In Vitro Metabolic Kinetics Characteristic And Thyroid Disruption Effects Of Organophosphate Esters In Fish

Organophosphorus flame retardants(OPFRs),as a new type of flame retardant,are physically added to a variety of products,such as furniture,textiles,and electronic products.In recent years,organophosphate esters(OPEs),one of the main chemicals of OPFRs,have been increasing application of OPEs in the flame retardant market.The higher detectable quantity of OPEs was detected in environmental medium,and toxicity effects and ecological risk were gradually appeared.Numerous studies have shown that most OPEs can induce the developmental and reproductive toxicity,neurotoxicity,organ toxicity,and endocrine disruption effecys on aquatic organisms.These OPEs also have the characteristics of bioaccumulation and biomagnification.However,the current research on the toxicity mechanism of operators is still exhausted and unclear,which severely restricts the water quality criteria and ecological risk assessment of aquatic organisms of OPEs.Therefore,three types of OPEs as the target targets were selected to study in vitro metabolic kinetics and thyroid endocrine disrupting effects on aquatic organism.These results were as follows:(1)This study conducted a systematic analysis of the three toxic effects of twelve OPEs,and proposed an adverse outcome pathway(AOP)of different toxicity effects caused by OPEs in aquatic organisms(zebrafish,Chinese rare minnow and Japanese medaka).Through molecular initiation events(MIEs),key events(KEs)and adverse outcomes(AOs),AOP can organically arrange the existing OPEs toxic effect mechanisms and toxicity endpoint,and provide a theoretical basis for subsequent health hazards and ecological risk assessments of OPEs.(2)A typical cresyl diphenyl phosphate(CDP)was selected to carry out in vitro metabolic kinetics in crucian carp liver microsomes.The results showed that the metabolism was consistent with Michaelis-Menten model.It is best to accurately calculate the corresponding metabolic rate V_max=12700±2120 pmol·min^-1·mg^-1protein,in vitro liver clearance C_Lint=12.3?L·min^-1·mg^-1 protein and Michaelis-Menten constant K_m=1030±212?mol·L^-1.The V_max and C_Lint values of CDP(and the same aryl triphenyl phosphate(TPHP))are greater than alkyl and chlorinated OPEs,which may be related to the higher log K_OW and bioconcentration factors(BCFs)of aryl-OPEs.(3)Tris(isopropyl)phosphate(TIPP),CDP,and tris(2-chloroisopropyl)phosphate(TCIPP)were selected to analyze the biological treatment of zebrafish after 28d of exposure and molecular docking.The results have showed that OPEs can be combined with thyroxine-binding globulin(TBG)and transthyretin(TTR)to be transported in the body and cause the thyroid hormone receptor binding process,thyroid development process,thyroid hormone transmembrane transporter activity,gonadal development,cell differentiation,neuroactive ligand-receptor interaction and MAPK signaling pathway and other signal pathways,which leads to zebrafish growth inhibition.