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PubMed1994

Do the long fatty acid chains of sphingolipids interdigitate across the center of a bilayer of shorter chain symmetric phospholipids?

Novel cerebroside sulfate (CBS) spin labels containing long chain C24 or C26 fatty acids with a nitroxide spin label on the 22nd carbon were synthesized and used to investigate the ability of the long fatty acid chains of glycosphingolipids to interdigitate across the center of a non-interdigitated bilayer of phospholipids formed of symmetric saturated or unsaturated shorter fatty acid chain species, in the presence or absence of cholesterol. The motion of these long chain spin labels incorporated at 1 mole% in dimyristoylphosphatidylcholine (diC14-PC), dipalmitoylphosphatidylcholine (diC16-PC), distearoylphosphatidylcholine (diC18-PC), dibehenoylphosphatidylcholine (diC22-PC), spingomyelin (SM), 1-stearoyl-2-oleoylphosphatidylcholine (18:0.18:1-PC), and dimyristoylphosphatidylethanolamine (diC14-PE) was compared to that of CBS spin labels containing stearic acid spin labeled at the 5th carbon and at the 16th carbon. The results indicated that the C26 chain is interdigitated in the gel phase of diC14-PC, diC16-PC, SM, and possibly diC18-PC, but not diC14-PE, and the C24 chain may interdigitate in diC14-PC but not in the other phospholipids. Thus in order to interdigitate across the center of gel phase bilayers, the long acyl chain of the sphingolipid probably must be long enough to nearly span the phospholipid bilayer. The inability to interdigitate in diC14-PE is likely due to the close packing of this lipid in the gel phase. The C26 chain may also be interdigitated in these lipids in the presence of cholesterol at low temperatures. However, at physiological temperatures in the presence of cholesterol and in the liquid-crystalline phase of all the lipids, the results indicate that the long acyl chain of the glycosphingolipid is not interdigitated, but rather must terminate at the bilayer center. This may force the carbohydrate headgroup of the glycosphingolipid farther above the bilayer surface, allowing it to be recognized better by various carbohydrate binding ligands and proteins.

Cerebrosides↗
PubMed1996

Identification of a new sphingolipid 3-O-acyl-D-erythro-sphingomyelin in newborn pig and infant plasma.

A new sphingolipid was found in newborn pig plasma at a level of 2.5 +/- 0.4% of total lipids. The compound decreased to less than half that amount by day one of age and virtually disappeared by the fourth week. On thin-layer chromatography (TLC) the new lipid migrated close to phosphatidylethanolamine. The compound was isolated by TLC from the plasma of newborn piglets and identified as a 3-O-acyl-D-erythro-sphingomyelin by chemical and chromatographic techniques, 1H- and 13C-nuclear magnetic resonance and fast-atom bombardment mass spectrometry. Mild alkaline hydrolysis at room temperature gave mainly C16 and C18 fatty acids and sphingomyelin. Subsequent reaction with Ba(OH)2 released long-chain saturated and monounsaturated fatty acids from C14 to C24, and sphingosine which was identified as the erythro configuration by gas chromatography. Less than 1% of the sphingosine was of the C20 isomer. No hydroxy fatty acids were found. The acylated sphingomyelin was only found in plasma lipids of newborn piglets and not in their red blood cell membranes or platelets of newborn piglets, or in sow plasma. This compound was tentatively identified by chromatography in trace amounts in the serum of cord blood of newborn infants, but not in the plasma lipids of adults.

Acylation↗
PubMed1996

Sphingolipid synthesis and membrane formation by Plasmodium.

Plasmodium falciparum is a protozoan parasite that causes the most virulent o f human malarias. The asexual blood-stage organism invades and multiplies in a vacuole in the mature erythrocyte. During intravacuolar growth, it induces the formation of a novel network o f tubovesicular membranes, the TVM, that is not present in uninfected red blood cells. Recent data suggest that sphingomyelin biosynthesis by the parasite is an essential requirement for the assembly o f the TVM. Furthermore, sphingolipid synthesis as well as the formation and function o f the TVM may provide new targets for chemotherapy against malaria parasites.

Journal Article↗
PubMed2006

Level of M(IP)2C sphingolipid affects plant defensin sensitivity, oxidative stress resistance and chronological life-span in yeast.

The antifungal plant defensin DmAMP1 interacts with fungal sphingolipids of mannosyldiinositolphosphorylceramide (M(IP)2C) class. We screened a Saccharomyces cerevisiae transposon (Tn) mutant library against DmAMP1 and identified one DmAMP1-resistant mutant with the Tn inserted in the M(IP)2C biosynthesis gene IPT1 (DmTn11) and one DmAMP1-hypersensitive mutant with the Tn inserted in rDNA (HsTnII). However, tetrad analysis pointed to HsTnII as a spontaneous mutant. Apparently, membranes of DmTn11 lack M(IP)2C, whereas membranes of HsTnII have increased M(IP)2C levels. In addition, DmTn11 and HsTnII are characterized by increased and reduced oxidative stress resistance/chronological life-span (CL), respectively. A putative involvement of M(IP)2C in oxidative stress and CL in yeast is discussed.

Defensins↗
PubMed2000

Conformational studies of sphingolipids by NMR spectroscopy. II. Sphingomyelin.

Sphingomyelin (SM) is the most prevalent sphingolipid in the majority of mammalian membranes. Proton and 31P nuclear magnetic resonance spectral data were acquired to establish the nature of intra- and intermolecular H-bonds in the monomeric and aggregated forms of SM and to assess possible differences between this lipid and dihydrosphingomyelin (DHSM), which lacks the double bond between carbons 4 and 5 of the sphingoid base. The spectral trends suggest the formation of an intramolecular H-bond between the OH group of the sphingosine moiety and the phosphate ester oxygen of the head group. The narrower linewidth and the downfield shift of the resonance corresponding to OH proton in SM suggest that this H-bond is stronger in SM than in DHSM. The NH group appears to be involved predominantly in intramolecular H-bonding in the monomer. As the concentration of SM increases and the molecules come in closer proximity, these intramolecular bonds are partially disrupted and the NH group becomes involved in lipid-water interactions. The difference between the SM and DHSM appears to be not in the nature of these interactions but rather in the degree to which these intermolecular interactions prevail. As SM molecules cannot come as close together as DHSM molecules can, both the NH and OH moieties remain, on average, more intramolecularly bonded as compared to DHSM.

Animals↗
PubMed2002

Sphingomyelinase cleavage of sphingomyelin in pure and mixed lipid membranes. Influence of the physical state of the sphingolipid.

Sphingomyelin hydrolysis by sphingomyelinase is essential in regulating membrane levels of ceramide, a well-known metabolic signal. Since natural sphingomyelins have a gel-to-fluid transition temperature in the range of the physiological temperatures of mammals and birds, it is important to understand the influence of the physical state of the lipid on the enzyme activity. With that aim, large unilamellar vesicles consisting of pure egg sphingomyelin (gel-to-fluid crystalline transition temperature ca. 39 degrees C) were treated with sphingomyelinase in the temperature range 10-70 degrees C. The vesicles were also examined by differential scanning calorimetry (DSC). Shingomyelinase was active on pure sphingomyelin bilayers, leading to concomitant lipid hydrolysis, vesicle aggregation, and leakage of aqueous liposomal contents. Enzyme activity was found to be much higher when the substrate was in the fluid than when it was in the gel state. Sphingomyelinase activity was found to exhibit lag times, followed by bursts of activity. Lag times decreased markedly when the substrate went from the gel to the fluid state. When egg phosphatidylcholine, or egg phosphatidylethanolamine were included in the bilayer composition together with sphingomyelin, sphingomyelinase activity at 37 degrees C, that was negligible for the pure sphingolipid bilayers, was seen to increase with the proportion of glycerophospholipid, while the latency times became progressively shorter. A DSC study of the mixed-lipid vesicles revealed that both phosphatidylcholine and phosphatidyletanolamine decreased in a dose-dependent way the transition temperature of sphingomyelin. Thus, as those glycerophospholipids were added to the membrane composition, the proportion of sphingomyelin in the fluid state at 37 degrees C increased accordingly, in this way becoming amenable to rapid hydrolysis by the enzyme. Thus sphingomyelinase requires the substrate in bilayer form to be in the fluid state, irrespective of whether this is achieved through a thermotropic transition or by modulating bilayer composition.

Bacillus cereus↗
PubMed2001

Functional characterization of sphingolipid C4-hydroxylase genes from Arabidopsis thaliana.

In the genome of Arabidopsis thaliana, two genes were identified encoding isoenzymes for C4-hydroxylation of long chain bases (LCB) in plant sphingolipids. Both predicted proteins consist of 258 amino acid residues (77% identity) which show sequence similarity to di-iron-binding enzymes, such as Sur2p and Erg3p from yeast, involved in oxygen-dependent lipid modifications. Heterologous expression of these genes in a yeast sur2Delta-null mutant lacking C4-LCB hydroxylation resulted in the formation of D-ribo-C(18)- and -C(20)-phytosphinganine. The identity and stereochemical configuration of the isolated trihydroxybases was confirmed by electrospray ionization-mass spectroscopy, gas-liquid chromatography-mass spectrometry and 1H-nuclear magnetic resonance spectroscopy. These results represent the first functional identification of SUR2 genes from plants as well as from any organism other than yeast.

Arabidopsis↗
PubMed2002

Fumonisin B(1) alters sphingolipid metabolism and tumor necrosis factor alpha expression in heart and lung of mice.

Fumonisin B(1) (FB(1)), produced by Fusarium verticillioides, is a common contaminant in foods and feeds. Increase in tissue free sphingoid bases resulting from the inhibition of ceramide synthase is a biomarker of fumonisin exposure. Tumor necrosis factor alpha (TNFalpha) is induced in liver in response to FB(1) treatment. This study determined whether fumonisin B(1) caused increases in free sphingoid bases and altered the expression of TNFalpha in heart and lung, organs that are not targets of FB(1) toxicity, of male and female mice treated with 5-daily subcutaneous injection of 2.25 mg/kg FB(1). A significant increase in free sphingoid bases was observed in both heart and lung of FB(1)-exposed mice. The magnitude of increases in free sphingoid bases in both organs of female mice was much higher than that in males. The expression of TNFalpha was increased by FB(1) treatment in the lung of male mice and in the heart of female mice, whereas the expression of interferon gamma was unaltered. Results suggest that both sphingolipid accumulation and TNFalpha induction are observed in the tissues of mice that are not associated with FB(1) toxicity.

Animals↗
PubMed1999

Broad screening test for sphingolipid-storage diseases.

BACKGROUND: Lipid-storage diseases are collectively important because they cause substantial morbidity and mortality, and because they may present as dementia, major psychiatric illness, developmental delay, or cerebral palsy. At present, no single assay can be used as an initial general screen for lipid-storage diseases. METHODS: We used a fluorescent analogue of lactosylceramide, called N-[5-(5,7-dimethylborondipyrromethenedifluoride)-1-pentanoyl]D- lactosylsphingosine (BODIPY-LacCer), the emission of which changes from green to red wavelengths with increasing concentrations in membranes, to examine the intracellular distribution of the lipid within living cells. FINDINGS: During a brief pulse-chase experiment, the fluorescent lipid accumulated in the lysosomes of fibroblasts from patients with Fabry's disease, GM1 gangliosidosis, GM2 gangliosidosis (Tay-Sachs and Sandhoff forms), metachromatic leucodystrophy, mucolipidosis type IV, Niemann-Pick disease (types A, B, and C), and sphingolipid-activator-protein-precursor (prosaposin) deficiency. In control cells, the lipid was mainly confined to the Golgi complex. In a masked study, replicate samples of 25 of 26 unique cell lines representing ten different lipid-storage diseases, and 18 of 20 unique cell lines representing controls were correctly identified; the sensitivity was 96.2% (95% CI 80.4-99.9) and the specificity 90.0% (68.3-98.8). INTERPRETATION: This method may be useful as an initial general screen for lipid-storage diseases, and, with modification, could be used for large-scale automated screening of drugs to abrogate lysosomal storage in various lipidoses. The unexpected accumulation of BODIPY-LacCer in several biochemically distinct diseases raises important questions about common mechanisms of cellular dysfunction in these disorders.

Antigens, CD↗
PubMed1995

Inhibition of sphingolipid synthesis: effects on glycosphingolipid-GPI-anchored protein microdomains.

The idea that the transport and sorting of glycosylphosphatidylinositol (GPI)-anchored proteins depends on their interaction with glycosphingolipids was first proposed five or six years ago. Until recently, only circumstantial evidence was available to support this suggestion. During the past year, compelling support for this hypothesis has been provided by observations that inhibition of sphingolipid synthesis reduces the rate of transport of GPI-anchored proteins in yeast, and abolishes the polarized sorting of a GPI-anchored protein in epithelia.

Journal Article↗
PubMed1999

Characterization of sphingolipids from mycopathogens: factors correlating with expression of 2-hydroxy fatty acyl (E)-Delta 3-unsaturation in cerebrosides of Paracoccidioides brasiliensis and Aspergillus fumigatus.

Significant differences exist between mammals and fungi with respect to glycosphingolipid (GSL) structure and biosynthesis. Thus, these compounds, as well as the cellular machinery regulating their expression, have considerable potential as targets for the diagnosis and treatment of fungal diseases. In this study, the major neutral GSL components extracted from both yeast and mycelium forms of the thermally dimorphic mycopathogen Paracoccidioides brasiliensis were purified and characterized by 1H and 13C NMR spectroscopy, ESI-MS and ESI-MS/CID-MS, and GC-MS. The major GSLs of both forms were identified as beta-glucopyranosylceramides (GlcCer) having (4E, 8E)-9-methyl-4,8-sphingadienine as long chain base in combination with either N-2'-hydroxyoctadecanoate or N-2'-hydroxy-(E)-3'-octadecenoate. The mycelium form GlcCer had both fatty acids in a approximately 1:1 ratio, while that of the yeast form had on average only approximately 15% of the (E)-Delta 3-unsaturated fatty acid. Cerebrosides from two strains of Aspergillus fumigatus (237 and ATCC 9197) expressing both GalCer and GlcCer were also purified and characterized by similar methods. The GalCer fractions were found to have approximately 70% and approximately 90% N-2'-hydroxy-(E)-3'-octadecenoate, respectively, in the two strains. In contrast, the GlcCer fractions had N-2'-hydroxy-(E)-3'-octadecenoate at only approximately 20 and approximately 50%, respectively. The remainder in all cases was the saturated 2-OH fatty acid, which has not been previously reported in cerebrosides from A. fumigatus. The availability of detailed structures of both glycosylinositol phosphorylceramides [Levery, S. B., Toledo, M. S., Straus, A. H., and Takahashi, H. K. (1998) Biochemistry 37, 8764-8775] and cerebrosides from P. brasiliensis revealed parallel quantitative differences in expression between yeast and mycelium forms, as well as a striking general partitioning of ceramide structure between the two classes of GSLs. These results are discussed with respect to possible functional roles for fungal sphingolipids, particularly as they relate to the morphological transitions exhibited by P. brasiliensis.

Acylation↗
PubMed1999

Transport of (glyco)sphingolipids in and between cellular membranes; multidrug transporters and lateral domains.

Sphingolipids are highly enriched in the outer leaflet of the plasma membrane lipid bilayer. However, the first glycolipid, glucosylceramide, is synthesized in the opposite, cytosolic leaflet of the Golgi membrane. This has led us to experiments which suggest that the level of glucosylceramide in the cytosolic surface is carefully regulated both by the balance between synthesis and hydrolysis and by transport away from this surface through translocators, multidrug transporters, the same molecules that make cancer cells resistant to chemotherapy. Our data suggest a role for newly synthesized glucosylceramide not only in the formation of domains in the luminal leaflet of the Golgi but also on the cytosolic surface of this organelle.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Isolation and characterization of a cDNA encoding a Delta8 sphingolipid desaturase from Aquilegia vulgaris.

We have isolated a cDNA encoding the Delta(8) sphingolipid desaturase from the plant Aquilegia vulgaris L. via a PCR-based strategy using primers designed to target the conserved histidine box regions of microsomal desaturases. The function of the cDNA was confirmed by expression in the yeast, Saccharomyces cerevisiae. Analysis of the long-chain sphingoid bases as their dinitrophenyl derivatives by reverse-phase HPLC demonstrated the accumulation of cis - and trans -desaturated sphingoid bases which were not present in the wild-type yeast cells. The Delta(8) desaturated products co-eluted with known Delta(8)-desaturated phytosphingenine and the molecular mass of these products was confirmed by liquid chromatography-MS. The Delta(8) long-chain base desaturase was also able to desaturate dihydrosphingosine substrates. This is the first report of the functional characterization of an A. vulgaris gene product.

Aquilegia↗
PubMed2003

VEGF induces S1P1 receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors.

Sphingosine 1-phosphate (S1P) is a platelet-derived sphingolipid that binds to S1P1 (EDG-1) receptors and activates the endothelial isoform of NO synthase (eNOS). S1P and the polypeptide growth factor vascular endothelial growth factor (VEGF) act independently to modulate angiogenesis and activate eNOS. In these studies, we explored the cross-talk between S1P and VEGF signaling pathways. When cultured bovine aortic endothelial cells were treated with VEGF (10 ng/ml), the expression of S1P1 protein and mRNA increased by approximately 4-fold. S1P1 up-regulation by VEGF was seen within 30 min of VEGF addition and reached a maximum after 1.5 h. By contrast, expression of neither bradykinin B2 receptors nor the scaffolding protein caveolin-1 was altered by VEGF treatment. The EC50 for VEGF-promoted induction of S1P1 expression was approximately 2 ng/ml, within its physiological concentration range. S1P1 induction by VEGF was attenuated by the tyrosine kinase inhibitor genistein and by the PKC inhibitor calphostin C. Preincubation of bovine aortic endothelial cells with VEGF (10 ng/ml for 90 min) markedly enhanced subsequent S1P-dependent eNOS activation. VEGF pretreatment of cultured endothelial cells also markedly potentiated S1P-promoted eNOS phosphorylation at Ser-1179, as well as S1P-mediated activation of kinase Akt. In isolated rat arteries, VEGF pretreatment markedly potentiated S1P-mediated vasorelaxation and eNOS Ser-1179 phosphorylation. Taken together, these data indicate that VEGF specifically induces expression of S1P1 receptors, associated with enhanced intracellular signaling responses to S1P and the potentiation of S1P-mediated vasorelaxation. We suggest that VEGF acts to sensitize the vascular endothelium to the effects of lipid mediators by promoting the induction of S1P1 receptors, representing a potentially important point of cross-talk between receptor-regulated eNOS signaling pathways in the vasculature.

Animals↗
PubMed1996

Biosynthesis, processing, and targeting of sphingolipid activator protein (SAP )precursor in cultured human fibroblasts. Mannose 6-phosphate receptor-independent endocytosis of SAP precursor.

Sphingolipid activator proteins (SAPs) are essential cofactors for the lysosomal degradation of glycosphingolipids with short oligosaccharide chains by acidic exohydrolases. SAP-A, -B, -C, and -D derive from proteolysis of a 73-kDa glycoprotein, the SAP precursor. In the present publication, we studied the intracellular transport and the endocytosis of SAP precursor in human skin fibroblasts. Our data indicate that SAP precursor bears phosphate residues on noncomplex carbohydrate chains linked to the SAP-C and the SAP-D domain and sulfate residues on complex carbohydrate chains located within the SAP-A, -C, and possibly the SAP-D domain. Treatment of fibroblasts with either bafilomycin A1 or 3-methyladenine indicates that proteolytic cleavage of SAP precursor begins as early as in the late endosomes. To determine whether targeting of SAP precursor depends on mannose 6-phosphate residues, we analyzed the processing of SAP precursor in I-cell disease fibroblasts. In these cells nearly normal amounts of newly synthesized SAP-C were found, although secretion of SAP precursor was enhanced 2-3-fold. Moreover, SAP-C could be localized to lysosomal structures by indirect immunofluorescence in normal and in I-cell disease fibroblasts. Mannose 6-phosphate was not found to interfere significantly with endocytosis of SAP precursor. Normal fibroblasts internalized SAP precursor secreted from I-cells nearly as efficiently as the protein secreted from normal cells. To our surprise, deglycosylated SAP precursor was taken up by mannose 6-phosphate receptor double knock out mouse fibroblasts more efficiently than the glycosylated protein. We propose that intracellular targeting of SAP precursor to lysosomes is only partially dependent on mannose 6-phosphate residues, whereas its endocytosis occurs in a carbohydrate-independent manner.

Animals↗
PubMed2000

Identification of a novel sequence involved in lysosomal sorting of the sphingolipid activator protein prosaposin.

Prosaposin is synthesized as a 53-kDa protein, post-translationally modified to a 65-kDa form and further glycosylated to a 70-kDa secretory product. The 65-kDa protein is associated to Golgi membranes and is targeted to lysosomes, where four smaller nonenzymatic saposins implicated in the hydrolysis of sphingolipids are generated by its partial proteolysis. The targeting of the 65-kDa protein to lysosomes is not mediated by the mannose 6-phosphate receptor. The Golgi apparatus appears to accomplish the molecular sorting of the 65-kDa prosaposin by decoding a signal from its amino acid backbone. This investigation deals with the characterization of the sequence involved in this process by deleting the saposin functional domains A, B, C, and D and the highly conserved N and C termini of prosaposin. The truncated cDNAs were subcloned into expression vectors and transfected to COS-7 cells. The destination of the mutated proteins was assessed by immunocytochemistry. Deletion of the C terminus did not interfere with the secretion of prosaposin but abolished its transport to lysosomes. Deletion of saposins and the N-terminal domain did not affect the lysosomal or secretory routing of prosaposin. A chimeric construct of albumin and the C terminus of prosaposin was not directed to lysosomes. However, albumin connected to the C terminus and one or more functional domains of prosaposin reached lysosomes, indicating that the C terminus and at least one saposin domain are required for this process. In summary, we are reporting a novel sequence involved in the targeting of prosaposin to lysosomes.

Amino Acid Sequence↗
PubMed2005

Spatial and functional heterogeneity of sphingolipid-rich membrane domains.

Little is known about the organization of lipids in biomembranes. Lipid rafts are defined as sphingolipid- and cholesterol-rich clusters in the membrane. Details of the lipid distribution of lipid rafts are not well characterized mainly because of a lack of appropriate probes. Ganglioside GM1-specific protein, cholera toxin, has long been the only lipid probe of lipid rafts. Recently it was shown that earthworm toxin, lysenin, specifically recognizes sphingomyelin-rich membrane domains. Binding of lysenin to sphingomyelin is accompanied by the oligomerization of the toxin that leads to pore formation in the target membrane. In this study, we generated a truncated lysenin mutant that does not oligomerize and thus is non-toxic. Using this mutant lysenin, we showed that plasma membrane sphingomyelin-rich domains are spatially distinct from ganglioside GM1-rich membrane domains in Jurkat T cells. Like T cell receptor activation and cross-linking of GM1, cross-linking of sphingomyelin induced calcium influx and ERK phosphorylation in the cell. However, unlike CD3 or GM1, cross-linking of sphingomyelin did not induce significant protein tyrosine phosphorylation. Combination of lysenin and sphingomyelinase treatment suggested the involvement of G-protein-coupled receptor in sphingomyelin-mediated signal transduction. These results thus suggest that the sphingomyelin-rich domain provides a functional signal cascade platform that is distinct from those provided by T cell receptor or GM1. Our study therefore elucidates the spatial and functional heterogeneity of lipid rafts.

Cell Line↗
PubMed2001

The induction and persistence of altered sphingolipid biosynthesis in rats treated with fumonisin B1.

The fumonisins produced by Fusarium spp. are carcinogenic in rodents and possibly carcinogenic to humans. One action of fumonisins is to inhibit the enzyme ceramide synthase and as a consequence disrupt de novo sphingolipid biosynthesis. Measurement of the ratio of sphinganine (Sa) to sphingosine (So) in urine, serum and tissues has thus been made in various animal species as a marker of exposure to this mycotoxin. In this study in male BDIV rats, the effect of increasing daily gavage doses (0.01-5 mg/kg b.w.) of fumonisin B1 (FB1) on the Sa/So ratio in various tissues and urine was examined as was the persistence of the effects after cessation of treatment. The lowest dose of FB1 which induced an alteration of Sa/So in any tissue was 1 mg/kg b.w. The tissue most affected was the kidney, with the liver affected to a much lesser extent and the lung and oesophagus not at all. Only a modest indication of an alteration in Sa/So ratio was obtained in the urine. The large interindividual variations in urinary Sa and So in this strain of rat, even in the absence of FB1 treatment, made interpretation of these data difficult. After cessation of treatment, the Sa/So ratio returned to normal in kidney after a period of 1-3 weeks. These data suggest that altered Sa/So ratios reflect recent exposure to FB1 in the rat.

Animals↗