Accumulation,Transformation And Toxicity Mechanism Of Tris(1,3-dichloro-2-propyl)phosphate(TDCIPP)in Mice

Organophosphorus flame retardants(OPFRs)constitute a group of synthetic chemicals which are widely used in foams,plastics,textiles and furniture,and now have been frequently detected in environmental and human samples around the world.Increasing evidences showed that OPFRs have biologically toxicities,rising an emerging concern about their health risk of chronic exposure.Previous studies on OPFRs bioaccumulation,biotransformation and toxicology mostly used aquatic organisms as model organisms,while studies in mammals were extremely scarce.In the present study,the bioaccumulation,biotransformation and toxicology of tris(1,3-dichloro-2-propyl)phosphate(TDCIPP),one of the most widely-used OPFRs which has been frequently detected in environmental media and biological samples,were investigated in C57BL/6 mice.After exposure to TDCIPP for 35 days,we applied chemical analysis to explore the accumulation and transformation of TDCIPP in mice,and an integrated analytical approach by combing toxicological analysis,metabolomics,gene sequencing and bioinformatics technology to explore the toxic effects and underlying mechanisms of tissue damage,metabolic imbalance,and intestinal microecological disorders caused by TDCIPP exposure.This study used traditional chemical analysis,toxicological analysis and new multi-omics technologies to build a bridge between pollutant exposure and health effects,which may help to evaluate the adverse effects of OPFRs exposure on human health.The main contents and results of this research are as follows:The accumulation of TDCIPP and its main metabolite BDCIPP in mice tissues showed opposite pattern.TDCIPP had the highest concentration in muscle tissue [535.7 ± 192.2 ng/g wet weight(ww)],which was significantly higher than that of liver(186.9 ± 55.0 ng/g ww,p < 0.05)and kidney(43.5 ± 12.0 ng/g ww,p < 0.05);BDCIPP had the highest concentration in kidney(2189.2 ± 420.7 ng/g ww),which was significantly higher than that in liver(1337.1 ± 249.6 ng/g ww,p < 0.05)and muscle(162.5 ± 37.1 ng/g ww,p < 0.05).The difference in tissue distribution may be related to the blood perfusion rate,metabolic rate and function of different tissues.In the collected mice tissue samples,hair contributed94.2% of the total TDCIPP and 79.5% of the total BDCIPP in all tissues,suggesting that hair can be used as a reliable biological monitoring indicator for TDCIPP and BDCIPP.The metabolite BDCIPP was the main compound in mice urine and feces,and the metabolite of TDCIPP mainly exists in urine.The primary metabolic pathways of TDCIPP in mice may include: oxidative dealkylation,oxidative dehalogenation,oxidative dehalogenation plus reoxidation and dehydrogenation reactions.TDCIPP exposure caused disorders of the metabolic pathways in mice,by significantly changing endogenous metabolic molecules such as amino acids,organic acids,alkaloids,carbohydrates,and polyunsaturated fatty acids after exposure.These metabolic molecules are related to oxidative stress damage,immune response,inflammation and energy metabolism disorders.TDCIPP exposure caused changes in the m RNA expression levels of neuroinflammation and neurotrophic-related genes in the cerebral cortex of mice,by significantly up-regulating the gene expression levels of IL-6,IL-1β,TNF-α,i NOS,GDNF(p < 0.05)and significantly down-regulating the gene expression levels of Ntf3(p < 0.05),suggesting that TDCIPP may cause neuroinflammation and increase the risk of neuronal damage.Meanwhile,TDCIPP caused changes in oxidative stress-related biomarkers and enzyme activities in mice liver,which were shown as decreased GST,GSH-PX,SOD enzyme activities and increased MDA accumulation in the liver,suggesting that TDCIPP exposure may lead to liver oxidative stress damage.TDCIPP exposure significantly changed the gut microbiome composition,abundance and function in mice,with a remarkable increased Firmicutes at the expense of Bacteroidetes at the phylum level after exposure(p < 0.05).Several important families perturbed by TDCIPP were identified,such as Bifidobacteriaceae,Bacteroidaceae,Rhodospirillaceae,which are key components of the gut microbiome and have important physiological functions to the host.Perturbed gut metabolic profiles in fecal of TDCIPP-exposured mice were observed,including butyrate,propionate,β-Glucose,Lysine,Proline,choline,and were closely related with altered gut microbiome.These results suggested that TDCIPP exposure has great influence on the gut ecosystem as reflected by perturbation of microbiome community structure,core microbial species,and gut metabolites which were closely related to host’s physiological functions,resulting in the gut ecosystem disorders and metabolic dysfunction.