Arch. Environ. Contain. Toxicol.
28, 524-528 (1995)
Decrease of 12-Hydroxyeicosatetraenoic Acid Production in Mouse Lungs Following
Dietary Oleic Anilide Consumption: Implications for the Toxic Oil Syndrome
S. H. Yoshida 1"2, B. A. Bruenner 1, J. B. German 1, M. E. Gershwin 2
i Department of Food Science and Technology, University of California, Davis, California 95616, USA
2 Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, California 95616, USA
Received: 29 July 1994/Revised:8 October 1994
Abstract. A study was performed to examine the ability of
dietary oleic anilide to alter 12-hydroxyeicosatetraenoic acid
(12-HETE) production. The structure of oleic anilide, synthe-
sized by reacting oleic acid with aniline, was confirmed by
mass spectrometry. The purity of oleic anilide, 75%, was mea-
sured by gas chromatography. Oleic acid, which constituted the
remaining 25%, is a major component of the rapeseed oil vehi-
cle. Balb/c mice were fed oleic anilide as 0.75% of their diet by
weight for three weeks. Their lungs were excised and examined
for 12-HETE production in vitro. The 12-HETE levels were
significantly (p < 0.01) lower in mice fed oleic anilide than in
mice fed the oleic acid control diet. This result illustrates ei-
cosanoid production as a target of fatty acid anilide toxicity.
The fatty acid composition, including arachidonic acid, of
mouse lungs from both dietary groups was not different. This
confirms the availability of substrate for 12-1ipoxygenase in
both groups. Spleen weights were higher in mice fed oleic
anilide than in control mice (p < 0.005). These observations
are relevant to immunoregulation and the autoimmune syn-
dromes noted in patients of the Toxic Oil Syndrome (TOS).
Chemical and microbial environmental factors, and genetic
susceptibilities are important in the expression of autoimmu-
nity. However, the environmental etiologic agents responsible
for the induction of autoimmune diseases are generally un-
known. One possible example of chemical etiology is the Toxic
Oil Syndrome (TOS). In Spain in 1981, a mass poisoning
resulted from the consumption of oil adulterated with aniline,
and this public health illness was termed the Toxic Oil Syn-
drome. The major suspect toxicants are fatty acid anilides (A1-
dridge 1992; Guitart and Gelpi 1992), and the manifestations of
toxicity are at least partially mediated by the immune system.
Early signs of toxicity include high circulating levels of IgE and
eosinophils. Later stages of the syndrome include alopecia,
myalgia, scleroderma, and Sicca syndrome (Kilbourne et al.
Correspondence to: S. H. Yoshida
A R C H I V E S OF
Environmental
Contamination
a n d Toxicology
© 1995 Springer-VerlagNew York Inc.
1992). Thus, information gained from the TOS implicates envi-
ronmental chemicals as factors in the etiology of human au-
toimmune diseases.
Oxidative mechanisms may be important in the pathogenesis
of chemically-induced autoimmune disease, including the
TOS. Data supporting this hypothesis include the potential
ability of anilides to produce peroxides (Fournier et al. 1982),
the presence of 4-hydroxy-neonenals in case oils (Esterbauer
et al. 1991), and decreased levels of reduced glutathione in
oleic anilide-fed rats (Suarez et al. 1985). Because the toxic oil
samples were very sensitive to oxidation, Pestana and Munoz
(1982) speculated that they contained low levels of tocopherols
relative to natural occurring oils. Furthermore, oxidative dam-
age to the intimal layer of lung endothelia is thought to be the
primary lesion of the TOS (Borda and Posada de la Paz 1992).
In this context, this paper presents data demonstrating the lung
to be a target organ in mice exposed to oleic anilide through
their diet. Since oxygenases are well described targets of oxi-
dant stress (Fitzsimmons and Rokach 1989; German and Hu
1990; van der Donk et al. 1991; Percival et al. 1992; Ishii et al.
1993), lipoxygenase activity of lung epithelia was examined for
alterations by dietary oleic anilide. 12-HETE was chosen for
consideration, since it was not yet studied in the context of the
TOS.
Materials and M e t h o d s
Synthesis o f Anilides
Oleic anilide was prepared as described by Bell et al. (1992). Briefly,
aniline and oleic acid (Sigma, St. Louis, MO) were mixed and incu-
bated under nitrogen for 48 h in a 150° C oven. The oil was dissolved in
anhydrous diethyl ether, the excess aniline was removed by extraction
with 10% HC1 in water, and the excess acid was removed with
NaHCO3. The mixture was then passed through a Whatman #1 filter
paper, and the ether was evaporated with nitrogen.
M a s s Spectrometry
Synthetic anilides were characterized by gas chromatography/mass
spectrometry (GC/MS). Mass spectra were obtained on a VG Trio-2
Oleic anilide and 12-HETE production
quadrupole mass spectrometer, using electron impact ionization at 70
eV. Samples were analyzed on a 15 m DB-5 capillary column (J&W
Scientific, Folsom, CA) using helium as the carrier gas. The oven
temperature was programmed from 150 to 290°C at 10°C/min, and the
injector temperature was 290°C. The purified anilides were treated
with diazomethane prior to GC/MS analysis to form methyl esters of
any unreacted fatty acids. Purity of the anilide was estimated by com-
paring the peak area of the oleyl anilide to that of the oleic acid methyl
ester present in each sample. No other compounds were evident.
Feeding Protocol
Ten female, 6-week-old Balb/c mice were fed a fiet of AIN76A
(Dyets, Inc., PA) reconstituted with 10% fat. The fat was composed of
9% (w/w) rapeseed oil and 1% oleic anilide preparation; the diet thus
contained 0.75% oleic anilide. The 0.25% of oleic acid derived from
the anilide preparation was considered insignificant since oleic acid is a
major component of rapeseed oil, including those of case oils. Ten
control mice received a similar diet that contained 1% heated oleic
acid. The remaining 9% fat was derived from commercial rapeseed oil.
The oleic anilide or control oleic acid was added to the rapeseed oil
vehicle, then subsequently mixed with the AIN76A. Both diets were
stored at - 2 0 ° C until use. The anilide diets were prepared weekly.
The mice were fed ad libitum for three weeks prior to sacrifice and
analysis.
Mouse Lung Preparation
Freshly excised mouse lungs were homogenized with 2 ml of phos-
phate buffered saline and allowed to incubate for 3 h in a 37 ° C water
bath. Two ml of ethyl acetate and a prostaglandin B 1 standard were
added and vortexed. The lung homogenates were centrifuged and the
ethyl acetate (top) layer was removed. The solvent was evaporated
with nitrogen and the samples were redissolved in 100 ml of MeOH.
Product Analyses
12-HETE measurements were done as previously described (German
and Hu 1990). High performance liquid chromatographic analyses
were performed on a Hewlett Packard 1090 HPLC equipped with a
diode array detector. Reverse phase analyses were performed with a
25 x 4.6 mm C-18 column (Supelco, Bellefonte, PA). The com-
pounds were eluted isocratically, using a solvent system of
MeOH:H20 (70:30) buffered with 5 mM ammonium acetate and 1 mM
EDTA (pH 5.7).
Fatty acid analysis was done as previously described (Berger and
German 1990). Essentially, following 12-HETE analysis, mouse lung
samples were dried with nitrogen and reacted with diazomethane for 10
min. After the solvent was evaporated, samples were reconstituted
with 50 ml H20 and 100 ml hexane, centrifuged, and the hexane layers
analyzed by GC. These fatty acid methyl esters were separated with a
Hewlett-Packard GC Model 5890A (Hewlett-Packard Co., Palo Alto,
CA) equipped with a flame ionization detector, model 3392A integra-
tor, and a DB-225 capillary column (30 m x -0.25 mm i.d.; J&W
Scientific, Folsom, CA). Oven, injector, and detector temperatures
were, respectively, 170, 250 and 280 ° C. The make-up gas was nitro-
gen and the carrier gas was hydrogen; the split was 30:1.
Immunological Parameters
The enzyme-linked immunosorbent assay used to measure serum IgM
and IgG was done as described by Yoshida et al. (1987). Surface
525
phenotyping of spleen cells by fluoresceinated monoclonal antibodies
and flow cytometry was done as described by Naiki et al. (1993).
Statistics
The Mann-Whitney U test was performed with the StatView statistical
program on a Macintosh IIci computer.
Results
Structural Analysis of Fatty Acid Anilides
As shown in Figure 1, analysis of the oleic anilide preparations
by GC/MS revealed mass spectra similar to that previously
published (Wheals et al. 1982), thus confirming anilide forma-
tion. Molecular ions were observed at m/z 357 for oleic anil-
ides. The purity of oleic anilides showed that approximately
75% of the oleic acid present in the samples reacted with
aniline. The other chromatographic peak had a retention time
that corresponded to oleic acid.
12-HETE Production
Food consumption during the first week was similar between
both groups (Table 1). There was also no difference in mean
body weights just prior to sacrifice (Table 1). High perfor-
mance liquid chromatography analysis showed that 12-HETE
production by mice fed oleic anilide was significantly lower as
compared to that by oleic acid controls (Table 2). Total fatty
acid analysis of lung homogenates showed no differences in
arachidonic acid levels between the two diet groups (Table 3).
This latter information demonstrates that substrate availability
was not a limiting factor in 12-HETE production. Other esteri-
fled fatty acids from lung homogenates also were not signifi-
cantly different between groups (Table 3). Therefore, in the
short term, oleic anilide consumption did not severely affect the
general fatty acid composition of lung.
Immunological Parameters
There were no differences in total serum IgM/IgG levels or
spleen cell phenotypes between the groups (Table 4). Balb/c
mice fed oleic anilide had a higher mean spleen weight than
mice fed oleic acid ( 0 . 1 7 + - 0 . 0 2 versus 0 . 1 3 - - - 0 . 0 1 ;
mean -+ SD; p < 0.005).
Discussion
Data presented in this paper show that the feeding of oleic
anilide to Balb/c mice decreased 12-HETE production by lung
tissue. The results assume particular relevance due to the fol-
lowing three observations. First, oxidant stress has been sug-
gested as a possible mechanism for the toxicity observed in the
TOS (Fournier et al. 1982; Pestana and Munoz 1982; Suarez
et al. 1985; Esterbauer et al. 1991). Second, lungs are the
earliest target of anilide poisoning (Borda and Posada de la Paz
526 S.H. Yoshida et al.

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Fig. 1. Electron impact mass spectra of oleic anilide. In order to visualize the molecular ions better, the mass fragment intensities are magnified by
30 times at m/z/> 300

Table 1. Food consumption and body weights of mice fed AIN76A
supplemented with either oleic acid or oleic anilide
Diet group
Oleic acid
Food consumption (g/day/mouse)
Day
4 5.7 4.9
5 6.3 7.7
6 6.9 5.5
7 5.2 5.5
Mean --- SD of body weights prior to sacrifice (g)
22.1 4- 1.1 21.0 4- 0.9
AIN76A is the designation of a standardized, semi-purified mouse diet
1992). Finally, decreases in lung superoxide dismutase and
glutathione peroxidase activities have been reported in guinea
pigs given fatty acid anilides (Mukherjee e t a l . 1994).
Increased spleen weights following fatty acid anilide con-
sumption were noted in this study and by Khan e t a l . (1991).
The localization of ~4C in rat spleens following oral intake of
~4C-labeled oleic acid anilide also implicates this lymphoid
tissue as a target organ (Altmann and Grunow 1983). However,
no group differences in spleen cell phenotypes or serum immu-
noglobulins were observed in the present study. Other signs of
Table 2. 12-HETE production in lung homogenates of mice fed
AIN76A supplemented with either oleic acid or oleic anilide
Treatment 12-HETE
Oleic anilide Oleic acid 14185 4- 1905ab
Oleic anilide 8775 4- 2050
aMean 4- SD of total lung 12-HETE (ng) by HPLC
bp < 0,01, Mann-Whitney U test
12-HETE: 12-hydroxyeicosatetraenoic acid
AIN76A is the designation of a standardized, semi-purified mouse diet
toxicity were not seen (body weights, food intake, fatty acid
composition of lung tissue, etc.). This suggests that overt tox-
icity and immune dysfunction are preceded by subtle physio-
logic changes. Due to the broad range of functions of lipoxyge-
nase products, alterations in lipoxygenase activity could lead to
a very large number of definable physiologic abnormalities, as
were noted in patients of the Toxic Oil Syndrome.
Although the present work does not provide direct evidence
describing the mechanism by which 12-HETE production is
reduced, lipoxygenase inactivation by oxidants is suggested.
Oxygenases are a family of proteins with known susceptibility
to oxidant stresses. Products of lipoxygenase activity, such as
hydroperoxyeicosatetraenoic acids (van der Donk e t a l . 1991),
and other oxidants such as H202 can inactivate lipoxygenases
(Fitzsimmons and Rokach 1989; Percival e t a l . 1992). Hyper-
Oleic anilide and 12-HETEproduction 527

Table 3. Esterified fatty acid composition of lung homogenates of anilide toxicity (Khan et al. 1991; Blasco and Ruiz-Gutierrez
mice fed AIN76A supplemented with either oleic acid or oleic anilide 1992). Thus, the preferential elimination of regulatory CD8 + T
cells may lead to a loss of immunological self-tolerance and
Treatment
contribute to the induction of autoimmune diseases.
Fatty acids Oleic acid Oleic anilide Recent reports on the in vitro exposure of human endothelial
16:0 30.0 - 0.& 29.7 ± 1.4 cells to fatty acid anilides show that these compounds are able
18:0 13.6 ± 0.8 12.1 ± 1.1 to stimulate or inhibit arachidonic acid metabolism, depending
18:1 (9+11) 24.9 ± 1.6 27.6 --- 4.1 on concentration and duration of contact. In general, relatively
18:2 n6 7.3 - 0.3 7.4 ± 0.7 low concentrations of, and shorter preincubation times with,
18:3 n3 0.5 ± 0.1 0.6 ± 0.2 fatty acid anilides elicited 6-keto-PGF~ and PGF2,~production.
20:2 n6 0.3 ± 0.1 0.3 ± 0.1 However, higher concentrations and longer incubation times
20:3 n6 0.5 ± 0.4 0.5 ± 0.4 tended to inhibit release, possibly through the inactivation of
20:4 n6 (arachidonic acid) 2.6 ± 0.6 2.3 ± 0.3 cyclooxygenase or phospholipase (de Castellarnau et al. 1993;
22:6 n6 2.4 + 0.6 2.8 --- 0.4
Pich et al. 1993). It is not known if fatty acid anilides had a
Others 18.0 - 0.8 16.8 - 2.1
direct effect on the cultured endothelial cells or if oxidized
aMean -+ SD of mol % products derived from anilides were responsible.
AIN76A is the designation of a standardized, semi-purified mouse diet The importance of developing in vivo models of fatty acid
anilide toxicity is clear. There is the possibility that in vivo,
anilides act directly as cellular toxicants. However, they may
Table 4. Comparisons of serum immunoglobulin levels and spleen cell
also activate inflammatory responses and other complex inter-
phenotypes between mice fed AIN76A supplemented with either oleic
acid or oleic anilide actions which are impossible to model entirely in vitro. This is
reflected by the unchanged 12-HETE production that followed
Treatment the addition of oleic anilide directly to mouse lung homoge-
nates from mice not fed anilide (data not shown). The possibil-
Immunological parameters Oleic acid Oleic anilide
ity that the data presented here accurately reflects overall oxida-
Serum immunoglobulinsa tive stress induced by dietary oleic anilide will direct further
IgM 0.671 --- 0.089 b 0.708 -+ 0.132 investigations on both the causal events leading to the TOS,
IgG 1.255 ± 0.281 1.310 -+ 0.222 including mechanisms underlying oleic anilide reactivities with
Spleen cell phenotypes epithelial lipoxygenases, and potential intervention strategies.
CD4+ CD8- 65.3 -+ 2.1 ° 67.1 ± 1.6
Additionally, the importance of information on oxidant imbal-
CD4- CD8 + 25.2 -+ 2.6 24.5 + 1.9
CD4- CD8- 8.4 -+ 1.3 6.8 -+ 1.9 ances generated by such animal studies will undoubtedly extend
CD4+ CD8 + 1.0 -+ 0.2 1.6 + 0.8 to models of other pathological conditions.

aSera dilution, 1:104

bMean + SD of absorbance
CMean -+ SD of frequency among CD3 + spleen cells
AIN76A is the designation of a standardized, semi-purified mouse diet
oxia has also been shown to decrease cyclooxygenase activity
(Ishii et al. 1993). Previous work (German and Hu 1990) has
also demonstrated the inhibition of 12-1ipoxygenase by oxi-
dants.
It is unlikely that 12-HETE production was altered by an
effect on phospholipase A2 since free arachidonic acid levels
were similar in both groups of mice (Table 3). Also, phospho-
lipase A2 activity is downregulated by glucocorticoids (Glaser
et al. 1993). However, the global immunosuppressive effects
of glucocorticoids (Goulding and Guyre 1993) are not reflected
by the immunological data presented in Table 4. Thus, an effect
on lipoxygenase is probably responsible for the decreased 12-
HETE production.
Evidence of oxidant stress has been noted in chronic immu-
nologic diseases. Patients with HIV infections are known to be
under oxidant stress (Roederer et al. 1991; Droge et al. 1992).
Thiol oxidation of T lymphocytes (Brown-Galatoli and Hall
1992) and monocytes (McKeown et al. 1984) has also been
noted in rheumatoid arthritis. CD8 + T cells may be more sus-
ceptible to oxidant-induced inactivation than CD4 + T cells
(Gmunder and Droge 1991; Veis et al. 1993; Grigolo et al.
1994). Also, decreases in CD8 + T cells have been observed in
the TOS (Lahoz et al. 1992), as well as experimental studies on
Acknowledgments. This work was supported by Hatch funds (JBG) and
National Institutes of Health Grant CA 20816 (MEG). The authors
greatly appreciate the services of Ms. Cora Morgan for proofreading
the manuscript. This work is also sponsored in part by NOAA, Na-
tional Sea Grant College Program, Department of Commerce, under
grant number NA89AA-D-SG138, project number R/F-113 through
the California Sea Grant College Program and in part by the California
State Resources Agency. The U.S. Government is authorized to repro-
duce and distribute for governmental purposes.
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