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 Soy
and the Brain
By John MacArthur
"Tofu Shrinks Brain!" No science fiction scenario, this
sobering soybean revelation is for real. But how did the "poster
bean" of the ’90s go wrong? Apparently, in many ways--none
of which bode well for the brain.
In a major ongoing study involving 3,734 elderly Japanese-American
men, those who ate the most tofu during midlife had up to 2.4 times
the risk of later developing Alzheimer’s disease. As part of
the three-decade long Honolulu-Asia Aging Study, 27 foods and drinks
were correlated with participants’ health. Men who consumed tofu
at least twice weekly had more cognitive impairment than those who
rarely or never ate the soybean curd.1, 2
"The test results were about equivalent to what they would have
been if they were five years older," said lead researcher Dr.
Lon R. White from the Hawaii Center for Health Research. For the guys
who ate no tofu, however, they tested as though they were five years
younger.
What’s more, higher midlife tofu consumption was also associated
with low brain weight. Brain atrophy was assessed in 574 men using
MRI results and in 290 men using autopsy information. Shrinkage occurs
naturally with age, but for the men who had consumed more tofu, White
said "their brains seemed to be showing an exaggeration of the
usual patterns we see in aging."
Phytoestrogens--Soy Self Defense
Tofu and other soybean foods contain isoflavones, three-ringed molecules
bearing a structural resemblance to mammalian steroidal hormones. White
and his fellow researchers speculate that soy’s estrogen-like
compounds (phytoestrogens) might compete with the body’s natural
estrogens for estrogen receptors in brain cells.
Plants have evolved many different strategies to protect themselves
from predators. Some have thorns or spines, while others smell bad,
taste bad, or poison animals that eat them. Some plants took a different
route, using birth control as a way to counter the critters who were
wont to munch.
Plants such as soy are making oral contraceptives to defend themselves,
says Claude Hughes, Ph.D., a neuroendocrinologist at Cedars-Sinai Medical
Center. They evolved compounds that mimic natural estrogen. These phytoestrogens
can interfere with the mammalian hormones involved in reproduction
and growth--a strategy to reduce the number and size of predators.
Toxicologists Concerned about Soy’s Health Risks
The soy industry says that White’s study only shows an association
between tofu consumption and brain aging, but does not prove cause
and effect. On the other hand, soy experts at the National Center for
Toxicological Research, Daniel Sheehan, Ph.D., and Daniel Doerge, Ph.D.,
consider this tofu study very important. "It is one of the more
robust, well-designed prospective epidemiological studies generally
available. . . We rarely have such power in human studies, as well
as a potential mechanism."
In a 1999 letter to the FDA (and on the ABC News program 20/20),
the two toxicologists expressed their opposition to the agency’s
health claims for soy, saying the Honolulu study "provides evidence
that soy (tofu) phytoestrogens cause vascular dementia. Given that
estrogens are important for maintenance of brain function in women;
that the male brain contains aromatase, the enzyme that converts testosterone
to estradiol; and that isoflavones inhibit this enzymatic activity,
there is a mechanistic basis for the human findings." 3
Although estrogen’s role in the central nervous system is not
well understood, White notes that "a growing body of information
suggests that estrogens may be needed for optimal repair and replacement
of neural structures eroded with aging."
One link to the puzzle may involve calcium-binding proteins, which
are associated with protection against neurodegenerative diseases.
In recent animal studies at Brigham Young University’s Neuroscience
Center, researchers found that consumption of phytoestrogens via a
soy diet for a relatively short interval can significantly elevate
phytoestrogen levels in the brain and decrease brain calcium-binding
proteins.4
Concerns About Giving Soy to Infants
The most serious problem with soy may be its use in infant formulas. "The
amount of phytoestrogens that are in a day’s worth of soy infant
formula equals 5 birth control pills," says Mike Fitzpatrick,
a New Zealand toxicologist. Fitzpatrick and other scientists believe
that infant exposure to high amounts of phytoestrogens is associated
with early puberty in girls and retarded physical maturation in boys.5
A study reported in The Lancet found that the "daily
exposure of infants to isoflavones in soy infant-formulas is 6-11 fold
higher on a bodyweight basis than the dose that has hormonal effects
in adults consuming soy foods." (This dose, equivalent to two
glasses of soy milk per day, was enough to change menstrual patterns
in women.6 In the blood of infants tested, concentrations
of isoflavones were 13,000-22,000 times higher than natural estrogen
concentrations in early life.7 )
Soy Interferes with Enzymes
While soybeans are relatively high in protein compared to other legumes,
they are a poor source of protein because other proteins found in soybeans
act as potent enzyme inhibitors. These "anti-nutrients" block
the action of trypsin and other enzymes needed for protein digestion.
Trypsin inhibitors are large, tightly folded proteins that are not
completely deactivated during ordinary cooking and can reduce protein
digestion. Therefore, soy consumption may lead to chronic deficiencies
in amino acid uptake.8
Soy’s ability to interfere with enzymes and amino acids may
have direct consequence for the brain. As White and his colleagues
suggest, "isoflavones in tofu and other soyfoods might exert their
influence through interference with tyrosine kinase-dependent mechanisms
required for optimal hippocampal function, structure and plasticity."2
High amounts of protein tyrosine kinases are found in the hippocampus,
a brain region involved with learning and memory. One of soy’s
primary isoflavones, genistein, has been shown to inhibit tyrosine
kinase in the hippocampus, where it blocked "long-term potentiation," a
mechanism of memory formation.9
Tyrosine, Dopamine,
and Parkinson’s Disease
The brain uses the amino acids tyrosine or phenylalanine to synthesize
the key neurotransmitters dopamine and norepinephrine, brain chemicals
that promote alertness and activity. Dopamine is crucial to fine muscle
coordination. People whose hands tremble from Parkinson’s disease
have a diminished ability to synthesize dopamine. An increased incidence
of depression and other mood disorders are associated with low levels
of dopamine and norepinephrine. Also, the current scientific consensus
on attention-deficit disorder points to a dopamine imbalance.
Soy has been shown to affect tyrosine hydroxylase activity in animals,
causing the utilization rate of dopamine to be "profoundly disturbed." When
soy lecithin supplements were given throughout perinatal development,
they reduced activity in the cerebral cortex and "altered synaptic
characteristics in a manner consistent with disturbances in neural
function."10
Researchers at Sweden’s Karolinska Institute and at the National
Institutes of Health are finding a connection between tyrosine hydroxylase
activity, thyroid hormone receptors, and depleted dopamine levels in
the brain--particularly in the substantia nigra, a region associated
with the movement difficulties characteristic of Parkinson’s
disease.11,12,13
Soy Affects the Brain via the Thyroid Gland
Tyrosine is crucial to the brain in another way. It’s needed
for the body to make active thyroid hormones, which are a major physiological
regulator of mammalian brain development. By affecting the rate of
cell differentiation and gene expression, thyroid hormones regulate
the growth and migration of neurons, including synaptic development
and myelin formation in specific brain regions. Low blood levels of
tyrosine are associated with an underactive thyroid gland.
It is well known that isoflavones in soy products can depress thyroid
function, causing goiter (enlarged thyroid gland) and autoimmune thyroid
disease. In the early 1960s, goiter and hypothyroidism were reported
in infants fed soybean diets.14 Scientists at the National
Center for Toxicological Research showed that the soy isoflavones genistein
and daidzein "inhibit thyroid peroxidase-catalyzed reactions essential
to thyroid hormone synthesis."15
Japanese researchers studied effects on the thyroid from soybeans
administered to healthy subjects. They reported that consumption of
as little as 30 grams (two tablespoons) of soybeans per day for only
one month resulted in a significant increase in thyroid stimulating
hormone (TSH), which is produced by the brain’s pituitary gland
when thyroid hormones are too low. Their findings suggested that "excessive
soybean ingestion for a certain duration might suppress thyroid function
and cause goiters in healthy people, especially elderly subjects."16
Thyroid Hormones and
Fetal Brain Development
Thyroid alterations are among the most frequently encountered autoimmune
conditions in children. Researchers at Cornell University Medical College
showed that the "frequency of feedings with soy-based milk formulas
in early life was significantly higher in children with autoimmune
thyroid disease."17 In a previous study, they found
that twice as many diabetic children had received soy formula in infancy
as compared to non-diabetic children.18
Recognizing the risk, Swiss health authorities recommend "very
restrictive use" of soy for babies. In England and Australia,
public health agencies tell parents to first seek advice from a doctor
before giving their infants soy formula. The New Zealand Ministry of
Health recommends that "Soy formula should only be used under
the direction of a health professional for specific medical indications.
. . Clinicians who are treating children with a soy-based infant formula
for medical conditions should be aware of the potential interaction
between soy infant formula and thyroid function."19
Thyroid hormones exert their influence during discrete windows of
time during development of the infant. Inappropriate hormone levels
can have a devastating effect on the developing human brain, especially
during the first 12 weeks of pregnancy when the fetus depends on the
mother’s thyroid hormones for brain development. After that,
both maternal and fetal thyroid hormone levels affect the central nervous
system.
A 1999 study published in the New England Journal of Medicine showed
that pregnant women with underactive thyroids were four times more
likely to have children with low IQs if the disorder were left untreated.
The study found that 19 percent of the children born to mothers with
thyroid deficiency had IQ scores of 85 or lower, compared with only
5 percent of those born to mothers without such problems.20
Thyroid, Brain, and Environmental Toxins
Children exposed prenatally and during infancy to common environmental
toxins like dioxin and polychlorinated biphenyls (PCBs) can suffer
behavioral, learning, and memory problems because these chemicals may
be disrupting the normal action of thyroid hormone.21
Soybeans grown in the United States contain residues of the pesticide
dieldrin, an organochlorine similar to DDT. Although both chemicals
were banned in the 1970s, dieldrin still persists in soils and is absorbed
through the roots. Today it is the most toxic residue found on domestic
soybeans.22 In Silent Spring, Rachel Carson warned
that dieldrin is nearly 50 times as poisonous as DDT. In addition to
disrupting hormones, it can have long delayed neurological effects,
ranging from loss of memory to mania.23 Chinese aphids were
recently discovered in fields scattered across Wisconsin, so increased
pesticide applications are likely.
Combinations of insecticides, weed killers, and artificial fertilizers--even
at low levels--have measurable detrimental effects on thyroid and other
hormones as well as on the brain.24 EPA scientists now want
to upgrade the commonly used herbicide, atrazine, to a "likely
carcinogen." In animal tests, atrazine attaches to sites on the
hypothalamus, a crucial brain region involved with regulating levels
of stress and sex hormones.25
Individuals newly diagnosed with Parkinson’s disease were more
than twice as likely to have been exposed to insecticides in their
home, compared to those without the disease.26 In September
2000, The Lancet reported that farmers and gardeners regularly
exposed to pesticides may have more than five times the risk of developing
mild cognitive dysfunction.
Soy formulas for infants can contain other neurotoxins: aluminum,
cadmium, and fluoride. Studies found that aluminum concentrations in
soy-based formulas were a 100-fold greater compared to human breast
milk,27 while cadmium content was 8-15 times higher than
in milk-based formulas.28 In an Australian study, the fluoride
content of soy-based formulas ranged from 1.08 to 2.86 parts per million.
The authors concluded that "prolonged consumption (beyond 12 months
of age) of infant formula reconstituted with optimally-fluoridated
water could result in excessive amounts of fluoride being ingested."29 A
study of Connecticut children revealed that mild to moderate fluorosis
was strongly associated with soy-based infant formula use.30
In May 2000, Boston Physicians for Social Responsibility released
their report, "The Toxic Threats to Child Development." In
the section on neurotoxins, they concluded, "Studies in animals
and human populations suggest that fluoride exposure, at levels that
are experienced by a significant proportion of the population whose
drinking water is fluoridated, may have adverse impacts on the developing
brain."31
Iodine versus Fluorine
The thyroid gland uses tyrosine and the natural element iodine to
make thyroxine (T4), a thyroid hormone containing four iodine atoms.
The other, much more biologically active thyroid hormone is tri-iodothyronine
(T3), which has three iodine atoms. Lack of dietary iodine has long
been identified as the problem in diminished thyroid hormone synthesis.
According to the International Council for the Control of Iodine
Deficiency Disorders: "Iodine deficiency has been called the world’s
major cause of preventable mental retardation. Its severity can vary
from mild intellectual blunting to frank cretinism, a condition that
includes gross mental retardation, deaf mutism, short stature, and
various other defects. . . The damage to the developing brain results
in individuals poorly equipped to fight disease, learn, work effectively,
or reproduce satisfactorily."
This crucial role of iodine is another reason why the thyroid gland
is especially vulnerable today. Canadian researcher Andreas Schuld
has documented more than 100 studies during the last 70 years that
demonstrate adverse effects of fluoride on the thyroid gland.32 Schuld
says, "Fluorine, being the strongest in the group of halogens,
will seriously interfere with iodine and iodine synthesis, forcing
more urinary elimination of ingested iodine as fluoride ingestion or
absorption increases." (See page 21.)
Soy Inhibits Zinc Absorption
The high phytic-acid content in soy may also have adverse effects
on brain function. Phytic acid is an organic acid present in the outer
portion of all seeds which blocks the uptake of essential minerals
in the intestinal tract: calcium, magnesium, iron, and especially zinc.
Soybeans have very high levels of a form of phytic acid that is particularly
difficult to neutralize and which interferes with zinc absorption more
completely than with other minerals.
The soy industry acknowledges the problem with the admission that
while "one-half cup of cooked soybeans contains one mg of zinc
. . . zinc is poorly absorbed from soyfoods." As for iron, "both
phytate and soy protein reduce iron absorption so that the iron in
soyfoods is generally poorly absorbed."33
According to unpublished documents, researchers testing soy formula
found that it caused negative zinc balance in every infant to whom
it was given.34 Even when the diets were additionally supplemented
with zinc, there was a strong correlation between phytate content in
formula and poor growth.
Zinc and the Brain
Relatively high levels of zinc are found in the brain, especially
the hippocampus. Zinc plays an important role in the transmission of
the nerve impulse between brain cells. Deficiency of zinc during pregnancy
and lactation has been shown to be related to many congenital abnormalities
of the nervous system in offspring. In children, "insufficient
levels of zinc have been associated with lowered learning ability,
apathy, lethargy, and mental retardation."35
The USDA references a study of 372 Chinese school children with very
low levels of zinc in their bodies. The children who received zinc
supplements had the most improved performance--especially in perception,
memory, reasoning, and psychomotor skills such as eye-hand coordination.
Three earlier studies with adults also showed that changes in zinc
intake affected cognitive function.36
New research has identified a specific contingent of neurons, called "zinc-containing" neurons,
which are found almost exclusively in the forebrain, where in mammals
they have evolved into a "complex and elaborate associational
network that interconnects most of the cerebral cortices and limbic
structures." This suggests the importance of zinc in the normal
and pathological processes of the cerebral cortex.37 Furthermore,
age-related tissue zinc deficiency may contribute to brain cell death
in Alzheimer’s dementia.38
Not a Good Idea
High levels of phytoestrogens and zinc-blocking phytic acid, plus
additional neurotoxic compounds such as dieldrin, aluminum, fluoride
and cadmium combine in soy to yield a veritable witches’ brew
that can have adverse effects on the brain during development and throughout
life.
Unfortunately, many American are now consuming soy foods in high
amounts as infant formula, soy milk and tofu-based products, usually
as a substitute for nourishing animal foods. In Asia, soy is consumed
in small amounts as a fermented condiment and not as a substitute for
animal foods.
Asians recognize the need for "brain foods" like eggs and
fish and realize that large amounts of soy can cause thyroid problems
and inhibit growth. They know that for optimum mental function, soy
foods are not a good idea.
References
1. White LR, Petrovich H, Ross GW, Masaki KH, Association of mid-life
consumption of tofu with late life cognitive impairment and dementia:
the Honolulu-Asia Aging Study. Fifth International Conference on Alzheimer’s
Disease, #487, 27 July 1996, Osaka, Japan.
2. White LR, Petrovitch H, Ross GW, Masaki KH, Hardman J, Nelson
J, Davis D, Markesbery W, Brain aging and midlife tofu consumption. J
Am Coll Nutr 2000 Apr;19(2):242-55.
3. Doerge and Sheehan, Letter to the FDA, Feb 18, 1999. (http://abcnews.go.com/onair/2020/2020_000609_soyfdaletter_feature.htm)
4. Lephart ED, Thompson JM, Setchell KD, Adlercreutz H, Weber KS,
Phytoestrogens decrease brain calcium-binding proteins... Brain
Res 2000 Mar 17;859(1):123-31.
5. Soy Infant Formula Could Be Harmful to Infants: Groups Want it
Pulled. Nutrition Week, Dec 10, 1999;29(46):1-2; See also www.soyonlineservice.co.nz
6. Cassidy A, Bingham S, Setchell KD, Biological effects of a diet
of soy protein rich in isoflavones on the menstrual cycle of premenopausal
women. Am J Clin Nutr 1994 Sep;60(3):333-40.
7. Setchell KD, Zimmer-Nechemias L, Cai J, Heubi JE, Exposure of
infants to phyto-oestrogens from soy-based infant formula. Lancet 1997
Jul 5;350(9070):23-27.
8. Fallon SA, Enig MG, Tragedy and Hype, The Third International
Soy Symposium. Nexus Magazine, Vol 7, No 3, April-May 2000.
9. O’Dell TJ, Kandel ER, Grant SG, Long-term potentiation in
the hippocampus is blocked by tyrosine kinase inhibitors. Nature 1991
Oct 10 353:6344 558-60.
10. Bell JM, Whitmore WL, Cowdery T, Slotkin TA, Perinatal dietary
supplementation with a soy lecithin preparation: effects on development
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11. Zetterstrom RH, Williams R, Perlmann T, Olson L, Cellular expression
of the immediate early transcription factors Nurr1 and NGFI-B suggests
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dopamine system. Brain Res Mol Brain Res 1996 Sep 5;41(1-2):111-20.
12. Castillo SO, Baffi JS, Palkovits M, Goldstein DS, Kopin IJ, Witta
J, Magnuson MA, Nikodem VM, Dopamine biosynthesis is selectively abolished
in substantia nigra... Mol Cell Neurosci 1998 May;11(1-2):36-46.
13. Baffi JS, Palkovits M, Castillo SO, Mezey E, Nikodem VM, Differential
expression of tyrosine hydroxylase in catecholaminergic neurons of
neonatal wild-type and Nurr1-deficient mice. Neuroscience 1999;93(2):631-42.
14. Shepard TH, Soybean goiter. New Eng J Med 1960;262:1099-1103.
15. Divi RL, Chang HC, Doerge DR, Anti-thyroid isoflavones from soybean:
isolation, characterization, mechanisms of action. Biochem Pharmacol 1997
Nov 15;54(10):1087-96.
16. Ishizuki Y, Hirooka Y, Murata Y, Togashi K, The effects on the
thyroid gland of soybeans administered experimentally in healthy subjects. Nippon
Naibunpi Gakkai Zasshi 1991 May 20;67(5):622-29.
17. Fort P, Moses N, Fasano M, Goldberg T, Lifshitz F, Breast and
soy-formula feedings in early infancy and the prevalence of autoimmune
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18. Fort P, Lanes R, Dahlem S, Recker B, Weyman-Daum M, Pugliese
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of Health Position Statement on Soy Formulas (http://www.soyonlineservice.co.nz/regulat.htm)(Adobe
Acrobat PDF file: http://www.soyonlineservice.co.nz/files/mohsoy.pdf)
20. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon
J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein
RZ, Maternal thyroid deficiency during pregnancy and subsequent neuropsychological
development of the child. N Engl J Med 1999 Aug 19;341(8):549-55.
21. Hauser P, McMillin JM, Bhatara VS, Resistance to thyroid hormone:
implications for neurodevelopmental research on the effects of thyroid
hormone disruptors. Toxicol Ind Health 1998 Jan-Apr;14(1-2):85-101.
22. Groth E, Benbrook CM, Lutz K, Update: pesticides in children’s
foods, an analysis of 1998 USDA PDP data on pesticide residues, Consumers
Union of U.S., Inc., May, 2000 (Adobe Acrobat PDF file).
23. Hayes WJ, The toxicity of dieldrin to man. Bull World Health
Organ 1959;20:891-92.
24. Porter WP, Jaeger JW, Carlson IH, Endocrine, immune and behavioral
effects of aldicarb (carbamate), atrazine (triazine) and nitrate (fertilizer)
mixtures at groundwater concentrations. Toxicol Ind Health 1999
Jan-Mar;15(1-2):133-50.
25. Watson, Traci, Common herbicide likely causes cancer. USA
Today, June 29, 2000.
26. Nelson L, American Academy of Neurology’s 52nd annual meeting
in San Diego, CA, April 29-May 6, 2000.
27. McGraw M, Bishop N, Jameson R, Robinson MJ, O’Hara M, Hewitt
CD, Day JP, Aluminium content of milk formulae and intravenous fluids
used in infants.Lancet 1986 Jan 18;1(8473):157.
28. Dabeka RW, McKenzie AD, Lead, cadmium, and fluoride levels in
market milk and infant formulas in Canada. J Assoc Off Anal Chem 1987;70(4):754-57.
29. Silva M, Reynolds EC, Fluoride content of infant formulae in
Australia. Aust Dent J 1996 Feb;41(1):37-42.
30. Pendrys DG, Katz RV, Morse DE, Risk factors for enamel fluorosis
in a fluoridated population. Am J Epidemiol 1994 Sep 1;140(5):461-71.
31. Schettler T, Stein J, Reich F, Valenti M, In Harm’s Way:
Toxic Threats to Child Development. (http://www.igc.org/psr/ihw.htm)
Greater Boston Physicians for Social Responsibility, May 2000.
32. Studies dealing with fluoride and thyroid. (http://www.bruha.com/fluoride/html/thyroid_studies.htm)See
also: Fluoride Controversy in the Townsend Letter for Doctors and Patients.
(http://www.tldp.com/fluoride.htm)
33. Soy Nutritive Content, United Soybean Board. (http://www.talksoy.com/nutritive1.htm)
34. Pfeiffer CC, Braverman ER, Zinc, the brain and behavior. Biol
Psychiatry 1982 Apr;17(4):513-32.
35. Personal communication with Dr. Mary G. Enig
36. U.S. Department of Agriculture, Agricultural Research Service,
Food & Nutrition Research Briefs, July 1997. (http://www.nal.usda.gov/fnic/usda/fnrb/fnrb797.html)
37. Frederickson CJ, Suh SW, Silva D, Frederickson CJ, Thompson RB,
Importance of zinc in the central nervous system: the zinc-containing
neuron. J Nutr 2000 May;130(5S Suppl):1471S-83S.
38. Ho LH, Ratnaike RN, Zalewski PD, Involvement of intracellular
labile zinc in suppression of DEVD-caspase activity in human neuroblastoma
cells. Biochem Biophys Res Commun 2000 Feb 5;268(1):148-54.
About the Author
John D. MacArthur is a freelance writer who’s recently been researching
neuroscience topics for Brain.com. This report was originally published
by Brain.com in July 2000, as "The Trouble with Tofu." Since
then John D. MacArthur researched and wrote a comprehensive section
for the Franklin Institute Science Museum about how to nourish, exercise,
protect, and rest your brain.
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