Bisphenol F exposure induces depression-like changes: Roles of the kynurenine metabolic pathway along the “liver-brain” axis

Bisphenol F (BPF), one of the major alternatives of Bisphenol A (BPA), is becoming extensively used in industrial production with great harm to human beings and environment. Recent studies have revealed that environmental exposure is crucial to the initiation and development of depression. Thereby, the aim the present study is to ascertain the correlationship between the BPF exposure and depression occurrence. In the current study, BPF strikingly triggered depression-like changes in mice through the sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST), accompanied by the perturbation of the kynurenine (KYN) metabolic pathway along the "liver-brain" axis. Mechanistically, the neurotransmitters from the tryptophan metabolic pathway were converted to the toxic KYN pathway after BPF treatment. With the ELISA assay, it revealed that the toxic KYN metabolites, including KYN and 3-hydroxykynurenine (3-HK), were strikingly increased in the mouse brains which was ascribed to the enhanced expression of the rate-limiting enzymes Indoleamine 2,3-dioxygenase (IDO1) and Kynurenine 3-monooxygenase (KMO) respectively. Interestingly, the increased brain KYN induced by BPF was also validated partially from the periphery, since the ELISA and western blotting results indicated the significantly increased KYN in the serum and L-type amino acid transporter 1 (LAT1) in the brain, the key transporter responsible for KYN and 3-HK crossing the blood-brain barrier. Intriguingly, the liver-derived KYN metabolic pathway was the important source of the peripheral KYN and 3-HK, as BPF substantially enhanced hepatic IDO1, Tryptophan, 2, 3-dioxygenase (TDO2), and KMO levels indicated by western blotting. This study is the first to delineate previously unrecognized BPF-induced depression by regulating the KYN metabolic pathway along the "liver-brain" axis; therefore, targeting LAT1 or hepatic KYN signaling may provide a potentially unique therapeutic intervention in BPF-induced depression.