Serum Metabolomic Profiles in Neonatal Mice following Oral Brominated Flame Retardant Exposures to Hexabromocyclododecane (HBCD) Alpha, Gamma, and Commercial Mixture

BACKGROUND: Hexabromocyclododecane (HBCD) is a high production volume brominated flame retardant added to building insulation foams, electronics, and textiles. HBCD is a commercial mixture (CM-HBCD) composed of three main stereoisomers: alpha-HBCD (10%), alpha-HBCD (10%), and gamma-HBCD (80%). A shift from the dominant stereoisomer gamma-HBCD to alpha-HBCD is detected in humans and wildlife. OBJECTIVES: Considering CM-HBCD has been implicated in neurodevelopment and endocrine disruption, with expected metabolism perturbations, we performed metabolomics on mice serum obtained during a window-of-developmental neurotoxicity to draw correlations between early-life exposures and developmental outcomes and to predict health risks. METHODS: Six female C57BL/6 mice at postnatal day (PND) 10 were administered a single gavage dose of alpha-, gamma-, or CM-HBCD at 3, 10, and 30 mg/kg. Nuclear magnetic resonance metabolomics was used to analyze 60 mu L serum aliquots of blood collected 4 days post-oral exposure. RESULTS: Infantile mice exposed to alpha-, gamma-, or CM-HBCD demonstrated differences in endogenous metabolites by treatment and dose groups, including metabolites involved in glycolysis, gluconeogenesis, lipid metabolism, citric acid cycle, and neurodevelopment. Ketone bodies, 3-hydroxybutyrate, and acetoacetate, were nonstatistically elevated, when compared with mean control levels, in all treatment and dose groups, while glucose, pyruvate, and alanine varied. Acetoacetate was significantly increased in the 10 mg/kg alpha-HBCD and was nonsignificantly decreased with CM-HBCD. A third ketone body, acetone, was significantly lower in the 30 mg/kg alpha-HBCD group with significant increases in pyruvate at the same treatment and dose group. Metabolites significant in differentiating treatment and dose groups were also identified, including decreases in amino acids glutamate (excitatory neurotransmitter in learning and memory) and phenylalanine (neurotransmitter precursor) after alpha-HBCD and gamma-HBCD exposure, respectively. CONCLUSIONS: We demonstrated that 4 days following a single neonatal oral exposure to alpha-, gamma-, and CM-HBCD resulted in different serum metabolomic profiles, indicating stereoisomer-and mixture-specific effects and possible mechanisms of action.