenv.2025.180073
Abstract

Bisphenol F (BPF), one of the major substitutes for bisphenol A (BPA), is increasingly used in pharmaceuticals, food packaging, and chemical manufacturing. Emerging evidence suggests its potential neuropsychiatric risks. However, the underlying mechanisms remain poorly characterized. Thus, the present study was performed to investigate the roles of the kynurenine (KYN) pathway in BPF induced anxiety- and depression-like behaviors, especially the keys roles of the toxic metabolite 3-hydroxykynurenine (3-HK). The mice were administrated with BPF (10, 40, 160 μg/kg/day) for 30 consecutive days, and the behaviors as well as the changes of the KYN pathway were examined. Noteworthily, even low-dose of BPF exposure (40 μg/kg/day) elicited pronounced anxiety- and depression-like behaviors, molecularly shown as the synaptic marker proteins (PSD95, SYN) and dendritic spine proteins (Drebrin) loss in the prefrontal cortex and hippocampus, along with impaired synaptic connection. The UHPLC-MS/MS metabolomic profiling revealed the aberrant metabolism of the KYN pathway, as shown by the elevated neurotoxic metabolite 3-HK and decreased neuroprotective metabolite kynurenic acid (KynA). Mechanistic analyses demonstrated that the 3-HK rate-limiting enzyme KMO was upregulated while the KynA rate-limiting enzyme KAT2 was downregulated in mouse brain. Notably, pharmalogical inhibition of KMO (GSK180) or blockage kynurenine generation with the TDO2 inhibitor (680C91) substantially ameliorated the BPF induced anxiety- and depression-like behaviors and synaptic impairments. Collectively, the present study unravels a previously unrecognized the BPF induced anxiety- and depression-like behaviors in mice via KMO and 3-HK increase. Therefore, targeting the KMO may provide novel interventive strategy for BPF induced neurobehavioral disorders.

Keywords

3-hydroxykynurenine; Bisphenol F; Depression and anxiety; Kynurenine metabolism.

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