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Co-exposure to PCB126 and PFOS increases biomarkers associated with cardiovascular disease risk and liver injury in mice.

ABSTRACT: Polychlorinated biphenyl (PCB)126 and perfluorooctane sulfonic acid (PFOS) are halogenated organic pollutants of high concern. Exposure to these chemicals is ubiquitous, and can lead to potential synergistic adverse effects in individuals exposed to both classes of chemicals. The present study was designed to identify interactions between PCB126 and PFOS that might promote acute changes in inflammatory pathways associated with cardiovascular disease and liver injury. Male C57BL/6 mice were exposed to vehicle, PCB126, PFOS, or a mixture of both pollutants. Plasma and liver samples were collected at 48 h after exposure. Changes in the expression of hepatic genes involved in oxidative stress, inflammation, and atherosclerosis were investigated. Plasma and liver samples was analyzed using untargeted lipidomic method. Hepatic mRNA levels for Nqo1, Icam1, and PAI1 were significantly increased in the mixture-exposed mice. Plasma levels of PAI1, a marker of fibrosis and thrombosis, were also significantly elevated in the mixture-exposed group. Liver injury was observed only in the mixture-exposed mice. Lipidomic analysis revealed that co-exposure to the mixture enhanced hepatic lipid accumulation and elevated oxidized phospholipids levels. In summary, this study shows that acute co-exposure to PCB126 and PFOS in mice results in liver injury and increased cardiovascular disease risk.

SUBMITTER: Deng P

PROVIDER: S-EPMC7725976 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Two year cancer bioassays conducted by the National Toxicology Program have shown chronic exposure to dioxin-like compounds (DLCs) to lead to the development of both neoplastic and non-neoplastic lesions in the hepatic tissue of female Sprague Dawley rats. Most, if not all, of the hepatotoxic effects induced by DLC's are believed to involve the binding and activation of the transcription factor, the aryl hydrocarbon receptor (AhR). Toxicogenomics was implemented to identify genomic responses that may be contributing to the development of hepatotoxicity in rats.Through comparative analysis of time-course microarray data, unique hepatic gene expression signatures were identified for the DLCs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (100 ng/kg/day) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) (1000 ng/kg/day) and the non-DLC 2,2',4,4',5,5',-hexachlorobiphenyl (PCB153) (1000 ?g/kg/day). A common time independent signature of 41 AhR genomic biomarkers was identified which exhibited at least a 2-fold change in expression following subchronic (13-wk) and chronic (52-wk) p.o. exposure to TCDD and PCB126, but not the non DLC, PCB153. Real time qPCR analysis validated that 30 of these genes also exhibited at least a 2-fold change in hepatic expression at 24 hr following a single exposure to TCDD (5 ?g/kg, po). Phenotypic anchoring was conducted which identified forty-six genes that were differently expressed both following chronic p.o. exposure to DLCs and in previously reported studies of cholangiocarcinoma or hepatocellular adenoma.Together these analyses provide a comprehensive description of the genomic responses which occur in rat hepatic tissue with exposure to AhR ligands and will help to isolate those genomic responses which are contributing to the hepatotoxicity observed with exposure to DLCs. In addition, the time independent gene expression signature of the AhR ligands may assist in identifying other agents with the potential to elicit dioxin-like hepatotoxic responses.

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Co-exposure to PCB126 and PFOS increases biomarkers associated with cardiovascular disease risk and liver injury in mice.

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