Dibromoacetonitrile mediated depression-like behavior in mice and induced HT22 cytotoxicity through the MKP-1/P38 MAPK signaling pathway and the antagonistic effect of N-acetylcysteine

Abstract

Environmental pollutants are an important cause of depression. Dibromoacetonitrile (DBAN) is a disinfection by-product, which is neurotoxic and induces oxidative stress. This study aimed to elucidate whether and how DBAN provoked depression-like behavior. Mitogen-activated protein kinase phosphatase-1 (MKP-1) and P38 mitogen-activated protein kinase (MAPK) are key factors in depression. In mice, 8-week gavage with 20 mg/kg DBAN caused depressive symptoms, serotonin (5-HT) loss, hippocampal neuronal damage, and elevated MKP-1/P38 MAPK signaling; 80 mg/kg proved lethal. DBAN disturbed the intestinal flora of mice. Depression-related bacteria Firmicutes increased. Bacteroidota showed a decreasing trend, and the relative abundance of Bifidobacterium also showed a decreasing trend. Co-treatment with antioxidant N-acetylcysteine (NAC, 150 mg/kg) prevented mortality, restored 5-HT and norepinephrine, normalized MKP-1/P38 phosphorylation, and alleviated behavioral deficits. 10 μM DBAN raised reactive oxygen species (ROS), upregulated MKP-1, increased the phosphorylation levels of P38 and c-Jun amino-terminal kinase (JNK), and decreased the phosphorylation levels of the extracellular signal-regulated kinase (ERK1/2) in HT22 cells. Following HT22 cell MKP-1 knockdown and DBAN exposure, HT22 cells exhibited decreased MKP-1 expression along with decreased P38 and JNK phosphorylation levels. Still, the levels of ERK1/2 phosphorylation were not significantly affected. NAC exerts a prophylactic protective effect against these adverse outcomes.