Developmental and Neurobehavioral Toxicity of Tetrabromobisphenol A Mono(2-hydroxyethyl) Ether (TBBPA-MHEE) in Zebrafish Larvae: Oxidative/Inflammatory Responses and Candidate ErbB-Related Signaling

Tetrabromobisphenol A mono(2-hydroxyethyl) ether (TBBPA-MHEE) is an important byproduct during the production of tetrabromobisphenol A (TBBPA) and its related derivatives. Although it has been detected in aquatic environments, its in vivo developmental toxicity and underlying mechanisms remain poorly understood. In this study, zebrafish were used as a model organism to evaluate the early developmental toxicity, neurobehavioral toxicity, and candidate molecular responses associated with TBBPA-MHEE. The 96 h median lethal concentration (96 h-LC50) of TBBPA-MHEE for zebrafish embryos/larvae was 1.684 mg/L. Sublethal nominal exposure concentrations (2, 20, and 200 μg/L) caused developmental abnormalities, including reduced body length, pericardial edema, impaired swim bladder development, and significantly inhibited spontaneous motor activity as well as the response to light–dark transition and mechanical stimulation. Transgenic reporter assays further showed shortened motor neuron projections, reduced brain-region fluorescence in Tg(gad1b:mCherry) larvae, and downregulated the expression of neurodevelopment-related genes. Network toxicology analysis suggested that MTOR, SRC, MAPK3, and GSK3B were identified as candidate targets potentially associated with TBBPA-MHEE-induced neurotoxicity, with significant enrichment of the ErbB signaling pathway and possible perturbation of PI3K/Akt/mTOR-related responses. In addition, TBBPA-MHEE exposure increased the accumulation of reactive oxygen species (ROS) in the larval brain and induced inflammatory and apoptotic responses. Quercetin intervention partially alleviated ROS accumulation and inflammation and improved the developmental and motor phenotypes. Collectively, these findings indicate that TBBPA-MHEE induces neurodevelopmental toxicity in zebrafish, possibly associated with altered transcriptional responses related to ErbB signaling and the PI3K/Akt/mTOR axis, accompanied by oxidative stress, inflammatory responses, and apoptosis-related events. Because exposure concentrations were not analytically verified, all treatment levels are reported as nominal concentrations. This study provides experimental evidence for the toxicological assessment and environmental risk evaluation of TBBPA derivative pollutants.