Pollutant–Diet Interactions Drive Distinct Mechanisms of Tetrabromobisphenol A-Induced Hepatic Insulin Resistance in Zebrafish

Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, bioaccumulates in the liver and disrupts glucolipid homeostasis, yet its diet-dependent metabolic effects remain unclear. This study investigated how differing dietary fat levels modulate TBBPA-induced hepatic disturbances. Adult zebrafish were exposed to environmentally relevant concentrations of TBBPA (10 and 100 nM) for 4 weeks under normal-fat (6% crude fat) or high-fat (24% crude fat) diets. Morphological and biochemical assessments, combined with integrated metabolomic and transcriptomic analyses, revealed distinct diet-specific mechanisms. Under normal-fat conditions, TBBPA activated the <i>akt-foxo1</i> and <i>prkcz-srebf1</i> axes, enhancing gluconeogenesis and lipogenesis and inducing selective hepatic insulin resistance manifested by hyperglycemia, hyperinsulinemia, and adiposity. Conversely, under high-fat conditions, TBBPA decreased IRS1 abundance and phosphorylation, suppressing insulin signaling and leading to complete hepatic insulin resistance with hyperglycemia, reduced lipid deposition, and body-weight loss. These findings demonstrate that the dietary fat content critically shapes TBBPA-induced metabolic toxicity and highlight the need to incorporate nutritional status into the health-risk assessment of brominated flame retardants.