Environment And Exposure Research,Metabolomic Pathway Analysis And Risk Of Thyroid Hormonal Perturbation On Perfluoroalkyl Substances Including Perfluorooctane Sulfonate Isomers

Perfluoroalkyl substances(PFASs),as an additive in commercial products and industries,have been produced and used for more than 60 years.PFASs could enter our environment during the lifetime of product.PFASs have been identified as global contaminants,and detected in all kinds of environmental matrices.PFASs can result in liver toxicity,development toxicity,immunotoxicity,and hormonal effects.Therefore,perfluorooctane sulfonate(PFOS)were listed in the Stockholm Convention on Persistent Organic Pollutants.Meanwhile,several perfluorinated alternatives was produced.Jiangsu province,located in central-east China,is a highly industrialized and densely populated region.In this thesis,we determinated the concentration of PFASs,PFOS isomers,and polyfluoroalkyl phosphate diesters(diPAPs)in water environemt,drinking water,and human serum in Jiangsu province.Then,we selected PFOA as a typical compound to perform a metabolomic study,and detected the metabolite level to characterize PFOA-induced alterations of metabolism in target organ of mice.Finally,we developed a method to evaluate the risk of thyroid hormonal perturbation from combined PFASs,and assessed the risk of thyroid hormonal perturbation in drinking water and human serum.The main conclusions are described as follows(1)Distribution of PFASs including PFOS isomers was investigated in Huai River Basin and Tai Lake.In water samples from Huai River Basin,PFOA and PFOS were the major compounds(mean 18 ng/L and 4.7 ng/L,respectively),while in samples from Taihu Lake,PFOA,perfluorohexanoic acid,and PFOS were the major compounds(mean 56 ng/L,19 ng/L,and 15 ng/L,respectively).Branched PFOS(Br-PFOS)isomers accounting for 48.1%to 62.5%of PFOS were enriched in all samples from Taihu Lake,compared to electrochemical fluorination(ECF)PFOS(Br-PFOS?30.0%),which implied that there was the fractionation effect of PFOS isomers in environment processes.Occurrence of PFASs was investigated in confined and unconfined aquifers,rivers,and coastal waters in the water cycle from Huai River Basin to Yellow Sea.PFASs had contaminated all concerned water environment,even confined aquifers(mean 4.6 ng/L,range 2.7-6.8 ng/L).PFOS and PFOA,accounting for 49.1%(0.8-84.8%)and 33.3%(6.3-92.2%)of total PFASs,were the major PFASs in water samples.Perfluoropentanoic acid,a kind of short chain PFASs,accounted for 10.3%(1.9-24.6%)of total PFASs,was another major PFASs in rivers and coastal waters.We reported distribution of PFASs including PFOS isomers in drinking water.Compared to 30%in ECF PFOS,the levels of Br-PFOS in drinking water were increased to 30.7-43.7%of total PFOS.which could contribute to enrichment of Br-PFOS in blood.We investigated PFASs,PFOS isomers,and diPAPs in human serum from Jiang province.PFOA(1.6-177 ng/mL)and PFOS(3.3-331 ng/mL)had a higher concentration than developed countries.The percentage of Br-PFOS in serum had a negative correlation with PFOS levels.Compared to ECF PFOS,enrichment of Br-PFOS was found in serum with a lower PFOS level.The detected frequencies of 6:2diPAP,6:2/8:2diPAP,and 8:2diPAP were 17%,12%,and 25%,respectively,and the maximum concentrations of 6:2diPAP,6:2/8:2diPAP,and 8:2diPAP were 0.080 ng/mL,0.072 ng/mL,and 0.100 ng/mL,which were lower than developed countries.Because of PFOA with a high level in environment and exposure researches,we identified it as the precedence-controlled PFASs.(2)We applied a target metabolomics approach(278 metabolites)to investigate the metabolic effects of PFOA in brain and liver of mice,which received a 28 days sub-chronic PFOA exposure and were separated by three groups,control group,low-dose group(0.5 mg/kg/day),and high-dose group(2.5 mg/kg/day).Multivariate statistical analysis indicated that PFOA could induce metabolic disorders in two PFOA-exposure groups.By Mann-Whitney U test,we identified 10 and 18 metabolites as potential biomarkers for PFOA-induced metabolic disorders in brain and liver,respectively.These potential biomarkers mainly involved in lipid metabolism.Pathway analysis suggested that PFOA could affect amino acid,lipid,carbohydrate,and energy metabolism.PFOA could affect neurotransmitter(serotonin,dopamine,norepinephrine,and glutamate)levels and downregulate phosphatidylcholines levels in brain,and this gave a new understanding of PFOA-induced neurobehavioral effects.Lipid profiles implied that ?-oxidation and biosynthesis of unsaturated fatty acids involved in PFOA-induced liver toxicity.Meanwhile,alterations of arachidonic acid metabolism indicated PFOA exposure result in inflammation response in liver.(3)We selected thyroid hormonal perturbation as the health effect and applied the thyroid hormone binding model to develop a new method to evaluate the risk of combined PFASs.The risks associated with PFOS in drinking water would be overestimated by 10.0%-91.7%if contributions from individual PFOS isomers were not considered,and the risks associated with PFOS in serum would be underestimated when the precentage of Br-PFOS was lower than ECF PFOS.The results revealed that the PFOS isomer profile and the toxicity of individual PFOS isomers were important factors in risk assessment of PFOS and should be considered in the future risk assessments.PFOA and PFOS were the major compounds responsible for risk of thyroid hormonal perturbation in drinking water and serum.Although thyroid hormonal perturbation is the second effect of PFOA,PFOA is not negligible for evaluating the risk of thyroid hormonal perturbation.Risk quotients of combined PFASs in all drinking water and serum samples were lower than 1,suggesting that the PFASs in drinking water and serum may not pose a risk of TH perturbation.