- 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.
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.
2 excerpts below give a little background on gap junctions. The
discusses gap junctions and G-proteins.
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)....
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.
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.
2001. Am J Physiol Cell Physiol 281: C1211-C1222.
junction assembly: PTX-sensitive G proteins regulate the distribution
of connexin43 within cells; by Paul
D. Lampe et al.
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.
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.
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.
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.
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.
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
... 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.
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.