Skip Navigation



ToxSci Advance Access published online on August 13, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh244
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
82/1/333    most recent
kfh244v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by O'Brien, T. M.
Right arrow Articles by Wallace, K. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by O'Brien, T. M.
Right arrow Articles by Wallace, K. B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received June 1, 2004
Accepted August 3, 2004

Systems Toxicology

Mitochondrial Permeability Transition as the Critical Target of N-Acetyl Perfluorooctane Sulfonamide Toxicity in Vitro

Timothy M. O'Brien 1 Kendall B. Wallace 1*

1 Department of Biochemistry and Molecular Biology, Toxicology Graduate Program, University of Minnesota School of Medicine, 1035 University Drive, Duluth, Minnesota 55812

* To whom correspondence should be addressed. E-mail: kwallace{at}d.umn.edu.


  Abstract

Perfluorooctanyl compounds with active functional groups have been shown to disrupt mitochondrial bioenergetics by three distinct mechanisms: protonophoric uncoupling of mitochondrial respiration, induction of the mitochondrial permeability transition (MPT)or a non-selective increase in membrane permeability. The purpose of this investigation was to identify the initial target and specific sequence of events associated with the N-acetyl substituted perflourooctanesulfonamides induced MPT. N-acetyl-perfluorooctanesufonamide (FOSAA), N-ethyl-N-acetyl-perfluorooctanesulfonamide (N-Et-FOSAA), perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and N-ethyl-N-(2-ethoxy)-perfluorooctanesulfonamide (N-Et-FOSE) were added individually to liver mitochondria freshly isolated from Sprague-Dawley rats. Mitochondrial swelling and cytochrome c release were recorded spectrophotometrically, oxygen uptake was monitored with a Clark-type oxygen electrode, and reactive oxygen species (ROS) were monitored by dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence. FOSAA (45 µM) and N-Et-FOSAA (7.5 µM) induced calcium-dependent mitochondrial swelling, the release of cytochrome c, inhibition of uncoupled mitochondrial respiration, and ROS generation, all of which were inhibited by cyclosporin-A (CsA). PFOA (200 µM) displayed slight CsA sensitive activity, but neither PFOS (10 µM) nor N-Et-FOSE (70 µM) induced the MPT. Results of this investigation demonstrate two important findings; 1) MPT induction is specific to the N-acetyl substituted perfluorooctanesulfonamides and, 2) the sequence of events is initiated by induction of the MPT, which causes the release of cytochrome c as well as other cofactors leading to inhibition of respiration and ROS generation. The toxicity of N-acetyl perfluorooctanyl compounds may therefore reflect the mitochondrial dysfunction, which is compounded by the ensuing oxidative injury.

Keywords: mitochondria; permeability transition; PFOA; PFOS.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
C. Lau, K. Anitole, C. Hodes, D. Lai, A. Pfahles-Hutchens, and J. Seed
Perfluoroalkyl Acids: A Review of Monitoring and Toxicological Findings
Toxicol. Sci., October 1, 2007; 99(2): 366 - 394.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.