Tetrabromobisphenol A Induces Neurotoxicity in Adult Zebrafish: Insights from the Gut Microbiota-Bile Acid-Brain Axis
Xinxin Ren, Zhixiang Xu, Yongyong Guo, Taotao Zhang, Bingjie Li, Jun Men, Jian Han, Lihua Yang, Yuxi Zhou, Bingsheng Zhou
Abstract
Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, has been reported to have neurotoxicity and risks in inducing obesity. However, the underlying mechanisms remain incompletely understood, especially with respect to diet-induced susceptibility. In this study, we systematically investigated the neurotoxic effects of environmentally relevant TBBPA exposure in adult zebrafish under both normal-diet (ND) and high-fat-diet (HFD) conditions. Behavioral assessment and histopathology revealed that TBBPA induced pronounced anxiety-like behaviors and neuronal damage, with the HFD markedly augmenting these effects. Integrated multiomics analysis demonstrated that TBBPA exposure alters gut microbial composition, leading to substantial dysbiosis and a profound reduction of glycodeoxycholic acid (GDCA), a key secondary bile acid mediating gut-brain communication. Additionally, TBBPA induces mitochondrial dysfunction and activates inflammasome-mediated neuroinflammatory pathways in the brain. Notably, dietary GDCA supplementation effectively rescued TBBPA-induced behavioral deficits, mitochondrial dysfunction, and neuroinflammation. To our knowledge, this study is the first to delineate a diet-dependent gut microbiota-bile acid-brain axis as a critical mediator of TBBPA-induced neurotoxicity, highlighting the significance of bile acid metabolism and the diet factor in maintaining neurophysiological homeostasis. These findings reveal a novel mechanism underlying brominated flame retardant neurotoxicity, providing new insights into environmental health risk assessment of other environmental pollutants.