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...more soybean grist for the mill...

Charles Miller rellim at tulane.edu
Tue Sep 12 08:45:38 EST 2000

This article appeared on the BRAIN.COM website (9-12-00,

"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 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 phytoestrogens 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 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. [5]

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. [6]) In the
blood of infants tested, concentrations of isoflavones were 13000-22000
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,
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. [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 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 disease. [11-13]

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.

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. [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.

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.
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. [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] 

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.

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]

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." [31]

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 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."

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."
[33] 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. [34]

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. [35]) Also, approximately 45 million pounds of hydrogen
fluoride are released from U.S. coal-fired plants every year into the

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." [36]

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 nervous system."

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." [37]

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. [38]

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. [39] Furthermore, age-related
tissue zinc deficiency may contribute to brain cell death in Alzheimer's
dementia. [40] 

Safe Soy 
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 minerals.

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 
Weston A. Price Foundation

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

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

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

8. Enig MG, Fallon SA, 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

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

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 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, 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 Apr;9(2):164-67.

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 Acrobat file).

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 file).

23. Hayes WJ, The toxicity of dieldrin to man. Bull World Health Organ

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

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 1958;18:1102-10.

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

35. Fluoridation Status of Some Countries, Fluoride: Protected Pollutant or

36. Soy Nutritive Content, United Soybean Board.

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 1997.

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 Feb 5;268(1):148-54. 


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