Increased PFOS toxicity and accumulation is associated with perturbed prostaglandin metabolism and increased organic anion transport protein expression

Description

Perfluorooctanesulfonic acid (PFOS) is a widespread environmental pollutant with a half-life of 5.4 years in humans. PFOS is associated with various adverse health outcomes, including obesity, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice generated in our laboratory were treated with 0, 1, or 10 mg/kg/day PFOS for 21 days, and it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than Cyp2b-null mice providing a new model for analyzing the mechanisms behind PFOS retention and elimination. The purpose of this study was to use -omic data (lipidomics and transcriptomics) to help determine novel mechanisms behind PFOS retention. Hepatic targeted lipidomics by LC-MS/MS for distinct free and total oxylipins and hepatic transcriptomics from PFOS treated Cyp2b-null and hCYP2B6-Tg mice were performed in addition to evaluating basic serum and liver parameters associated with liver retention such as albumin, and serum and liver FABP. Lipidomic PCA analysis indicates that several oxylipins, including prostaglandins, thromboxanes, and docosahexaenoic acid metabolites are associated or inversely associated with PFOS toxicity. FABPs are moderately associated with toxicity, but also inversely associated with toxicity in males. Thus, their ability to bind PFOS may have immediate benefits but long term problems associated with bioaccumulation. Last, differential gene expression analysis following RNAseq was performed with EdgeR, and differentially expressed genes were associated with changes in GO terms and KEGG pathways in the PFOS-treated mice. Several pathways are associated with retention and toxicity. Most interestingly, KEGG and PCA analysis indicates that several transporters are associated with increased retention probably due to increased uptake. The strongest association are Oatp1a4-6 genes, which are repressed in the Cyp2b-null mice - potentially limiting uptake. Not much work (or no work) has been done previously to study their role in PFOS transport. In summary, Cyp2b-null and hCYP2B6-Tg mice provide unique models for studying PFOS retention and toxicity. Our research indicates that poor DHA and prostaglandin metabolism is associated with toxicity and several, especially OATP transporters are associated with hepatic retention. Data enclosed includes serum, liver parameters, liver oxylipins, and liver RNAseq data from UT, 0, 1, 10 mg/kg/day PFOS-treated male and female, Cyp2b-null and humanized CYP2B6-transgenic mice.

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