Full
report available free at:
http://carcin.oupjournals.org/cgi/content/full/20/12/2237
1999
Carcinogenesis Dec;20(12):2237-46
Effects
of the rodent peroxisome proliferator and hepatocarcinogen,
perfluorooctanoic acid, on apoptosis in human hepatoma HepG2
cells.
Shabalina IG, Panaretakis T,
Bergstrand A, DePierre JW.
Unit of Biochemical
Toxicology, Department of Biochemistry, Wallenberg Laboratory,
Stockholm University, S-106 91 Stockholm, Sweden.
The effects of perfluorooctanoic acid
(PFOA), a potent hepatocarcinogen and peroxisome proliferator
in rodents, on human cells have not yet been examined.
In the present study we demonstrate that treatment of human
hepatoblastoma HepG2 cells with PFOA induces apoptosis, as well
as perturbs the cell cycle. This apoptosis was characterized
by electron microscopy, which revealed typical nucleosomal fragmentation
(also observed as a 'DNA ladder' upon electrophoresis on agarose)
and was quantitated using propidium iodide staining of cellular
DNA and the terminal deoxynucleotidyl transferase-mediated dUTP
nick end labeling (TUNEL) assay. This process was dose- and
time-dependent: apoptosis became manifest with 200 microM and
maximal (45% of the cells) upon exposure to 450 microM PFOA
for 24 h. Electrophoresis of the DNA from HepG2 cells exposed
to 500 microM PFOA for 24 h or to 400 microM PFOA for 48 h revealed
a smear typical of non-specific degradation. These findings
indicate that in the presence of high concentrations of PFOA
for long times, HepG2 cells undergo primary and secondary necrosis.
Quantitation of trypan blue exclusion supported this conclusion.
Flow cytometric analysis revealed that the cell cycle of HepG2
cells was perturbed by exposure to 50-150 microM PFOA. A 50
microM concentration resulted in a significant increase in the
proportion of G(2)/M cells and, simultaneously, a decrease in
the number of cells in the S phase, whereas treatment with 100
or 150 microM PFOA increased the proportion of cells in the
G(0)/G(1) phase and decreased the number of cells in the G(2)/M
and S phases. Simultaneous flow cytometric analysis of apoptosis-associated
DNA strand breaks using the TUNEL procedure and of propidium
iodide staining of cellular DNA revealed DNA breaks in HepG2
cells exposed to 150 microM PFOA, prior to nuclear fragmentation.
PMID: 10590214 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10528994&dopt=Abstract
1999
Chem Biol Interact Sep 30;122(2):73-87
Hypophysectomy
and/or peroxisome proliferators strongly influence the levels
of phase II xenobiotic metabolizing enzymes in rat
testis.
Mehrotra K, Morgenstern R, Ahlberg
MB, Georgellis A.
Department of Biochemistry, Wallenberg Laboratory, Stockholm
University, Sweden.
The objectives of the present work were to determine the influence
of hypophysectomy and/or peroxisome proliferators (PP) on certain
xenobiotic-metabolizing enzyme activities, i.e. glutathione
transferases (GST), glutathione peroxidase (GPX), phenol sulphotransferases
(pSULT), phenol UDP-glucuronosyl transferases (pUGT), catalase,
NADP(H) quinone oxidoreductase (QR) and epoxide hydrolases (EH)
in the rat testes. Adult male rats, hypophysectomized and their
sham-operated controls, were treated for 10 days with clofibrate
(0.5%), perfluorooctanoic acid (0.05%,
PFOA), acetylsalicylic acid (1%, ASA) and di(2-ethylhexyl)phthalate
(2%, DEHP) in their diet. The results show that, in addition
to both body and testis weight, hypophysectomy caused dramatic
changes in most of the xenobiotic-metabolizing enzyme activities,
which have been measured here. The most pronounced effects were
seen in cytosolic QR (2.2-fold increase), pUGT (95% reduction),
pSULT (75% reduction), mitochondrial catalase (75% reduction),
microsomal EH (70% reduction) and microsomal GST (55% reduction).
Treatment with PP, i.e. perfluorooctanoic
acid (PFOA), clofibrate, acetyl salicylic acid (ASA)
and di(2-ethylhexyl)phthalate (DEHP) showed varied effects on
the xenobiotic-metabolizing enzyme activities, the highest effects
(10-60% reduction) were seen in sham-operated animals. These
effects were not so pronounced or were not seen in hypophysectomized
rats except for the case of PFOA treatment,
which caused increases of enzyme activities. The highest
increases were seen with microsomal GST (70%), GPX (75%) and
cytosolic EH (75%). It is concluded from these experiments
that the regulation of several xenobiotic-metabolizing enzymes
in the rat testis is affected by the pituitary and/or pituitary
hormones and that different peroxisome proliferators have variable
effects on the levels of these xenobiotic-metabolizing enzymes.
The general trend of reduction in enzyme
activities implies that the testis is less protected under conditions
that can perturb hormonal status.
PMID: 10528994 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10227579&dopt=Abstract
1999
Chem Biol Interact Mar 1;118(1):69-83
Alterations
by perfluorooctanoic acid of glycerolipid metabolism in rat
liver.
Kudo N, Mizuguchi H, Yamamoto A, Kawashima
Y.
Faculty of Pharmaceutical Sciences, Josai University, Sakado,
Saitama, Japan.
The effects of perfluorooctanoic acid (PFOA) feeding on hepatic
levels of glycerolipids and the underlying mechanism were investigated.
Feeding of rats with 0.01% of PFOA in the diet for 1 week caused
an increase in the contents of phosphatidylcholine (PtdCho),
phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns),
phosphatidylserine (PtdSer) and triglyceride (TG), which were
2.2, 2.4, 2.4, 1.6 and 5.2 times over control, respectively,
on the basis of whole liver. The activities of glycerol-3-phosphate
acyltransferase, diacylglycerol kinase and PtdSer decarboxylase
were significantly increased upon PFOA feeding, whereas the
activities of CTP:phosphoethanolamine cytidylyltransferase and
PtdEtn N-methyltransferase were decreased. On the other hand,
the activity of CTP:phosphocholine cytidylyltransferase was
not increased by PFOA. Upon PFOA feeding, hepatic level of 16:0-18:1
PtdCho was markedly increased and, by contrast, the levels of
molecular species of PtdCho which contain 18:2 were decreased,
resulting in the reduced concentration of molecular species
of serum PtdCho containing 18:2. The increase in the level of
hepatic 16:0-18:1 PtdCho seemed to be due to 3-fold increase
in the activities of both delta9 desaturase and 1-acylglycerophosphocholine
(1-acyl-GPC) acyltransferase. The mechanism by which PFOA causes
the accumulation of glycerolipids in liver was discussed.
PMID: 10227579 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10101272&dopt=Abstract
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.
Okochi E, Nishimaki-Mogami T, Suzuki K,
Takahashi A.
National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku,
Tokyo 158-8501, Japan.
The hypolipidemic effect is evoked by various peroxisome proliferators.
Modulation of gene transcription via peroxisome proliferator-activated
receptor (PPAR) is generally responsible for this effect. In
addition, we have found a PPAR-independent mechanism in which
fibrates, known peroxisome proliferators, decrease hepatic secretion
of very low density lipoproteins (VLDL) through inhibition of
phosphatidylcholine synthesis via methylation of phosphatidylethanolamine
(PE) (T. Nishimaki-Mogami et al., Biochim. Biophys. Acta 1304
(1996) 21-31). In the present study, we show a novel mechanism
by which perfluorooctanoic acid (PFOA), a potent peroxisome
proliferator and inhibitor of PE methylation, exerts its hypolipidemic
effect. PFOA (100 microM) added to the medium rapidly decreased
the secretion of triglyceride by cultured rat hepatocytes, which
was independent of the activity of cellular PE methylation.
Analysis of the density of apoB secreted into the medium showed
that PFOA decreased apoB48 in VLDL, but increased apoB48 in
the bottom d>1.21 fraction. This lipid-poor apoB48 was also
generated by incubating medium that had been harvested from
control cells with PFOA, indicating that
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.
PMID: 10101272 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10581215&dopt=Abstract
1999
Toxicol Appl Pharmacol Dec 1;161(2):209-18
trans-Activation
of PPARalpha and PPARgamma by structurally diverse environmental
chemicals.
Maloney EK, Waxman DJ.
Division of Cell and Molecular Biology, Boston University, Boston,
Massachusetts, 02215, USA.
A large number of industrial chemicals and environmental pollutants,
including trichloroethylene (TCE), di(2-ethylhexyl)phthalate
(DEHP), perfluorooctanoic acid (PFOA),
and various phenoxyacetic acid herbicides, are nongenotoxic
rodent hepatocarcinogens whose human health risk is uncertain.
Rodent model studies have identified the
receptor involved in the hepatotoxic and hepatocarcinogenic
actions of these chemicals as peroxisome proliferator-activated
receptor alpha (PPARalpha), a nuclear receptor that is highly
expressed in liver. Humans exhibit a weak response to
these peroxisome proliferator chemicals, which in part results
from the relatively low level of PPARalpha expression in human
liver. Cell transfection studies were carried out to investigate
the interactions of peroxisome proliferator chemicals with PPARalpha,
cloned from human and mouse, and with PPARgamma, a PPAR isoform
that is highly expressed in multiple human tissues and is an
important regulator of physiological processes such as adipogenesis
and hematopoiesis. With three environmental chemicals, TCE,
perchloroethylene, and DEHP, PPARalpha was found to be activated
by metabolites, but not by the parent chemical. A decreased
sensitivity of human PPARalpha compared to mouse PPARalpha to
trans-activation was observed with some (Wy-14, 643, PFOA),
but not other, peroxisome proliferators (TCE metabolites, trichloroacetate
and dichloroacetate; and DEHP metabolites, mono[2-ethylhexyl]phthalate
and 2-ethylhexanoic acid). Investigation of human and mouse
PPARgamma revealed the transcriptional activity of this receptor
to be stimulated by mono(2-ethylhexyl)phthalate, a DEHP metabolite
that induces developmental and reproductive organ toxicities
in rodents. This finding suggests that PPARgamma, which is highly
expressed in human adipose tissue, where many lipophilic foreign
chemicals tend to accumulate, as well as in colon, heart, liver,
testis, spleen, and hematopoietic cells, may be a heretofore
unrecognized target in human cells for a subset of industrial
and environmental chemicals of the peroxisome proliferator class.
Copyright 1999 Academic Press.
PMID: 10581215 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10491796&dopt=Abstract
1999
J Occup Environ Med Sep;41(9):799-806
Serum
perfluorooctane sulfonate and hepatic and lipid clinical chemistry
tests in fluorochemical production employees.
Olsen GW, Burris JM, Mandel JH,
Zobel LR.
Medical Department,
3M Company, St. Paul, MN 55144, USA.
The 3M Company manufactures fluorochemicals,
which have as a precursor perfluorooctane
sulfonyl fluoride (C8F17SO2F). These compounds may be
expected to transform metabolically, to an undetermined degree,
to perfluorooctane sulfonate (PFOS, C8F17SO3-)
as an end-stage metabolite. Subchronic
studies in rats and primates indicate a potential for cumulative
toxicity with PFOS with the primary effect related to metabolic
wasting with hypolipidemia as a consistent finding.
Biennial medical surveillance has been offered to the company's
fluorochemical production
workers located in Decatur, Alabama, and
Antwerp, Belgium. In 1995, the mean serum PFOS
level, as measured by high-performance liquid chromatography
mass spectrometry, for 178 male employees was 2.19
parts per million (ppm; range, 0.00 to 12.83 ppm), and
in 1997, for 149 male employees, it was 1.75
ppm (0.10 to 9.93 ppm). Our analyses suggest that among
these production employees, there were no substantial changes
in serum hepatic enzymes, cholesterol, or lipoproteins associated
with PFOS levels less than 6 ppm.
It was not possible to derive inferences from the few employees
who had serum PFOS levels > or = 6 ppm. These results may
be due to the lower levels of serum PFOS measured among these
production employees, compared to those suspected to cause effects
in laboratory animals.
Publication Types: Multicenter Study
PMID: 10491796 [PubMed - indexed for MEDLINE]
From
TOXNET
1999
SOIL SCIENCE SOCIETY
OF AMERICA JOURNAL; 63 (4). 1019-1031.
Phosphate
removal capacity of palustrine forested wetlands and adjacent
uplands in Virginia.
AXT
JR, WALBRIDGE MR
Environmental Assessment
Branch, U.S. Army Corps of Engineers, 26 Federal Plaza, New
York, NY, 10278-0090, USA.
Abstract: BIOSIS
COPYRIGHT: BIOL ABS. We examined the ability of soils in six
nontidal palustrine forested wetlands (PFOs) in Virginia's Piedmont
(PD) and Coastal Plain (CP) (n = 3 per physiographic province)
to remove dissolved inorganic P from solution, and we compared
the P sorption capacities of wetlands with those of streambanks
(within wetlands) and adjacent uplands. We hypothesized that
wetland soils would have higher P sorption capacities than streambank
and upland soils due to the higher concentration of noncrystalline
(oxa , Alo was correlated with P sorption capacity in wetland
soils (r2 = 0.80), but so was soil organic matter (as estimated
by mass loss on ignition (LOI)) (r2 = 0.78); in fact, Alo and
organic matter were positively correlated in wetland soils (r2
= 0.84). In contrast, clay and silt content were the two soil
parameters most highly positively correlated with P sorption
capacity in upland soils (r2 = 0.87). Overall, these results
suggest that differences in soil chemistry exist among landscape
posit
CAS Registry Numbers:
14265-44-2
14265-44-2
7723-14-0
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9797139&dopt=Abstract
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.
Upham BL, Deocampo ND, Wurl B,
Trosko JE.
Department of Pediatrics and Human Development, Michigan State
University, East Lansing 48824, USA. upham@pilot.msu.edu
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.
PMID:
9797139 [PubMed - indexed for MEDLINE]
From
TOXNET
1998
ENVIRONMENTAL SCIENCE & TECHNOLOGY; 32 (15). 2283-2287.
Defluorination
of organofluorine sulfur compounds by Pseudomonas sp. strain
D2.
KEY
BD, HOWELL RD, CRIDDLE CS
Dep. Civil Environmental
Engineering, Cent. Microbial Ecol., Michigan State Univ., East
Lansing, MI 48824, USA.
BIOSIS COPYRIGHT:
BIOL ABS. Little is known of the potential for biodegradation
of fluorinated sulfonates. To evaluate this potential, the following
model compounds were selected: difluoromethane sulfonate (DFMS),
trifluoromethane sulfonate (TFMS), 2,2,2-trifluoroethane sulfonate
(TES), perfluorooctane sulfonate (PFOS), and 1H,1H,2H,2H-perfluorooctane
sulfonate (H-PFOS). A laboratory isolate designated Pseudomonas
sp. strain D2 completely defluorinated DFMS under aerobic, sulfur-limiting
conditions in a defined mineral medium. Strain D2 utilized DFMS
as the sole source of sulfur, but not as a source of carbon
or energy. DFMS utilization was inhibited by other forms of
sulfur, and noncompetitive inhibition kinetics were observed,
with Ki values of 3-4 muM for sulfate, sulfite, methane sulfonate,
and cystine. Strain D2 was subsequently used to evaluate degradation
of other fluorinated sulfonates. Growth and defluorination were
only observed for those compounds containing hydrogen (TES and
H-PFOS).
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9688458&dopt=Abstract
1998
Gen Pharmacol Aug;31(2):187-97
Mechanisms
of peroxisome proliferation by perfluorooctanoic acid and endogenous
fatty acids.
Intrasuksri U, Rangwala SM, O'Brien
M, Noonan DJ, Feller DR.
Division of Pharmacology, College of Pharmacy, The Ohio State
University, Columbus 43210, USA.
1. The effects of endogenous fatty acids and perfluorooctanoic
acid (PFOA) and its analogs on peroxisomal acyl CoA oxidase
(ACO) and microsomal laurate hydroxylase (LH) activities were
evaluated in primary cultures of rat hepatocytes and activation
of peroxisome proliferator-activated receptor alpha (PPARalpha)
in CV-1 cells. The rank order for the stimulation of ACO activity
in hepatocytes for selected compounds was PFOA >> octanoic
acid>octanedioic acid, perfluorooctanol (inactive). Increases
in ACO activity by PFOA, like those of ciprofibrate, were associated
with a marked increase in peroxisome number and cytosolic occupancy
volume. Maximal effects of ciprofibrate and PFOA on the stimulation
of ACO activity were not additive, suggesting that these two
compounds share a common pathway of peroxisome proliferation.
2. Saturated monocarboxylic acids of C4 to C18 chain length
were inactive, and, among dicarboxylic acids, only small elevations
(40-45%) in ACO activity were observed with the long-chain C12
and C16 dioic acids. Of the C18 fatty acids tested, only oleic
and linoleic acids, at 1 mM, produced a two- to three-fold elevation
in ACO and LH activities. In comparison with endogenous fatty
acids, PFOA was more potent and exhibited a different time course
and greater magnitude of stimulation of ACO and LH activities
in cultured hepatocytes.
3. Addition of mitochondrial beta-oxidation inhibitors (3-mercaptopropionic
and 2-bromooctanoic acids) did not alter ACO activity in the
presence of octanoic acid or octanedioic acid; nor did they
modify the stimulation of ACO activity by PFOA. The carnitine
palmitoyltransferase I inhibitor 2-bromopalmitic acid produced
a 2.5-fold increase in ACO stimulatory activity and reduced
both ciprofibrate- and PFOA-mediated stimulations of ACO activity.
4. Cycloheximide treatment reduced PFOA- and ciprofibrate-induced
ACO activities; however, the response to oleic acid was not
blocked and increased slightly.
5. In rat and human PPARalpha transactivation assays, the rank
order of activation was ciprofibrate > PFOA > oleic acid
> or = octanoic acid > octanedioic acid or perfluorooctanol
(inactive). PFOA, ciprofibrate and oleic acid were activators
of rPPARalpha at concentrations that correlated favorably with
the changes in ACO activity in cell culture. Octanoic acid did
not increase ACO activity and was a weak activator of PPARalpha.
6. Our findings suggest that fatty acids such as oleic acid
(endogenous fatty acids) and PFOA (a stable
fatty acid) act through more than one pathway to increase
ACO activity in rat hepatocytes. We conclude
that the potent effects of PFOA are primarily mediated by a
mechanism that includes the activation of liver PPARalpha.
PMID: 9688458 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9675720&dopt=Abstract
1998
J Occup Environ Med Jul;40(7):614-22
An
epidemiologic investigation of reproductive hormones in men
with occupational exposure to perfluorooctanoic acid.
Olsen GW, Gilliland FD, Burlew MM, Burris
JM, Mandel JS, Mandel JH.
Medical Department,
3M Company, St. Paul, Minn. 55144, USA.
Perfluorooctanoic acid (PFOA), a potent
synthetic surfactant used in industrial applications, is a peroxisome
proliferator that has resulted in dose-related increases in
hepatic, pancreatic acinar, and Leydig cell adenomas
in laboratory animals. In addition,
PFOA increased serum estradiol levels through the induction
of hepatic aromatase activity. In 1993 and 1995, we conducted
two cross-sectional studies of 111 and 80 production workers,
respectively, and specifically measured their serum PFOA in
relation to several reproductive hormones to determine whether
such an effect occurs in humans. PFOA was not significantly
associated with estradiol or testosterone in either year's study.
A 10% increase in mean estradiol levels was observed among employees
who had the highest levels of serum PFOA, although this association
was confounded by body mass index. Neither was PFOA consistently
associated with the other measured hormones. Our results provide
reasonable assurance that, in this production setting, there
were no significant hormonal changes associated with PFOA at
the serum levels measured. Limitations of this investigation
include its cross-sectional design, the few subjects exposed
at the highest levels, and the lower levels of serum PFOA measured,
compared with those levels reported to cause effects in laboratory
animal studies.
PMID: 9675720 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9585473&dopt=Abstract
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.
Adinehzadeh M, Reo NV.
Departments of Biochemistry and Molecular Biology and of Physics,
WSU Magnetic Resonance Laboratory, Wright State University,
Cox Institute, Dayton, Ohio 45429, USA.
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.
PMID: 9585473 [PubMed - indexed for MEDLINE]
From
TOXNET
1998
SUPPORT:
LETTER
FROM 3M CO TO USEPA REGARDING EPIDEMIOLOGICAL STUDY OF BLOOD
SERA SAMPLES SHOWING PFOS AT VERY LOW (PPB) LEVELS, DATED
5/15/1998
Source: EPA/OTS;
Doc #000811744P
CAS Registry Numbers:
2795-39-3
Order Number: NTIS/OTS0204929-3
Classification Code:
TSCA Sect. 8E Rec 05/21/98
Year of Publication:
1998
Secondary Source
ID: TSCATS/445338
From
TOXNET
1998
SUPPORT:
LETTER
FROM 3M CO TO USEPA REGARDING EPIDEMIOLOGICAL STUDY OF BLOOD
SERA SAMPLES SHOWING PFOS AT VERY LOW (PPB) LEVELS, DATED
5/15/1998
Source: EPA/OTS;
Doc #000811745Q
CAS Registry Numbers:
2795-39-3
Order Number: NTIS/OTS0204929-3
Classification Code:
TSCA Sect. 8E Rec 05/21/98
Year of Publication:
1998
Secondary Source
ID: TSCATS/445339
From
TOXNET
1998
SUPPORT:
LETTER
FROM 3M CO TO USEPA REGARDING EPIDEMIOLOGICAL STUDY OF BLOOD
SERA SAMPLES SHOWING PFOS AT VERY LOW (PPB) LEVELS, DATED
5/15/1998
Source: EPA/OTS;
Doc #000811746R
CAS Registry Number:
2795-39-3
Order Number: NTIS/OTS0204926-5
Classification Code:
TSCA Sect. 8E Rec 05/21/98
Year of Publication:
1998
Secondary Source
ID: TSCATS/445340
See
full free report at
http://public.srce.hr/ccacaa/CCA-PDF/cca1998/v71-n4/CCA_71_1998_1075_1086_OTTEW.pdf
1998
CROATICA CHEMICA ACTA 71 (4)1075-1086
ISSN-0011-1643
Adsorption
of Ammonium Perfluorooctanoate at the Air–Water Interface
Geraldine
A.Ottewill (a) and Ronald H.Ottewill (b)
a School of Chemistry, Physics and Radiography, University of
Portsmouth, Portsmouth PO1 2DT, U.K.
b School of Chemistry, University of Bristol, Bristol BS8 1TS,
U.K.
The adsorption of ammonium perfluorooctanoate has been investigated
at the air-water interface as a function of surfactant concentration
at various concentrations of ammonium chloride.The area
occupied by the surfactant ion was then calculated from the
Gibbs equation with allowance for the presence of salt ions.Independently,the
area per surfactant ion at the interface was determined
by the technique of neutron reflectiviy.Within experimental
error the two sets of measurements were in good agreement.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9212780&dopt=Abstract
1997
Chem Biol Interact May 2;104(2-3):131-45
Effects
of peroxisome proliferators and/or hypothyroidism on xenobiotic-metabolizing
enzymes in rat testis.
Mehrotra K, Morgenstern R, Lundqvist G,
Becedas L, Bengtsson Ahlberg M, Georgellis A.
Department of Biochemistry, Wallenberg Laboratory, Stockholm
University, Sweden.
The objectives of the present work were to study the effects
of certain peroxisome proliferators on xenobiotic-metabolizing
enzyme activities in the testes
of normal and hypothyroid rats, i.e. phenol sulfotransferases
(pST), phenol UDP-glucuronosyl transferases (pUDPGT), glutathione
transferases (GST), catalase, epoxide hydrolase (EH), glutathione
peroxidase (GPX) and NAD(P)H quinone oxidoreductase (QR). Adult
male rats (normal and hypothyroid) were treated for 10 days
with clofibrate (0.5%), perfluorooctanoic acid (0.5%, PFOA),
acetylsalisylic acid (1%, ASA) and di(2-ethylhexyl)phthalate
(2%, DEHP) in their diet. The results show that treatment of
normal rats with peroxisome proliferators dramatically affects
the activities of xenobiotic-metabolizing enzymes (40-60% reduction).
The highest effects are seen in catalase activity (50-60% with
PFOA and ASA), pUDPGT (55% with PFOA), pST (55% with PFOA) and
QR (50% with DEHP). These effects are not seen or are weaker
after induction of hypothyroidism. Taken together, it
is concluded that different classes of peroxisome proliferators
have different effects on rat testicular xenobiotic-metabolizing
enzymes.
PMID: 9212780 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9089641&dopt=Abstract
1997
Mol Cell Biochem Apr;169(1-2):143-7
Activated
Kupffer cells attenuate the liver response to the peroxisome
proliferator perfluorooctanoic acid.
Youssef J, Badr M.
University of Missouri-Kansas City 64108, USA.
It has been suggested that peroxisome proliferators stimulate
Kupffer cells, an effect which may be involved in their mechanism
of action. To evaluate this hypothesis, this study was designed
to investigate the effect of stimulating Kupffer cells on basal
as well as induced peroxisomal enzyme activity. Twenty four
hours following treatment of male Sprague-Dawley rats with the
peroxisome proliferating agent perfluorooctanoic acid (PFOA),
in corn oil or with corn oil alone, hepatic peroxisomal beta-oxidation
was 4.6 +/- 0.2 and 1.8 +/- 0.1 U/g liver, respectively. As
expected, PFOA did not influence the catalase activity. Stimulating
Kupffer cells in vivo by zymosan A (25 mg/kg, i.v.) prior to
treatment with corn oil or PFOA diminished basal as well as
PFOA-induced peroxisomal beta-oxidation by 20-35%. Activation
of Kupffer cells by zymosan A also diminished catalase activity
by over 60%. Furthermore, PFOA reduced blood colloidal carbon
clearance by 35% within 2 h of its administration. The data
suggest that activation of Kupffer cells exerts a negative effect
on basal as well as PFOA-induced peroxisomal enzyme activities.
Data also suggest that PFOA inhibits Kupffer cells. Activated
Kupffer cells may indeed produce factors which interfere with
normal hepatic peroxisomal functions and responses.
PMID: 9089641 [PubMed - indexed for MEDLINE]
From
TOXNET
1997
ENVIRONMENTAL
SCIENCE & TECHNOLOGY; 31 (9). 2445-2454.
Fluorinated
organics in the biosphere.
KEY
BD, HOWELL RD, CRIDDLE CS
Dep. Civil Environ.
Eng., Mich. State Univ., East Lansing, MI 48824, USA.
Abstract: BIOSIS
COPYRIGHT: BIOL ABS. The use of organofluorine compounds has
increased throughout this century, and they are now ubiquitous
environmental contaminants. Although generally viewed as recalcitrant
because of their lack of chemical reactivity, many fluorinated
organics are biologically active. Several questions surround
their distribution, fate, and effects. Of particular interest
is the fate of perfluoroalkyl substituents, such as the trifluoromethyl
group. Most evidence to date suggest that such groups resist
defluorination, yet they can confer significant biological activity.
Certain volatile fluorinated compounds can be oxidized in the
troposphere yielding nonvolatile compounds, such as trifluoroacetic
acid. In addition, certain nonvolatile fluorinated compounds
can be transformed in the biosphere to volatile compounds. Research
is needed to assess the fate and effects of nonvolatile fluorinated
organics, the fluorinated impurities present in commercial formulations,
and the transformation [abstract truncated]
Fundamental
and Applied Toxicology, Vol. 30, No. 1, pages 102-108,
37 references, 1996
The
Direct Effect of Hepatic Peroxisome Proliferators on
Rat Leydig Cell Function In Vitro
Liu RCM, Hahn C, Hurtt ME
The effects of 11 peroxisome proliferators on rat Leydig
cells were investigated in-vitro. The compounds included
2,4-dichlorophenoxyacetic-acid (94-75-7) (2,4-D), acetylsalicylic-acid
(530-75-6), ammonium-perfluorooctanoate
(3825-26-1) (C8), ciprofibrate (52214-84-3),
clofibric-acid (882-09-7), gemfibrozil (25812-30-0)
(GEM), tiadenol (6964-20-1) (TIAD), tibric-acid (24358-29-0),
trichloroacetic-acid (76-03-9), trichloroethylene (79-01-6),
and Wyeth-14,643 (50892-23-4). Leydig cells were isolated
from adult CD-rats, and cultured. After cells were incubated
with one of the peroxisome proliferators for 21 hours,
the medium was assayed for estradiol. Leydig cells were
then cultured for an additional 3 hours with or without
human chorionic gonadotropin (hCG), and the medium was
assayed for testosterone. C8,
GEM, and TIAD reduced the basal
release of estradiol; the other compounds increased
estradiol production. All but 2,4-D reduced hCG stimulated
release of testosterone; 2,4-D reduced the testosterone
response to 70% of control (not significant). The
authors conclude that peroxisome proliferators may directly
modify the steroidogenic function on Leydig cells in-vitro.
The possible connection between the production of Leydig
cell tumors in rats by some peroxisome proliferators
and the induction of Leydig cell tumors in-vivo was
considered.
|
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8685914&dopt=Abstract
1996
Toxicol Lett Jul;86(1):1-11
Perfluorodecanoic
acid, a peroxisome proliferator, activates phospholipase C,
inhibits CTP:phosphocholine cytidylyltransferase, and elevates
diacylglycerol in rat liver.
Reo NV, Narayanan L, Kling KB, Adinehzadeh
M.
Department of Biochemistry and Molecular Biology, Wright State
University, Cox Institute, Dayton, Ohio 45429, USA.
Perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA)
are peroxisome proliferators that cause hepatotoxicity in rodents.
This study shows that PFDA activates liver phospholipase C (PLC)
and inhibits CTP:phosphocholine cytidylyltransferase (CT). PLC
cytosolic and microsomal activities were increased 1.4- and
1.7-fold, respectively. CT activates were decreased to 58% (cytosol)
and 36% (microsome) of control values. PFDA also caused a threefold
increase in liver diacylglycerol (DAG) concentration. PFOA had
no effect on the enzyme activities or DAG concentration. Together
with previous results, these data suggest that PFDA activates
a phosphatidylcholine-specific PLC causing an increase in liver
phosphocholine and DAG. These effects are discussed in relation
to cellular signalling processes that may provide a mechanism
for PFDA-induced hepatotoxicity.
PMID: 8685914 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8732932&dopt=Abstract
1996
Am J Ind Med May;29(5):560-8
Serum
perfluorooctanoic acid
and hepatic enzymes, lipoproteins, and
cholesterol: a study of occupationally exposed men.
Gilliland FD, Mandel JS.
Division of Environmental and Occupational Health, School of
Public Health, University of Minnesota, Minneapolis, USA.
Perfluorooctanoic acid (PFOA) produces
marked hepatic effects, including hepatomegaly, focal hepatocyte
necrosis, hypolipidemia, and alteration of hepatic lipid metabolism
in a number of animal species. In rodents, PFOA is a peroxisome
proliferator, an inducer of members of the cytochrome P450 superfamily
and other enzymes involved in xenobiotic metabolism, an uncoupler
of oxidative phosphorylation, and may not be a cancer promoter.
Although PFOA is the major organofluorine
compound found in humans, little information is available
concerning human responses to PFOA exposure. This study of 115
occupationally exposed workers examined the cross-sectional
associations between PFOA and hepatic enzymes, lipoproteins,
and cholesterol. The findings indicate that there is no significant
clinical hepatic toxicity at the PFOA levels observed in this
study. PFOA may modulate the previously described hepatic responses
to obesity and xenobiotics.
PMID: 8732932 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8741592&dopt=Abstract
1996
Biol Pharm Bull May;19(5):765-7
Differences
in the induction of carboxylesterase RL4 in rat liver microsomes
by various perfluorinated fatty acids, metabolically inert derivatives
of fatty acids.
Derbel M, Hosokawa M, Satoh T.
Laboratory of Biochemical Pharmacology and Toxicology, Faculty
of Pharmaceutical Sciences, Chiba University, Japan.
Differences in the ability of metabolically inert peroxisome
proliferators [perfluoro-n-decanoic acid (PFDA,
C10), perfluoro-n-octanoic acid (PFOA,
C8), perflorooctane sulfonic acid (PFOS,
C8) and 1H,1H-pentadecafluoro-n-octanol (PFOL,
C8)] to induce liver microsomal carboxylesterase RL4
in male rats were studied by evaluating changes in the RL4 content
by immunoblot analysis with a specific antibody. The administration
of PFOA, PFOS and PFOL markedly increase
the content of carboxylesterase RL4. On the other hand,
PFDA decreases PNPA, BUTA, and ISOC hydrolase activity, and
slightly increases the carboxylesterase RL4 content.
PMID: 8741592 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7610463&dopt=Abstract
1995
Toxicology May 23;99(3):169-78
Characterization
of hepatic responses of rat to administration of perfluorooctanoic
and perfluorodecanoic acids at low levels.
Kawashima Y, Kobayashi H, Miura H, Kozuka
H.
Faculty of Pharmaceutical Sciences, Josai University, Saitama,
Japan.
Male rats were fed a diet that contained perfluorooctanoic acid
(PFOA) and perfluorodecanoic acid (PFDA) at concentrations ranging
from 0.0025-0.04% (w/w) and from 0.00125-0.01% (w/w), respectively,
for 1 week. The hepatic responses of the rats to PFOA and PFDA
were examined. Upon the administration of PFOA and PFDA, three
peroxisome proliferator-responsive parameters, peroxisomal beta-oxidation,
microsomal 1-acylglycerophosphocholine (1-acyl-GPC) acyltransferase
and cytosolic long-chain acyl-CoA hydrolase, were induced in
a dose-dependent manner. A multiple regression analysis of the
three parameters revealed that the data from rats treated with
PFOA and PFDA shared one common line, indicating a marked correlation
among the inductions of the three parameters. The activities
of glutathione (GSH) S-transferases towards 1-chloro-2,4-dinitrobenzene
(CDNB) and 1,2-dichloro-4-nitrobenzene (DCNB) were depressed
by PFOA and PFDA. Significant inverse correlations were found
between activities of GSH S-transferases and peroxisomal beta-oxidation.
The administration of PFOA and PFDA significantly increased
hepatic concentration of triacylglycerol. The perfluorocarboxylic
acids at relatively high doses caused accumulation of cholesterol
in liver. Electron microscopic studies showed that the administration
of PFOA and PFDA caused an increase in cell size and proliferations
of peroxisomes, and that the treatment of rats with PFDA at
dietary concentration of 0.01% caused a marked increase in small
lipid droplet in hepatocytes, indicative of hepatotoxic manifestations.
The present results suggest that when PFOA and PFDA are administered
at low levels, there are no differences between the properties
of the perfluorocarboxylic acids as peroxisome proliferators,
although the administration of PFDA at the doses exceeding a
certain level becomes markedly toxic to hepatocytes.
PMID: 7610463 [PubMed - indexed for MEDLINE]
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