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PFOS - PFOA Index Page

• See section on G-Proteins for Sodium fluoride, which is a G-protein activator.

• Note from FAN:
While there has been no direct mention for a G-protein mechanism for perfluorinated chemicals in research studies (which is in its infancy), the following abstracts point to disruptions in intercellular communication/transduction. Because G-proteins are fundamental to this, we list the following abstracts under this category. We would appreciate any comments, either to support or dismiss the involvement of G-proteins. If you can clarify this issue, please contact us. Thanks. EC.

Abstract: Gap junctional intercellular communication (GJIC) is the major pathway of intercellular signal transduction, and is thus important for normal cell growth and function... PFOS, perfluorooctane sulfonamide (PFOSA), and perfluorohexane sulfonic acid (PFHA) were found to inhibit GJIC in a dose-dependent fashion, and this inhibition occurred rapidly and was reversible... A structure activity relationship was established among all 4 tested compounds, indicating that the inhibitory effect was determined by the length of fluorinated tail and not by the nature of the functional group. The results of the studies of the 2 cell lines and the in vivo exposure were comparable, suggesting that the inhibitory effects of the selected perfluorinated compounds on GJIC were neither species- nor tissue-specific and can occur both in vitro and in vivo.
Ref: 2002. Toxicol Sci Aug;68(2):429-36. Inhibition of gap junctional intercellular communication by perfluorinated compounds in rat liver and dolphin kidney epithelial cell lines in vitro and Sprague-Dawley rats in vivo; by Hu W, Jones PD, Upham BL, Trosko JE, Lau C, Giesy JP.

• Note: The 2 excerpts below give a little background on gap junctions. The •abstract• following discusses gap junctions and G-proteins.

Gap junctions participate in signal transductions by allowing cells to exchange ions and small water soluble molecules (i.e., secons messengers such as cAMP and Ca2+ ) and are believed to play a role in the regulation of cell proliferation and cell division(9). With the growth control mechanism impaired in carcinogenesis, researchers believe that the loss of gap junctional intercellular communication (GJIC) may contribute to the cell's lack of control. The accumulation of replication signals in the cell due to the inhibition of GJIC leads researchers to this conclusion(9)....
Ref: http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/Oncogenes/FUNCTION.HTML

Gap-junctional intercellular coupling is necessary for the coordination of endothelial cells during angiogenesis. The reconstitution of cell-cell communications is of particular importance in the final steps of regeneration of the vascular network.
Ref: http://mendel.imp.univie.ac.at/SEQUENCES/TEMS/mainpgs/sum/sum.html

•Abstract•: Cells expressing connexin43 are able to upregulate gap junction (GJ) communication by enhancing the assembly of new GJs, apparently through increased connexin trafficking. Because G proteins are known to regulate different aspects of protein trafficking, we examined the effects of pertussis toxin (PTX; a specific inhibitor of certain G proteins) on GJ assembly. Dissociated Novikoff hepatoma cells were reaggregated for 60 min to form nascent junctions. PTX inhibited GJ assembly, as indicated by a reduction in dye transfer. Electron microscopy also revealed a 60% decrease in the number of GJ channels per cell interface. Importantly, PTX blocked the twofold enhancement in GJ assembly found in the presence of low-density lipoprotein. Two Gi proteins (Gi2 and Gi3), which have been implicated in the control of membrane trafficking, reacted with PTX in ADP-ribosylation studies. PTX and/or the trafficking inhibitors, brefeldin A and monensin, inhibited GJ assembly to comparable degrees. In addition, assays for GJ hemichannels demonstrated reduced plasma membrane levels of connexin43 following PTX treatment. These results suggest that PTX-sensitive G proteins regulate connexin43 trafficking, and, as a result of inhibition with PTX, the number of plasma membrane hemichannels available for GJ assembly is reduced.
Ref: 2001. Am J Physiol Cell Physiol 281: C1211-C1222. Gap junction assembly: PTX-sensitive G proteins regulate the distribution of connexin43 within cells; by Paul D. Lampe et al.

Abstract: Perfluorinated fatty acids (PFFAs), such as perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA), are known peroxisome proliferators and hepatocarcinogens. A causal link between an increase in the oxidative stress by peroxisomes and tumor promotion has been proposed to explain the hepatocarcinogenicity of PFOA and PFDA. However, the down-regulation of gap junctional intercellular communication (GJIC) has also been linked to the tumor-promoting properties of many carcinogens. Therefore, the effect of PFFAs on GJIC in WB-rat liver epithelial cells was determined. The chain length of the PFFAs tested for an effect on GJIC ranged from 2 to 10, 16 and 18 carbons. Carbon lengths of 7 to 10 inhibited GJIC in a dose-response fashion, whereas carbon lengths of 2 to 5, 16 and 18 did not appreciably inhibit GJIC. Inhibition occurred within 15 min and was reversible, with total recovery from inhibition occurring within 30 min after the removal of the compound from the growth medium. This short time of inhibition suggests that GJIC was modified at the post-translational level. Also, this short time period was not long enough for peroxisome proliferation. The post-translational modification of the gap junction proteins was not a consequence of altered phosphorylation as determined by Western blot analysis. Perfluorooctanesulfonic acid also inhibited GJIC in a dose-response fashion similar to PFDA, indicating that the determining factor of inhibition was probably the fluorinated tail, which required 7-10 carbons. Our results suggest that PFFAs could potentially act as hepatocarcinogens at the level of gap junctions in addition to or instead of through peroxisome proliferation.
Ref: 1998. Int J Cancer Nov 9;78(4):491-5. Inhibition of gap junctional intercellular communication by perfluorinated fatty acids is dependent on the chain length of the fluorinated tail; by Upham BL, Deocampo ND, Wurl B, Trosko JE.

Abstract: Perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), clofibrate, di(2-ethylhexyl)phthalate (DEHP), and Wy-14,643 represent a class of compounds known as peroxisome proliferators (PPs). Such compounds induce biogenesis of liver peroxisomes and cause a varying degree of hepatotoxicity and carcinogenesis in rodents. We examined the effects of these PPs on rat hepatic lipids and phospholipid profiles using phosphorus-31 NMR spectroscopy. All PPs caused a 25-57% increase in hepatic phospholipid content, while all but clofibrate increased the total lipid content by 26-156%. Treatments also influenced the composition of liver phospholipids. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEth) contents were significantly increased in all treatment groups. Most notably, PFDA caused the largest increase in PtdCho and PtdEth content (ca. 70%), while PFOA and Wy-14,643 were the only test compounds that influenced the PtdCho:PtdEth ratio. PFDA also caused an ca. 30% decrease in sphingomyelin (SphM) from 24 to 120 h postdose. SphM is a key lipid in signal transduction processes involved in apoptosis. Hydrolysis of SphM can be mediated through the action of tumor necrosis factor (TNF-alpha). We measured the TNF-alpha concentrations in rat sera at 24 h post-PFDA-exposure and found an 8-fold increase relative to vehicle-treated controls. These data demonstrate that an increase in the serum TNF-alpha level correlates with the time frame for the observed reduction in hepatic SphM. PFOA, a structurally similar compound, had no effect on hepatic SphM content, nor did it affect the serum TNF-alpha concentration. These effects may be related to differences in the tumorigenicity associated with these compounds. We postulate that PFDA activates the SphM signal transduction pathway via the release of TNF-alpha. This then stimulates cytotoxic responses and processes of apoptosis and may suppress cell proliferative and mitogenic responses.
Ref: 1998. Chem Res Toxicol May;11(5):428-40. Effects of peroxisome proliferators on rat liver phospholipids: sphingomyelin degradation may be involved in hepatotoxic mechanism of perfluorodecanoic acid; by Adinehzadeh M, Reo NV.

Abstract excerpt: The amphiphillic nature of PFCs [perfluorinated compounds] suggests that their effects could be primarily on cell membranes... Of the PFCs tested, only perfluorooctane sulfonic acid (PFOS) increased the permeability of cell membranes to the hydrophobic ligands used. Three PFCs were tested in the membrane fluidity assay: PFOS, perfluorohexane sulfonic acid (PFHS), and perfluorobutane sulfonic acid (PFBS). PFOS increased membrane fluidity in fish leukocytes in a dose-dependent fashion, while PFHS and PFBS had no effect in the concentration range tested. The lowest effective concentrations for the membrane fluidity effects of PFOS were 5-15 mg/l. Effects on mitochondrial membrane potential occurred in the same concentration range as effects on membrane fluidity. This suggests that PFOS effects membrane properties at concentrations below those associated with other adverse effects.
Ref: 2003. Comp Biochem Physiol C Toxicol Pharmacol. May;135(1):77-88. Alterations in cell membrane properties caused by perfluorinated compounds; by Hu W, Jones PD, DeCoen W, King L, Fraker P, Newsted J, Giesy JP.

Abstract excerpt: ... In the present study, we show a novel mechanism by which perfluorooctanoic acid (PFOA), a potent peroxisome proliferator and inhibitor of PE [phosphatidylethanolamine] methylation, exerts its hypolipidemic effect... PFOA has the ability to dissociate apoB48 from lipoprotein particles. Exposure of cells to PFOA for 2 h prior to the experiment was sufficient to generate lipid-poor apoB48, indicating that PFOA exerted its effect intracellularly. Taken together, the data suggest that a strong interaction of PFOA with apoB48 disturbs the association of apoB48 with lipids in the process of intracellular VLDL assembly, thereby inhibiting VLDL secretion. This study shows that the mechanisms of hypolipidemic effect caused by various classes of peroxisome proliferators are diverse.
Ref: 1999. Biochim Biophys Acta Mar 25;1437(3):393-401. Perfluorooctanoic acid, a peroxisome-proliferating hypolipidemic agent, dissociates apolipoprotein B48 from lipoprotein particles and decreases secretion of very low density lipoproteins by cultured rat hepatocytes; by Okochi E, Nishimaki-Mogami T, Suzuki K, Takahashi A.