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Department of Paediatrics, University of British Columbia, Vancouver, Canada V5Z 4H4
1To whom correspondence should be addressed. E-mail: sinnis{at}interchange.ubc.ca
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • arachidonic acid • docosahexaenoic acid • dopamine • brain development • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
Sastry 1985
). Although numerous studies have shown that
reductions in 22:6(n-3) in the central nervous system during
development result in decreased visual function and alterations in
behavior and learning (Bourre et al. 1989
, Enslen et al. 1991
, Frances et al. 1996
,
Neuringer et al. 1986
, Yamamoto et al. 1988
), the metabolic roles of 22:6(n-3) are still largely
unknown. Recent studies, however, have shown that diet-induced
reductions in 22:6(n-3) in the postnatal brain are accompanied by
decreased dopamine and serotonin (de la Presa Owens and Innis 1999
, Delion et al. 1994
, 1996).
Both AA [20:4(n-6)] and DHA [22:6(n-3)] can be formed from the
dietary essential fatty acids linoleic acid [18:2(n-6)] and
-linolenic acid [18:3(n-3)], respectively, (Sprecher et al. 1995
) and are also present in diets containing animal lipids.
The developing fetus is supplied with (n-6) and (n-3) from the maternal
circulation; these are derived from the maternal diet, and the
developing brain selectively accumulates 20:4(n-6) and 22:6(n-3), but
not 18:2(n-6) and 18:3(n-3) (Clandinin et al. 1981
,
Crawford et al. 1981
). Further, the concentrations of
20:4(n-6) and 22:6(n-3) in fetal plasma are higher, and 18:2(n-6) is
lower than those in maternal plasma (Crawford et al. 1981
), suggesting selective or regulated transfer of 20:4(n-6)
and 22:6(n-3) to the developing fetus. Manipulation of dietary (n-6)
and (n-3) fatty acids during development alters brain 20:4(n-6) and
22:6(n-3) and several aspects of brain growth and function, including
brain weight, auditory evoked brain responses, learning behaviors and
possibly dendritic growth when measured in postweaned animals
(Bourre et al. 1989
, Enslen et al. 1991
,
Frances et al. 1996
, Saste et al. 1998
,
Wainwright et al. 1997
and 1999
, Yamamoto et al. 1988
). Maternal (n-3) fatty acid supplementation increases
blood lipid 22:6(n-3) in the newborn (Connor et al. 1996
), suggesting the fetus may be at risk for increased as
well as decreased 22:6(n-3) with variations in maternal dietary fatty
acid composition. Whether changes in neuronal membrane (n-6) and (n-3)
fatty acids and neurotransmitter metabolism occur in utero due to
manipulation of the maternal dietary fat, however, is not known, but is
clearly relevant to the sensitive periods of brain development and the
importance of the maternal diet in gestation.
In contrast to the mature brain, the immature brain has comparatively
few synaptic terminals. During nervous system development,
differentiating neurons form axons and dendrites that are tipped with
nerve growth cones. The growth cone, which represents the amoeboid
leading edge of the growing neurite, plays a key role in controlling
neurite outgrowth and guidance (Negre-Aminou et al. 1996
). The large membrane expansion during neuronal growth
necessitates synthesis of membrane phospholipid requiring large amounts
of 20:4(n-6) and 22:6(n-3). We have used the technique of isolating
growth cone membranes from fetal and newborn rat brain to investigate
the effect of maternal dietary (n-3) fatty acid supply on the
developing fetal brain. The potential effect of the maternal dietary
(n-3) fatty acids on fetal brain monoaminergic neurotransmitters was
also studied to address the possibility that changes in behavior and
learning when measured in older animals could include effects from
alterations in the prenatal period.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Female Wistar rats (University of British Columbia, Animal Care,
Vancouver, Canada) were randomly assigned to one of three diets,
n = 11/group. The rats were housed individually in
a temperature- and humidity-controlled animal unit with a 12-h
light:dark cycle, with food and water freely available. Female rats
were fed the diets beginning 1 wk before mating and then throughout
gestation. The experimental diets were semipurified and contained 20
g/100 g fat as soybean oil, or safflower oil, or a high 22:6(n-3), low
20:5(n-3) fish oil (Table 1
). All of the components of the diets were identical with the exception
of the fat. The high 22:6(n-3) fish (tuna) oil was a gift from Ross
Laboratories (Columbus, OH). All of the oils were stored in opaque
containers at -70°C, and the diets prepared fresh daily by addition
of the appropriate amount of oil to a mix of other dietary components.
The procedures were approved by the Animal Care Committee of the
University of British Columbia and conformed to the guidelines of the
Canadian Council on Animal Care.
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Growth cones were prepared from homogenized brain of newborns; the
brain tissue was pooled for each litter within 12 h of birth by
subcellular fractionation as described by Pfenninger et al. (1983)
and Ellis et al. (1985)
with slight
modification. Briefly, whole brain was homogenized in 8 volumes of 1.0
mmol/L N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic
acid (TES) containing 0.32 mol/L sucrose and 1.0 mmol/L EDTA, pH 7.3,
with five strokes in a Teflon-glass homogenizer. The homogenate was
centrifuged at 1660 x g for 15 min in a Sorvall T
6000 B centrifuge (Mandel, Guelph, Canada). The resulting supernatant
was loaded onto a discontinuous sucrose gradient (0.32, 0.75, 1.0, 2.66
mol/L sucrose) and subcellular and cellular membranes separated
according to their buoyant density by high speed centrifugation at
242,000 x g, for 40 min at 4°C in a L7–55
ultracentrifuge equipped with 50.2 Ti type rotor (Beckman Instruments,
Palo Alto, CA). The fraction isolated at the interface between the 0.32
and 0.75 mol/L sucrose cushion was collected and diluted threefold with
0.32 mol/L sucrose (1 mmol/L TES, 1 mmol/L EDTA, pH 7.3), then
centrifuged at 39,800 x g for 30 min at 4°C in a
L7–55 ultracentrifuge equipped with 50.3 Ti type rotor (Beckman). The
growth cone membranes were recovered, then frozen at -70°C until
further analysis.
Analytical methods.
Growth cone membrane lipids were extracted (Folch et al. 1957
), and phosphatidylcholine (PC), phosphatidylethanolamine
(PE), phosphatidylinositol (PI) and phosphatidylserine (PS) were
separated on TLC plates (Whatman PK6F Silica Gel 60 A) using methyl
acetate/n-propanol/chloroform/methanol/KCl 0.25%
(25:25:28:10:7, v/v/v/v/v) followed by methyl
acetate/n-propanol/chloroform/methanol/KCl 2.5 g/L
(25:25:25:10:9, v/v/v/v/v) in the same dimension. The separated
phospholipids were recovered; the fatty acid components were converted
to their respective methyl esters, separated, identified and quantified
by gas-liquid chromatography (Innis et al. 1994
).
For analysis of monoamines, pooled brain tissue (150 mg), representing
individual litters, was homogenized (Sonics Materials, Danbury, CT) for
2 x 3 s using a 2-mm probe, with a power setting of 25 W in
1330 µL of 0.1 mol/L perchloric acid with 70
µL 3,4-dihydroxybenzylamine (3 mg/L) as an internal
standard. The resulting homogenate was then centrifuged at 172,381
x g for 1 h at 4°C in a L7–55
ultracentrifuge equipped with 50.3 Ti type rotor (Beckman). The
supernatant was then transferred to a low volume insert vial (Waters
Millipore, Milford, MA). Monoamine concentrations were then determined
by HPLC, using a Waters (Mississauga, Canada) 2690 separation module
(Alliance) equipped with a refrigerated autosampler with
electrochemical detection [EG&G (Princeton, NJ) Applied Research
electrochemical detector model 400, with a glass carbon electrode cell
block and reference electrode 3 mmol/L NaCl/Sat AgCl filling solution]
and a Symmetry C18, 2.1 x 150 mm analytical column coupled to a
guard column Sentry Symmetry C18, 3.9 x 20 mm (Waters) as
described in detail (de la Presa Owens and Innis 1999
).
These analyses allow separation and quantitation of dopamine and the
metabolites 3,4-dihydroxphenylacetic acid (DOPAC) and
4-hydroxy-3-methoxy-phenylacetic acid, serotonin and the metabolite
5-hydroxyindole acetic acid. Concentrations of epinephrine and
norepinephrine were <0.1nmol/g in all samples.
Statistical analyses.
Significant differences among the treatment groups were analyzed by ANOVA with post-hoc least significant difference tests. Differences were considered significant at P < 0.05. All analyses were done using SPSS version 9.0 (Chicago, IL). Values are means ± SEM, n = 6–9 litters/group.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The concentrations of 22:6(n-3) were significantly higher in PE, PS
and PI among the diet groups in the following order: fish oil > soybean oil > safflower oil. The concentrations of 22:6(n-3) in
the neuronal growth cone PC of offspring born to rats fed fish oil were
also significantly higher than in those fed safflower, but not compared
with those fed soybean oil. In contrast to 22:6(n-3), the
concentrations of 20:4(n-6), 22:4(n-6) and 22:5(n-6) in PE, PS and PC,
and 22:4(n-6) and 22:5(n-6) in PI were all significantly lower in the
growth cone membranes from offspring of rats fed fish oil than in those
fed either soybean or safflower oil. The concentrations of 20:4(n-6)
and 22:4(n-6) in PC and of 22:5(n-6) in PC, PE and PI were also
significantly lower in the safflower than in the soybean oil group.
Eicosapentaenoic acid [20:5(n-3)] represented 7.2% of the fatty
acids in the high 22:6(n-3) fish oil, but was present at <0.5% of the
fatty acids in growth cone membrane phospholipids, even in offspring of
rats fed the fish oil diet. Feeding the high 22:6(n-3) fish oil during
pregnancy, however, resulted in significantly higher concentrations of
18:1 in the growth cone membrane PE and PI than in offspring of rats
fed safflower or soybean oil (mean ± SEM, PE 8.2
± 0.1, 6.7 ± 0.3 and 7.3 ± 0.1%; PI 9.3 ± 0.3,
7.7 ± 0.3 and 7.3 ± 0.2% 18:1 for the fish, safflower and
soybean oil groups, respectively).
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). The concentrations of dopamine and its metabolite DOPAC were
significantly lower in brain of offspring from rats fed fish oil than
in those fed safflower oil. Serotonin, in contrast, was significantly
higher in brain of offspring from rats fed safflower than in those fed
soybean oil. The brain dopamine concentration decreased significantly
as the concentration of 22:6(n-3) in the growth cone membrane PE and PS
increased (P < 0.001), and increased as the
concentration of 20:4(n-6) in PC increased, P < 0.05
(Fig. 2
). There were no other significant relationships among the (n–6) and
(n-3) fatty acids, including 20:5(n-3), or the ratio of (n-6) to (n-3)
fatty acids with the concentration of dopamine, serotonin or their
metabolites.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), the
fatty acid composition of the developing fetal brain is very sensitive
to perturbation by the (n-6) and (n-3) fatty acid composition of the
maternal diet. We also provide the first evidence that maternal dietary
fat may alter fetal brain monoamine concentrations. Previous studies
with rats and non-human primates have shown that extended feeding
with diets containing minimal (n-3) fatty acids results in reduced
22:6(n-3), with a compensatory increase in 22:5(n-6) in brain
phospholipids (Bourre et al. 1989
, Neuringer et al. 1986
). The changes in learning behavior that accompany
reduced brain 22:6(n-3) suggest that this fatty acid plays a specific
role in normal brain function. Feeding with oils containing large
amounts of 22:6(n-3), on the other hand, increases brain lipid
22:6(n-3) and decreases 20:4(n-6) (Chalon et al. 1998
,
Lin et al. 1990
, Valencia et al. 1998
,
Wainwright et al. 1997
). Our studies extend these
findings in postnatal animals to show that when fed throughout
gestation, safflower oil with 74% 18:2(n-6) and 0.2% 18:3(n-3)
decreased 22:6(n-3) by >50% in PE and PS in the fetal brain growth
cones compared with a soybean oil diet with 55% 18:2(n-6) and 8%
18:3(n-3). The concentration of 20:4(n-6) was 
30% higher, but only
in the PC fraction, in the growth cone membrane of offspring from the
groups fed safflower oil compared with soybean oil [mean ± SEM, 6.2 ± 0.4, 3.3 ± 0.6% 20:4(n-6),
respectively]. The reason for the increase in 20:4(n-6) secondary to
feeding a diet high in 18:2(n-6) and low in 18:3(n-3) is not known, but
could involve an important regulatory role of (n-3) fatty acids in
20:4(n-6) or PC synthesis. Feeding high DHA fish oil throughout
gestation increased 22:6(n-3), but reduced 20:4(n-6) in the growth cone
PC, PS and PE, as well as 22:4(n-6) and 22:5(n-6) in PC, PE, PS and PI.
The decrease in (n-6) fatty acids in the group fed fish oil is
reasonably explained by the low (n-6) content of the diet.
During brain growth, differentiating neurons form axons and dendrites
that are tipped with growth cones. The nerve growth cones, which form
the distal ends of the developing neurites, contain mitochondria,
endoplasmic reticulum and a cytoskeleton of neurofilaments,
microtubules and actin filaments and are involved in guiding the
growing axon (Landis 1983
). Many of the events involved
in regulating growth cone activity and conversion to mature synapses
are not well understood (Martin and Bazan 1992
);
however, the process requires high amounts of 20:4(n-6) and 22:6(n-3)
for incorporation into the expanding membrane surface. An increase in
20:4(n-6) and a decrease in 22:6(n-3) accompany the maturation of the
growth cones to mature synapses (Martin and Bazan 1992
).
In addition to the maturational changes in 20:4(n-6) and 22:6(n-3), the
concentrations of monoamines in the rat brain are relatively low at
birth and increase as a consequence of progressive proliferation and
development of axon terminals (Loizou and Salt 1970
).
Our study has shown that alteration of 20:4(n-6) and 22:6(n-3) in the
growth cone phospholipids of the newborn during fetal development is
accompanied by alterations in the concentrations of dopamine and its
metabolite DOPAC, and serotonin. Furthermore, the change in the newborn
brain dopamine was inversely correlated with 22:6(n-3), but positively
correlated with the change in 20:4(n-6) concentration in specific
phospholipids in the growth cone membranes.
Considerable information is available to show that 20:4(n-6) and its
eicosanoid metabolites act as membrane permeant second messengers, as
synaptic modulators of neurotransmitter release and uptake, and in the
regulation of ion channels (Fraser et al. 1993
,
Harris and Poo 1992
, Keyser and Alger 1990
, L’Hirondel et al. 1995
, Ordway 1991
, Piomelli 1994
). Further, liberation of
20:4(n-6) appears to be involved in neurite outgrowth (Cei de Job and Suburo 1988
) and in stimulation of release and
inhibition of reuptake of dopamine (L’Hirondel et al. 1995
). Much less is known about the functional roles of
22:6(n-3), although in other tissues, 22:6(n-3) acts as an antagonist
to 20:4(n-6) by decreasing 20:4(n-6)–stimulated chloride secretion and
by stimulating plasma membrane Ca2+-ATPase
activity (Caldero et al. 1994
). Our studies show that
increased 22:6(n-3) in the neuronal growth cone was associated with
reduced dopamine in the newborn brain is consistent with an
antagonistic effect of high 22:6(n-3) on dopamine. However, depletion
of 22:6(n-3) in the postnatal rat and piglet brain, secondary to
feeding a diet deficient in 18:3(n-3), also reduced dopaminergic as
well as serotinergic function in the frontal cortex (de al Presa Owens and Innis 1999
, Delion et al. 1994
and 1996
). Dietary fish oil, on the other hand, had no effect on
frontal cortex 22:6(n-3), but decreased 20:4(n-6) and increased
dopamine and serotonin in the postnatal rat frontal cortex
(Chalon et al. 1998
). The explanation for these
contradictory findings indicating a relation between high 22:6(n-3) and
low 20:4(n-6) and decreased dopamine in the fetal-neonatal brain
and low 22:6(n-3) and decreased dopamine in the postnatal brain is not
clear. Possible explanations include important differences in the
balance of 20:4(n-6) and 22:6(n-3), or stage of brain development. It
may also be that, as with many other nutrients, both deficiency and
very high amounts of 22:6(n-3) have adverse effects on normal cell
function. It is also unclear why significant relationships are present
between dopamine and 20:4(n-6) and 22:6(n-3) in some phospholipids, but
not others. It may be that this reflects changes in 20:4(n-6) and
22:6(n-3) in phospholipids that are functionally important to dopamine
synthesis or turnover. Alternatively, the results might be explained by
alterations in neurite growth or maturation secondary to changes in the
availability of 20:4(n-6) and 22:6(n-3) for membrane structural lipid
synthesis that have subsequent indirect effects on the development of
dopaminergic systems. Dopamine, like other neurotransmitters, plays an
important role in neurite outgrowth, growth cone motility, target cell
selection and synaptogenesis (Gelbard et al. 1990
,
Spencer et al. 1998
, Weiss et al. 1998
).
Whether the changes in brain dopamine concentrations in the fetal rat
brain that result from manipulation of the maternal dietary (n-6) and
(n-3) fatty acids lead to altered neuronal growth, or whether this
might be related to later differences in behavioral tests of learning
in animals fed diets varying in (n-6) and (n-3) fatty acids awaits
further study.
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FOOTNOTES |
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Manuscript received April 11, 2000. Initial review completed June 6, 2000. Revision accepted September 19, 2000.
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 C. Song, M. S. Manku, and D. F. Horrobin Long-Chain Polyunsaturated Fatty Acids Modulate Interleukin-1{beta}-Induced Changes in Behavior, Monoaminergic Neurotransmitters, and Brain Inflammation in Rats J. Nutr., May 1, 2008; 138(5): 954 - 963. [Abstract] [Full Text] [PDF]
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J. L. Pongrac, P. J. Slack, and S. M. Innis Dietary Polyunsaturated Fat that Is Low in (n-3) and High in (n-6) Fatty Acids Alters the SNARE Protein Complex and Nitrosylation in Rat Hippocampus J. Nutr., August 1, 2007; 137(8): 1852 - 1856. [Abstract] [Full Text] [PDF]
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 M. P Judge, O. Harel, and C. J Lammi-Keefe Maternal consumption of a docosahexaenoic acid-containing functional food during pregnancy: benefit for infant performance on problem-solving but not on recognition memory tasks at age 9 mo Am. J. Clinical Nutrition, June 1, 2007; 85(6): 1572 - 1577. [Abstract] [Full Text] [PDF]
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S. M. Innis Dietary (n-3) Fatty Acids and Brain Development J. Nutr., April 1, 2007; 137(4): 855 - 859. [Abstract] [Full Text] [PDF]
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P. Coti Bertrand, J. R. O'Kusky, and S. M. Innis Maternal Dietary (n-3) Fatty Acid Deficiency Alters Neurogenesis in the Embryonic Rat Brain J. Nutr., June 1, 2006; 136(6): 1570 - 1575. [Abstract] [Full Text] [PDF]
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 R. Friesen and S. M. Innis Maternal dietary fat alters amniotic fluid and fetal intestinal membrane essential n-6 and n-3 fatty acids in the rat Am J Physiol Gastrointest Liver Physiol, March 1, 2006; 290(3): G505 - G510. [Abstract] [Full Text] [PDF]
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 J. C. DeMar Jr., K. Ma, J. M. Bell, M. Igarashi, D. Greenstein, and S. I. Rapoport One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats J. Lipid Res., January 1, 2006; 47(1): 172 - 180. [Abstract] [Full Text] [PDF]
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K. Jacobson, H. Mundra, and S. M. Innis Intestinal responsiveness to experimental colitis in young rats is altered by maternal diet Am J Physiol Gastrointest Liver Physiol, July 1, 2005; 289(1): G13 - G20. [Abstract] [Full Text] [PDF]
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