By John D. MacArthur
"Tofu Shrinks Brain!" Not a 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, compared with 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
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." 
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 phytoestrogens
levels in the brain and decrease brain calcium-binding proteins. 
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 Mary G. Enig,
Ph.D., president of the Maryland Nutritionists Association. She and other
nutrition experts believe that infant exposure to high amounts of phytoestrogens
is associated with early puberty in girls and retarded physical maturation
in boys. 
A study reported in the British medical journal
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." (A
dose, equivalent to two glasses of soy milk per day, that was enough to
change menstrual patterns in women. ) In the
blood of infants tested, concentrations of isoflavones were 13000-22000
times higher than natural estrogen concentrations in early life.
Soy Interferes with Enzymes
While soybeans are relatively high in protein compared
to other legumes, Enig says 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. 
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."
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. 
Tyrosine, Dopamine, and Parkinson's
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
Researchers at Sweden's Karolinska Institute at
the National Institutes of Health and 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
Soy Affects the Brain via the
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.
Scientists have known for years 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.  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." 
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." 
Thyroid Hormones and Fetal Brain
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."  In a previous study,
they found that twice as many diabetic children had received soy formula
in infancy as compared to non-diabetic children. 
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." 
Thyroid hormones exert their influence during discrete
windows of time. 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 is
left untreated. The study found that 19% of the children born to mothers
with thyroid deficiency had IQ scores of 85 or lower, compared with only
5% of those born to mothers without such problems. 
Thyroid, Brain, and Environmental
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. 
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.  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. 
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. 
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, while cadmium content was 8-15 times higher than in milk-based formulas.
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." A study of Connecticut children revealed
that mild-to-moderate fluorosis was strongly associated with soy-based
infant formula use. [27-30]
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."
Iodine vs. 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
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.
 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
Fluorides were actually used in the past, specifically
to reduce thyroid function. In the 1930s through to the 1960s fluorides
at 0.9mg to 4.5mg/day were given as effective anti-thyroid medication
to hyperthyroid patients."  Russian researchers in the 1980s
concluded that prolonged consumption of drinking water with a raised fluorine
content was a risk factor of more rapid development of thyroid pathology.
A major source of fluoride exposure in the United
States is fluoridated drinking water -- including foods and drinks
manufactured and processed with this treated water. (Only about 5% of
the world's population is fluoridated, and more than half live in North
America. 99% of western continental Europe has rejected, banned, or stopped
the addition of fluoride compounds to their drinking water. ) Also,
approximately 45 million pounds of hydrogen fluoride are released from
U.S. coal-fired plants every year into the environment.
Soy Phytates Inhibit Zinc Absorption
Another way that soybeans may affect brain function
is because of their phytic acid content. Phytic acid is an organic acid
present in the outer portion of all seeds. Also known as phytates, they
block the uptake of essential minerals in the intestinal tract: calcium,
magnesium, iron, and especially zinc. According to research cited by the
Weston A. Price Foundation, 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, noting
that "one-half cup of cooked soybeans contains one mg of zinc. However,
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." 
Nutritionist Sally Fallon, author of Nourishing
Traditions: The Cookbook that Challenges Politically Correct Nutrition
and the Diet Dictocrats, says that as early as 1967, researchers testing
soy formula found that it caused negative zinc balance in every infant
to whom it was given. Even when the diets were additionally supplemented
with zinc, there was a strong correlation between phytate content in formula
and poor growth. She warns that "a reduced rate of growth is especially
serious in the infant as it causes a delay in the accumulation of lipids
in the myelin, and hence jeopardizes the development of the brain and
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." 
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. 
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.  Furthermore, age-related tissue zinc deficiency
may contribute to brain cell death in Alzheimer's dementia. 
To produce soy milk, the beans are first soaked
in an alkaline solution, then heated to about 115 degrees C in order to
remove as much of the trypsin inhibitors as possible. Fallon says this
method destroys most, but not all of the anti-nutrients, however it has
the "unhappy side effect of so denaturing the proteins that they
become very difficult to digest and much reduced in effectiveness."
Furthermore, phytates remain in soy milk to block the uptake of essential
Only a long period of fermentation will significantly
reduce the phytate content of soybeans, as well as the trypsin inhibitors
that interfere with enzymes and amino acids. Therefore, fermented soy
products such as tempeh and miso
(not tofu) provide nourishment that is easily assimilated.
Links to Further Information:
Soy Online Service (http://www.soyonlineservice.co.nz/)
Weston A. Price Foundation (http://www.westonaprice.org/)
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,
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.
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.
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. Enig MG, Fallon SA, Tragedy and Hype,
The Third International Soy Symposium. Nexus Magazine Vol 7, No 3, April-May
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 of central catecholaminergic neurotransmitter systems.
Brain Res Bull 1986 Aug;17(2):189-95.
11. Zetterstrom RH, Williams R, Perlmann
T, Olson L, Cellular expression of the immediate early transcription factors
Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions
including the nigrostriatal dopamine system. Brain Res Mol Brain Res 1996
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, and 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 thyroid disease in children. J Am Coll Nutr 1990
18. Fort P, Lanes R, Dahlem S, Recker
B, Weyman-Daum M, Pugliese M, Lifshitz FJ, Breast feeding and insulin-dependent
diabetes mellitus in children. Am Coll Nutr 1986;5(5):439-41.
19. Regulatory Guidance in Other Countries:
New Zealand Ministry of Health Position Statement on Soy Formulas (Adobe
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
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
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
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. Greater Boston Physicians
for Social Responsibility, May 2000.
32. Studies Dealing with Fluoride and
the Thyroid Gland. See also: Fluoride Controversy in Townsend Letter for
Doctors and Patients.
33. Galetti PM, Joyet, G, Effect of
fluorine on thyroidal iodine metabolism in hyperthyroidism. J Clin Endocrinol
34. Bachinskii PP, Gutsalenko OA, Naryzhniuk
ND, Sidora VD, Shliakhta AI, Action of the body fluorine of healthy persons
and thyroidopathy patients on the function of hypophyseal-thyroid the
system. Probl Endokrinol (Mosk) 1985 Nov-Dec;31(6):25-29.
35. Fluoridation Status of Some Countries,
Fluoride: Protected Pollutant or Panacea?
36. Soy Nutritive Content, United Soybean
37. Pfeiffer CC, Braverman ER, Zinc,
the brain and behavior. Biol Psychiatry 1982 Apr;17(4):513-32.
38. U.S. Department of Agriculture,
Agricultural Research Service, Food & Nutrition Research Briefs, July
39. 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.
40. 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
Originally Appearing on