60, 379 –384 (2001)
Copyright © 2001 by the Society of Toxicology
TOXICOLOGICAL SCIENCES
Fumonisin B 1 Increases Serum Sphinganine Concentration but Does
Not Alter Serum Sphingosine Concentration or Induce
Cardiovascular Changes in Milk-Fed Calves
Sheerin Mathur,* Peter D. Constable,* ,1 Robert M. Eppley,† Mike E. Tumbleson,‡ Geoffrey W. Smith,*
William J. Tranquilli,* Dawn E. Morin,* and Wanda M. Haschek§
*Departments of Veterinary Clinical Medicine, ‡ Veterinary Biosciences, and §Veterinary Pathobiology, College of Veterinary Medicine,
University of Illinois, Urbana, Illinois 61802; and †U.S. Food and Drug Administration, Washington, DC
Received August 31, 2000; accepted December 11, 2000
Fumonisin B 1 is the most toxic and commonly occurring form of
a group of mycotoxins that alter sphingolipid biosynthesis and
induce leukoencephalomalacia in horses and pulmonary edema in
pigs. Purified fumonisin B 1 (1 mg/kg, iv, daily) increased serum
sphinganine and sphingosine concentrations and decreased cardiovascular function in pigs within 5 days. We therefore examined
whether the same dosage schedule of fumonisin B 1 produced a
similar effect in calves. Ten milk-fed male Holstein calves were
instrumented to obtain blood and cardiovascular measurements.
Treated calves (n ⴝ 5) were administered purified fumonisin B 1 at
1 mg/kg, iv, daily for 7 days and controls (n ⴝ 5) were administered 10 ml 0.9% NaCl, iv, daily. Each calf was euthanized on day
7. In treated calves, serum sphinganine concentration increased
from day 3 onward (day 7, 0.237 ⴞ 0.388 ␮mol/l; baseline, 0.010 ⴞ
0.007 ␮mol/l; mean ⴞ SD), whereas, serum sphingosine concentration was unchanged (day 7, 0.044 ⴞ 0.065 ␮mol/l; baseline,
0.021 ⴞ 0.025 ␮mol/l). Heart rate, cardiac output, stroke volume,
mean arterial pressure, mean pulmonary artery pressure, pulmonary artery wedge pressure, central venous pressure, plasma volume, base-apex electrocardiogram, arterial Po 2, and systemic oxygen delivery were unchanged in treated and control calves.
Fumonisin-treated calves developed metabolic acidosis (arterial
blood pH, 7.27 ⴞ 0.11; base excess, –9.1 ⴞ 7.6 mEq/l), but all
survived for 7 days. We conclude that calves are more resistant to
fumonisin B 1 cardiovascular toxicity than pigs.
Key Words: fumonisin; sphingosine; sphinganine; sphingolipid;
cardiovascular toxicity; metabolic acidosis.
Fumonisins are a group of naturally occurring mycotoxins
produced primarily by 2 fungi, Fusarium verticillioides (F. moniliforme) and F. proliferatum, which are found in corn. Fumonisin ingestion leads to altered sphingolipid biosynthesis and
dose-dependent increases in serum and tissue sphinganine and
A portion of the results in this article were reported as an Abstract at the
Society of Toxicology-2000 Annual Meeting in Philadelphia (abstract #1622).
1
To whom correspondence should be addressed at the University of Illinois
at Urbana-Champaign, Department of Veterinary Clinical Medicine, 1008 W.
Hazelwood Dr., Urbana, IL 61802. E-mail: [email protected].
sphingosine concentrations (Riley et al., 1993), and has been
implicated in field cases of equine leukoencephalomalacia (Ross
et al., 1993) and porcine pulmonary edema (Haschek et al., 1992;
Osweiler et al., 1992). Experimentally, fumonisin causes liver
damage in all species studied to date, and also has been found to
have species-specific target-organ toxicity, organs such as brain in
horses (Ross et al., 1993), heart in pigs (Casteel et al., 1994;
Constable et al., 2000; Smith et al., 1999, 2000), and kidney in
sheep (Edrington et al., 1995), rabbits (Gumprecht et al., 1995),
and rats (Voss et al., 1989). The reason for the species-specific
target organ toxicity remains enigmatic.
In pigs, ingestion of fumonisin B 1 as culture material affects
the cardiovascular system by decreasing cardiac contractility,
heart rate, cardiac output, mean arterial pressure, arterial and
mixed venous blood oxygen tensions, and systemic oxygen
delivery by increasing mean pulmonary artery pressure, pulmonary artery wedge pressure, oxygen consumption, and oxygen extraction ratio (Constable et al., 2000; Smith et al.,
1996, 1999). Intravenous administration of purified fumonisin
B 1 (1 mg/kg, daily) induces similar signs of cardiovascular
dysfunction within 5 days in pigs (Smith et al., 2000). Therefore, we were interested in determining whether intravenous
administration of purified fumonisin B 1 (1 mg/kg, daily) induced cardiovascular dysfunction in other species, and if so,
whether the cardiovascular dysfunction was similar to that in
pigs. The cardiovascular effects of fumonisin B 1 were studied
in milk-fed calves because of their ready availability, cost, and
ease of instrumentation for cardiovascular studies. This is the
first study examining the cardiovascular effects of fumonisin
B 1 in a species other than the pig. It was hoped the results of
the study would further expand our knowledge of the mechanism of fumonisin toxicity and provide insight into the effects
of fumonisin in species other than swine.
MATERIALS AND METHODS
Animals. Our institutional committee on the care and use of laboratory
animals approved this study. Ten healthy male Holstein calves, colostrum-fed
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and aged between 7 and 14 days (weight 43 ⫾ 7 kg, mean ⫾ SD), were
obtained from local sources. The calves were housed at an ambient temperature
of approximately 21°C in individual calf pens, and were fed a high-quality
milk replacement (milk origin protein, crude protein ⬎20%, crude fat ⬎20%,
crude fiber ⬍0.15%) at 10% of their body weight/day, divided into 2 feedings
at approximately 12-h intervals, for the duration of the study. Calves had
access to supplemental water at all times.
Instrumentation. Calves were instrumented to collect blood and urine
samples, and to determine heart rate (HR), cardiac output (CO), mean pulmonary-artery pressure (MPAP), pulmonary-artery wedge pressure (PAWP), central venous pressure (CVP), mean arterial pressure (MAP), and pulmonaryartery blood temperature as described previously (Smith et al., 1999; Walker
et al., 1998). Briefly, calves were anesthetized with xylazine (Astra USA, Inc.,
Westborough, MA) (0.1 mg/kg, I M) 8 to 12 h after feeding of milk replacement material, followed 5 to 10 min later by ketamine (Ketaset, Fort Dodge,
IA) (4 mg/kg, iv). Calves were intubated orotracheally, placed in dorsal
recumbency on a water-circulating heating blanket, and allowed to ventilate
spontaneously, breathing 1.5% halothane in 100% oxygen to maintain anesthesia.
The right jugular furrow was prepared aseptically and the right jugular vein
and carotid artery identified by surgical cut down. A 12-inch polyethylene
catheter (Abbott Critical Care Systems, North Chicago, IL) (3-mm outside
diameter) was placed in the right carotid artery for measurement of mean
arterial blood pressure and to obtain arterial blood for analysis. A 90-cm, 7-F
Swan-Ganz thermodilution catheter (Baxter Healthcare Corp, Irvine, CA) was
advanced via the right jugular vein, right atrium, and right ventricle, so that the
distal port was in the pulmonary artery and the proximal port in the cranial
vena cava or right atrium. Correct catheter position was determined by evaluating the characteristic pressure-waveform on a strip chart recorder (Gilson
Medical Electronics, Middleton, WI). Catheters were secured to the calf. The
Swan-Ganz catheter was flushed every 12 h with heparinized 0.9% NaCl
solution (40 IU heparin/ml) to prevent thrombosis.
Experimental protocol. Following full recovery from instrumentation (12
to 24 h), calves were assigned randomly to 2 groups. Treated calves (n ⫽ 5)
were administered purified fumonisin B 1 at 1 mg/kg, iv, daily for 7 days.
Fumonisin B 1 was purified (⬎95% free acid form) as described in Smith et al.,
2000, dissolved in phosphate-buffered saline (pH 7.0), and the concentration
adjusted to produce an administration volume of approximately 10 ml/day.
Control calves (n ⫽ 5) were administered 10 ml of isotonic saline solution
(0.9% NaCl), iv, daily at the same time as the treated calves. Hemodynamic
measurements were obtained at 24-h intervals (8 A.M.), immediately before
feeding the milk replacement. Samples for blood gas analysis, hemoglobin
concentration, plasma protein concentration (arterial), and serum sphingosine
and sphinganine concentrations (mixed venous) were obtained at the same time
as hemodynamic measurements. Blood for hematologic analysis was obtained
at the start (baseline) and end of the study (day 7). Body weight was recorded
every 24 h, immediately before feeding. At the completion of the study (day 7),
each calf was euthanized with an overdose of sodium pentobarbital (60 mg/kg,
iv). Serum biochemical and pathologic findings are described elsewhere
(Mathur et al., 2001).
Cardiovascular measurements. Cardiac output was measured by the thermodilution technique with the aid of a cardiac output computer (American
Edwards Laboratories, Inc., Irvine, CA). Three to 5 ml of 5% dextrose solution
(0° C) was injected rapidly into the proximal port of the Swan-Ganz catheter,
and the change in pulmonary artery temperature monitored. The mean value of
3 CO determinations was used as the experimental value. Heart rate was
obtained simultaneously with CO determination and stroke volume (SV)
calculated as SV ⫽ CO/HR. Arterial and venous pressure measurements were
obtained with the calf standing and referenced to the scapulo-humeral joint.
Systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR)
were calculated (in units of dyne s/cm 5) as SVR ⫽ CO ⫻ 80/(MAP-CVP) and
PVR ⫽ CO ⫻ 80/(MPAP-PAWP). A standard base-apex electrocardiogram
was obtained (PageWriter Xli, Hewlett-Packard, Boise, ID) with the calf
standing.
Blood pH, P O2 , P CO2 , and hemoglobin concentration were measured
(Ciba-Corning 288 Blood Gas System; Medfield, MA) and pH, Po 2 , Pco 2
values corrected for pulmonary artery blood temperature. Plasma-bicarbonate concentration and base-excess values were calculated using standard
equations. Systemic oxygen delivery, oxygen consumption, oxygen-extraction ratio, alveolar-arterial oxygen gradient, and physiologic shunt fraction
were calculated. Systemic O 2 delivery was calculated as the product of
arterial O 2 content and cardiac output, and was indexed to body weight.
Total blood O 2 content was calculated to be 1.39 ml of O 2 /g of hemoglobin
plus dissolved O 2 equal to 0.3 volume %/100 mm of Hg. Mass specific
oxygen consumption (V O2 ) was calculated from the difference between
arterial (Ca O2 ) and mixed venous oxygen content (Cv O2 ), multiplied by CO,
and indexed to body weight: V O2 (ml O 2 /min.kg) ⫽ CO ⫻ (Ca O2 –
Cv O2 )/body weight. Systemic O 2 extraction ratio was calculated as the ratio
of the arterio-venous O 2 content difference to the arterial O 2 content. Room
air alveolar-arterial O 2 gradient [P(A-a) O2 ] was calculated by use of the
alveolar gas equation: PA O2 ⫽ PI O2 – (Pa CO2 /R), where PI O2 is the inspired
partial pressure of oxygen calculated from the barometric pressure and
PA O2 is the alveolar O 2 tension. The respiratory exchange ratio (R) was
assumed to equal 0.8. The physiologic shunt to total blood flow ratio
(Qs/Qt) was calculated by use of the shunt equation: Qs/Qt ⫽ (Ci O2 –
Ca O2 )/(Ci O2 – Cv O2 ), where Ci O2 is the oxygen content of ideal endpulmonary capillary blood. Plasma protein concentration ([PP]) was determined by refractometry and change in plasma volume at day i (from
baseline), calculated as: change in plasma volume from baseline ⫽
([PP i ] – [PP baseline ]) ⫻ 100/[PP i ].
Serum and myocardial sphingolipid analysis. Mixed venous blood samples were collected, allowed to clot at room temperature, and the serum
harvested after centrifugation (3000 ⫻ g). Serum samples were stored at –20°
C and thawed immediately before determining free sphinganine and sphingosine concentrations by modification of the methods described by Riley et al.
(1994b) and Yoo et al. (1996). Serum sphingolipid concentrations were determined after adding 200 ml of 10% sulfosalicylic acid to each 1-ml aliquot
of serum. Samples were allowed to stand for 5 min at room temperature,
centrifuged, and the supernatant discarded. The precipitate was disrupted
mechanically, and the homogenates hydrolyzed and extracted with a mixture of
chloroform and 0.2 M KOH in methanol at 40°C for 2 h. Sphinganine C 20
(internal standard), 100 ml 2 N NH 4OH, and the chloroform mixture used for
extraction hydrolysis were added to the precipitated protein. Samples were
washed (Yoo et al., 1996), dried through Na 2SO 4 columns, evaporated to
dryness under a stream of nitrogen, and derivatized with o-phthaldialdehyde
(Riley et al., 1994b). Concentrations of sphinganine, sphingosine, and sphinganine C 20 were determined by high performance liquid chromatography with
fluorescence detection.
The left ventricular myocardium was obtained immediately after euthanasia,
stored at –20°C, thawed, and a 50-mg (fumonisin-treated calves) or 200-mg
(control calves) tissue sample homogenized in 0.05 M potassium phosphate
buffer before being processed, as stated previously, for sphingolipid determination.
Hematologic analysis. Red-blood-cell indices, white-blood-cell count,
and differential and platelet counts were determined using a hemocytometer
(Cell-Dyne 3500, Abbott Diagnostics, Santa Clara, CA).
Statistical analysis. Data were presented as mean ⫾ SD. Non normally
distributed variables were log transformed or ranked before statistical analyses
were performed. Two-way analysis of variance (group, time) with repeated
measures on one factor (time) was used for comparison. Appropriate Bonferroni-adjusted post-tests were conducted whenever the F test was significant.
Within-group comparisons were to the baseline value. Between-group comparisons for each variable were made at each time interval. A statistical
software package (SAS, release 6.12, SAS Institute, Inc., Cary, NC) was used
for analysis. A p value of ⬍0.05 was considered significant.
CARDIOVASCULAR EFFECTS OF FUMONISIN B 1 IN CALVES
381
FIG. 1. Effect of intravenous administration of fumonisin B 1 (fumonisin, n ⫽
5) or isotonic saline (control, n ⫽ 5) on
selected cardiovascular parameters.
MAP ⫽ mean arterial pressure, MPAP ⫽
mean pulmonary arterial pressure.
RESULTS
Cardiovascular parameters. Heart rate, cardiac output,
mean arterial pressure, and mean pulmonary-artery pressure
were unchanged in treated and control calves (Fig. 1). Stroke
volume, pulmonary-artery wedge pressure, central venous
pressure, systemic vascular resistance, pulmonary vascular resistance, and plasma volume were also unchanged in treated
and control calves (data not shown).
PR interval, QRS duration, and QT interval of the base-apex
electrocardiogram were unchanged in treated and control
calves (data not shown). Cardiac arrhythmias, other than sinus
arrhythmia, were not observed in treated or control calves.
Blood gas analysis. Arterial pH was decreased in fumonisin-treated calves on days 6 and 7, and arterial-plasma bicarbonate concentrations and base excess were decreased in
treated calves on days 5 to 7, with decreased arterial Pco 2 on
day 7 (Fig. 2). This indicates development of metabolic acidosis in treated calves, with partial respiratory compensation.
Arterial Po 2 and oxygen delivery remained constant in
treated and control calves (data not shown). For treated and
control calves on day 7, no differences were observed for
oxygen consumption (treated, 8.2 ⫾ 2.0 ml O 2/min/kg; control,
9.7 ⫾ 4.3 ml O 2/min/kg), oxygen extraction ratio (treated,
0.49 ⫾ 0.07; control, 0.49 ⫾ 0.16), P(A–a) O2 (treated, 34 ⫾ 15
mm Hg; control, 21 ⫾ 10 mm Hg), or physiologic shunt to
blood flow ratio (treated, 10 ⫾ 6%; control, 9 ⫾ 5%).
Serum and myocardial sphingolipid analysis. The baseline
serum sphinganine concentration was 0.010 ⫾ 0.007 ␮mol/l,
the baseline serum sphingosine concentration was 0.021 ⫾
0.025 ␮mol/l, and the baseline serum sphinganine to sphingosine ratio was 0.50 ⫾ 0.23. Serum sphinganine concentrations were increased in treated calves by day 3, and then
appeared to plateau from days 5 to 7 (Fig. 3). Serum sphingosine concentrations were unchanged in treated calves (Fig.
4), although they were numerically 4 to 5 times higher than
baseline values at the end of the study. Serum sphinganine and
sphingosine concentrations tended to decrease in control calves
over time.
Serum sphinganine to sphingosine ratio progressively increased from day 3 onwards in treated calves, to 5.01 ⫾ 2.81
by day 7. Serum sphinganine to sphingosine ratio at day 7, in
control calves, was similar to the baseline value.
The left ventricular sphinganine concentration in control
calves was 0.75 ⫾ 0.60 ␮mol/kg wet weight of tissue, the
sphingosine concentration was 1.90 ⫾ 1.00 ␮mol/kg, and the
sphinganine to sphingosine ratio was 0.40 ⫾ 0.13. Left ventricular sphinganine concentration (67.5 ⫾ 126.0 ␮mol/kg),
sphingosine concentration (18.5 ⫾ 21.5 ␮mol/kg), and sphinganine to sphingosine ratio (2.86 ⫾ 1.80) were markedly
increased in fumonisin-treated calves.
Hematologic analysis. Blood hemoglobin concentration
was increased transiently in treated calves on day 4 (8.8 ⫾ 2.4)
and day 5 (9.0 ⫾ 2.6), but had returned to baseline value (7.8 ⫾
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MATHUR ET AL.
FIG. 2. Effect of intravenous administration of fumonisin B 1 (fumonisin, n ⫽
5) or isotonic saline (control, n ⫽ 5) on
selected acid-base parameters; *p ⬍
0.05, compared with baseline value †p ⬍
0.05, compared with control value at the
same time.
1.9) by day 7. There was no change in erythrocyte count and
indices, total and differential leukocyte count, or platelet count
in treated or control calves (data not shown).
DISCUSSION
The major findings in this study were that intravenous administration of purified fumonisin B 1 (1 mg/kg, daily for 7
FIG. 3. Effect of intravenous administration of fumonisin B 1 (fumonisin,
n ⫽ 5) or isotonic saline (control, n ⫽ 5) on serum sphinganine concentration.
*p ⬍ 0.05, compared with baseline value, †p ⬍ 0.05, compared with control
value at the same time.
days) in milk-fed calves increased serum sphinganine and
myocardial sphinganine and sphingosine concentrations, but
did not significantly change serum sphingosine concentration
or induce cardiovascular changes. In contrast, we recently
reported that the same dosage regimen of purified fumonisin B 1
increased both serum and myocardial sphinganine and sphingosine concentrations in pigs, and decreased cardiovascular
function by day 5 of administration (Smith et al., 2000). The
absence of fumonisin-induced cardiovascular effects in milk-
FIG. 4. Effect of intravenous administration of fumonisin B 1 (fumonisin,
n ⫽ 5) or isotonic saline (control, n ⫽ 5) on serum sphingosine concentration.
*p ⬍ 0.05, compared with baseline value.
CARDIOVASCULAR EFFECTS OF FUMONISIN B 1 IN CALVES
fed calves may be related to the animals⬘ much lower serum
sphinganine (0.24 ␮mol/l) and sphingosine concentrations
(⬍0.05 ␮mol/l) following fumonisin administration. This result contrasts with plasma sphinganine and sphingosine concentrations of approximately 0.9 ␮mol/l and 0.4 ␮mol/l, respectively, in pigs with fumonisin-induced cardiovascular
dysfunction (Smith et al., 2000), and plasma sphinganine and
sphingosine concentrations ⱖ2.2 ␮mol/L and ⱖ1.0 ␮mol/L,
respectively, in pigs dying from fumonisin-induced cardiovascular dysfunction (Smith et al., 1999). Also in contrast, milkfed calves had higher myocardial sphinganine (68 ␮mol/kg)
and sphingosine (19 ␮mol/kg) concentrations following fumonisin administration, relative to myocardial sphinganine and
sphingosine concentrations of 8 –12 ␮mol/kg and 5–7 ␮mol/
kg, respectively, in pigs with fumonisin-induced cardiovascular dysfunction (Smith et al., 1996, 2000), and myocardial
sphinganine and sphingosine concentrations of approximately
19 ␮mol/kg and 12 ␮mol/kg, respectively, in pigs dying from
fumonisin-induced cardiovascular dysfunction (Smith et al.,
1999). The physiological importance of changes in extracellular sphingolipid concentration relative to changes in tissue
sphingolipid concentration is currently unclear.
There are alternative reasons for the absence of cardiovascular toxicity in calves; they include species differences in the
conversion rate of sphinganine to sphinganine-1-phosphate and
sphingosine to sphingosine-1-phosphate, differences in the
number or responsiveness of receptors to sphinganine and
sphingosine (as well as their metabolites), alternative pathways
for sphinganine and sphingosine metabolism, and differences
in the metabolic pathways for complex sphingolipids and ceramide. Obviously, much more work is required to characterize
the reason for the variation in species susceptibility to fumonisin.
In healthy milk-fed calves, normal ranges for serum sphinganine and sphingosine concentration were similar to those
reported in adult cattle (Prelusky et al., 1995), pigs (Smith et
al., 1999), horses (Goel et al., 1996; Wang et al., 1992; ), and
rats (Riley et al., 1994a), but lower than those reported for
vervet monkeys (Shephard et al., 1996).
Although fumonisin B 1 did not induce cardiovascular depression in milk-fed calves, intravenous fumonisin administration did induce metabolic acidosis. As there were no changes in
cardiac output, arterial P O2, blood hemoglobin concentration,
oxygen delivery, and oxygen consumption in treated calves,
metabolic acidosis was attributed to renal failure secondary to
proximal tubular damage (Mathur et al., 2001).
In conclusion, the results of the present study support findings that cattle are more resistant to the toxic effects of fumonisins than horses and pigs (Osweiler et al, 1993; Prelusky et
al., 1995; Richard et al., 1996) and indicate that calves are
more resistant to fumonisin B 1 cardiovascular toxicity than
pigs. The mechanism for this resistance remains to be determined.
383
ACKNOWLEDGMENTS
This article fulfilled part of the requirements for the MS degree for S.M. We
gratefully acknowledge the assistance of Ms. Amy Waggoner in completing
the serum sphingolipid analyses. This study was supported by funding from the
U.S. Department of Agriculture Cooperative Regional Project NC129: Fusarium mycotoxins in cereal grains. G.W.S was supported by an American Heart
Association Fellowship Award (9804717X).
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