Chlorine disinfection byproduct of diazepam affects nervous system function and possesses gender-related difference in zebrafish

Abstract

Chlorinated disinfection byproducts in water posed potential health threat to humans. Nowadays, chlorinated derivatives of diazepam were ubiquitously detected in drinking water. Among these derivatives, 2-methylamino-5-chlorobenzophenone (MACB) was capable of penetrating the blood-brain barrier (BBB) and induced microglial phagocytosis of neurons in zebrafish. However, little is known about the MACB metabolism in vivo. Here, we determined the metabolism of MACB in zebrafish and microglia cell model. We found that MACB mainly disrupted the metabolism of branched-chain amino acids (Leu, Ile and Val) in zebrafish model and gamma-aminobutyric acid (GABA) pathway-related amino acids in microglia model. Additionally, we demonstrated that MACB can be metabolized by the mixed-function oxidase CYP1A2 enzyme which could be inhibited by estrogen causing the gender-difference in the accumulation of MACB in vivo. These results indicated that MACB perturbed metabolism and induced neurological disorders, particularly in the female zebrafish.

Keywords

• 2-methylamino-5-chlorobenzophenone
• Zebrafish
• Gender-related difference
• CYP1A2