Subacute exposure to N-ethyl perfluorooctanesulfonamidoethanol results in the formation of perfluorooctanesulfonate and alters superoxide dismutase activity in female rats

Abstract

Perfluorooctanesulfonamides, such as N-ethyl perfluorooctanesulfonamidoethanol (N-EtFOSE), are large scale industrial chemicals but their disposition and toxicity are poorly understood despite significant human exposure. The hypothesis that subacute exposure to N-EtFOSE, a weak peroxisome proliferator, causes a redox imbalance in vivo was tested using the known peroxisome proliferator, ciprofibrate, as a positive control. Female Sprague–Dawley rats were treated orally with N-EtFOSE, ciprofibrate or corn oil (vehicle) for 21 days, and levels of N-EtFOSE and its metabolites as well as markers of peroxisome proliferation and oxidative stress were assessed in serum, liver and/or uterus. The N-EtFOSE metabolite profile in liver and serum was in good agreement with reported in vitro biotransformation pathways in rats and the metabolite levels decreasing in the order perfluorooctanesulfonate ≫ perfluorooctanesulfonamide ~ N-ethyl perfluorooctanesulfonamidoacetate ≫ perfluorooctanesulfonamidoethanol ~ N-EtFOSE. Although N-EtFOSE treatment significantly decreased the growth rate, increased relative liver weight and activity of superoxide dismutases (SOD) in liver and uterus (total SOD, CuZnSOD and MnSOD), a metabolic study revealed no differences in the metabolome in serum from N-EtFOSE-treated and control animals. Ciprofibrate treatment increased liver weight and peroxisomal acyl Co-A oxidase activity in the liver and altered antioxidant enzyme activities in the uterus and liver. According to NMR metabolomic studies, ciprofibrate treated animals had altered serum lipid profiles compared to N-EtFOSE-treated and control animals, whereas putative markers of peroxisome proliferation in serum were not affected. Overall, this study demonstrates the biotransformation of N-EtFOSE to PFOS in rats that is accompanied by N-EtFOSE-induced alterations in antioxidant enzyme activity.

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Acknowledgments

We thank Brett A. Wagner, Garry R. Buettner and The University of Iowa ESR Facility for invaluable support and Rama Rao V.V.V.N.S. for the synthesis of the perfluorooctanesulfonamides. The work was supported by a grant from the University of Iowa Center for Health Effects of Environmental Contamination (CHEEC). Additional support was provided by grants ES05605, ES013661 and ES012475 from the National Institute of Environmental Health Sciences, NIH, and by the Kentucky Agricultural Experiment Station. DRS and MCC were supported by NIH P30-CA086862.

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The authors declare that they have no conflict of interest.

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Correspondence to Hans-Joachim Lehmler.

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Xie, W., Wu, Q., Kania-Korwel, I. et al. Subacute exposure to N-ethyl perfluorooctanesulfonamidoethanol results in the formation of perfluorooctanesulfonate and alters superoxide dismutase activity in female rats. Arch Toxicol 83, 909–924 (2009). https://doi.org/10.1007/s00204-009-0450-y

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Keywords

  • Metabolomics
  • Perfluorooctanesulfonamides
  • Perfluorooctanesulfonate
  • Peroxisomal acyl Co-A oxidase
  • Superoxide dismutase