Thursday, July 7, 2011

Is Autism Caused by Sulfate Deficiency and Excess Aluminum Exposure?

My best friend’s son was recently diagnosed with autism spectrum disorder, and this has inspired me to do some research on autism. Vast amounts have already been written on the subject, yet it seems that we are still far from understanding the elusive cause(s). The experts clearly believe there is a strong genetic component, yet they have been frustrated in their diligent efforts to identify those genetic causes [8]. At the same time, it is now pretty much indisputable that the incidence of autism, particularly in the U.S., has been steadily on the rise over the last few decades, now estimated to be over one in a hundred, an astonishing number.

Despite the fact that the vaccine industry has built a strong case that vaccines don’t cause autism, the autism community persists in claiming that they do. My research has led me to believe that the aluminum in vaccines plays a contributory role, as does the aluminum often found in sunscreen. Aluminum is a very common metal, yet it has never been incorporated into any biological system, and is clearly toxic to neurons, a subject I will return to later.

But I also believe that other environmental factors play probably a larger role than aluminum. Or, to say it another way, certain nutritional deficiencies predispose a child to be especially vulnerable to aluminum. My investigative research has led me to consider cholesterol [11] and vitamin D [3] deficiencies as prime candidates.

The brain represents only 2% of the total body mass, yet it houses 25% of the body’s total cholesterol. Because of the current obsession in the U.S. against dietary cholesterol and saturated fat, I was led to explore the question of cholesterol supply to the fetus during pregnancy. I was richly rewarded, and initially left baffled, by an article with a very surprising revelation [17]. Women with high serum cholesterol typically give birth to children with low serum cholesterol who already at birth have developed fatty streaks in their arteries, and are predisposed to developing heart disease much later in life. There seemed to be an inverse relationship between the mother’s and the fetus’s cholesterol levels!

Given the importance of cholesterol to the nervous system, remarkably little research has been done to characterize the mechanisms by which the fetus supplies itself with cholesterol. It had been hypothesized that the fetus synthesizes all of its own cholesterol supply, which would be surprising, given that cholesterol synthesis is a complex twenty-five step process that might be difficult for a fledgling organism to carry out. However, the biological machinery that would be necessary to transport cholesterol across the placental barrier to the fetus did not seem to exist [18].

I believe I have found the answer in a 1997 article by a team of Japanese researchers [14]. These authors were inspired to look at the concentration of cholesterol sulfate in the placenta and in the mother’s blood, as a function of time throughout pregnancy. They discovered that cholesterol sulfate concentrations in the mother’s blood rose from 1.85 to 2.23 to 3.09 over the course of the three trimesters of pregnancy, whereas non-pregnant women had a serum level of only 1.56. However, the more remarkable observation was the increase in cholesterol sulfate noted in placental villi, hairlike projections from the placenta that provide lots of surface area for contact with fetal blood supply. The concentration of cholesterol sulfate here went up from 3.93 to 18.35 to 23.75 over the course of the three trimesters, a six-fold increase from the first trimester to the third trimester! It might have been anticipated that cholesterol sulfate is important to the fetus, as it is in fact critically involved in the sperm decapitation stage that allows the sperm to fertilize the egg [13].

I am inclined to hypothesize (somewhat boldly) that certain mothers (and, more generally, certain people) have high cholesterol to compensate for the fact that their cholesterol sulfate level is deficient. Their fetus has low cholesterol because of inadequacies in the supply chain, obligatorily mediated by cholesterol sulfate. I might also boldly add that high cholesterol, a risk factor for cardiovascular disease in both the mother and the child, is, by deduction, an indicator of low cholesterol sulfate, and therefore that cholesterol sulfate protects from cardiovascular disease. I will need to revisit this topic in a later post!

Cholesterol sulfate is an interesting and elusive molecule. It is synthesized in the skin upon exposure to sunlight, alongside vitamin D3 sulfate [10, 2] and so this might be the connection between autism and vitamin D deficiency. It could well be that the sulfated form of vitamin D3 can substitute for cholesterol sulfate to some extent in supplying the fetus with sulfate. And it might then be supposed that sulfate is a critical nutrient that is in short supply in fetuses destined to later develop into autistic children.

This idea gains strong support from an article in Press in the timely subject of sulfate in fetal development [5]. From several studies on humans with rare genetic disorders and on animal models involving genetically engineered defective genes, it is abundantly clear that sulfate is absolutely essential to healthy fetal development. Furthermore, sulfate plays an important role in detoxifying drugs that might damage the fetus or the infant, such as acetaminophen, the active ingredient in tylenol. In fact, an interesting review article proposes that vulnerability to damage by Tylenol given subsequent to a vaccine-induced fever may have been a risk factor for autism [6]. Further support for a sulfate deficit in autism comes from a study showing, with a highly significant p-value of ¡ .00002, that severely autistic kids are unable to sulfate (and therefore detoxify) toxic chemicals [1].

Another really remarkable thing about cholesterol sulfate is that, in part because of its negative charge, it is “amphiphilic”: soluble in both water and fat. This means that it can travel freely in the blood stream (does not have to be packaged up inside LDL particles), and easily enters cell walls (ten times as agile as cholesterol itself in penetrating cell walls) [19]. I suspect these unique properties make it also much easier for cholesterol sulfate to get across the placental barrier than would be the case for cholesterol. Furthermore, cholesterol sulfate plays an important role in the outer skin, in protecting the body from invasion by pathogens [16]. A deficiency in cholesterol sulfate in the skin might explain the fact that autistic children often have skin problems and are more prone to infection.

I’d like to now return to the subject of the supposed genetic component to autism, which has been justified in part because an identical twin is much more likely to also have autism given that his twin has autism than is the case for fraternal twins. However, there is a further interesting observation that even fraternal twins are much more likely to both have autism than two siblings who are not twins. The genetic distance between fraternal twins is the same as that between brothers, and therefore genes can not explain this phenomenon. Furthermore, just being a twin is a risk factor for autism [7]. It would seem to me that all of these observations can be nicely explained if the assumption is that inadequate supply of a scarce resource (e.g., cholesterol sulfate) is the source of the problem. Twins would place double the demand on the mother’s limited supply. And identical twins often share a single placenta, which means that the villi would have to be twice as proliferous to fully supply two fetuses simultaneously, an unlikely feat. This could account for the increased risk in identical twins, without involving genetics at all.

Finally, I would like to return to the subject of aluminum, by discussing a fascinating article involving an experiment with aluminum exposure to pregnant mice, followed by an investigation of the properties of neurons harvested from the brains of the offspring. But first I should mention a couple more facts about features of autism. One novel characteristic of the autistic brain is that it actually is larger than the non-autistic brain at the age of two or three [9]. This is a time when ordinarily the brain goes through a massive pruning process, to weed out neurons that have failed to build up sufficient synaptic connections to be worthy of survival.

Two biological molecules that pair up on either side of the synapse to promote the memory of synaptic stimuli are neurexin and neuroligin. Several of the rare genetic defects that sometimes show up in connection with autism are related to either neurexin [12], on the input side of the synapse, or neuroligin [21] on the output side, where these two work together synergistically to coordinate transmission of the neurotransmitter glutamate. Glutamate plays an important role in wiring up the brain during early development, and this function has been hypothesized to be disturbed in autism. Glutamate is also intimately involved in the stage where neurons are pruned due to the fact that they received little input and are thus deemed extraneous. Furthermore, cholesterol, through a scissors mechanism, has been shown to play a crucial role in greatly increasing the ability of two neurons to make contact at a synapse [20]. In line with this observation, in-vitro studies have shown that cholesterol deficient neurons exhibit impaired glutamate transport, causing excess glutamate to accumulate outside the neuron [3].

In this light, the experiment on the mice that were exposed to aluminum prenatally was highly relevant. One of the important roles glutamate carries out is to signal to an unworthy neuron that it should die: that it should commit “programmed cell death” or “apoptosis” during the massive pruning stage. The mouse experiment [15] showed that neurons taken from the brains of mice prenatally exposed to aluminum responded abnormally to glutamate exposure that should have led to apoptosis. Whereas the number of neurons in the petri dish harvested from control mice sharply decreased upon exposure to glutamate, the aluminum-exposed neurons were quite happy to keep on growing, effectively ignoring the glutamate signal. This seemed to be exactly the same thing that the neurons in the autistic brains were doing when they weren’t pruned!

In summary, it seems to me that a possible explanation for the recent steady and alarming increase in the rate of autism in the U.S. is the confluence of a number of factors leading to a perfect storm. The problem centers on the two American obsessions of avoiding dietary fat and cholesterol and overprotection from the sun. The problem is further compounded by the relentless increase in the number of vaccinations against a multitude of childhood diseases, increasingly mandated by the U.S. government. These environmental influences conspire to produce children who are grossly deficient in cholesterol sulfate, which leads to impaired neurotransmission in the brain and impaired immune systems. The infiltration of aluminum into the brain compounds the problem, by further disrupting the already impaired glutamate transmission. The aluminum toxicity builds up due to the combination of exposure to both vaccines and sunscreen applied far too frequently to the skin, in the context of sulfate deficiencies that impair natural detoxification processes. It seems that some major changes in the American attitude towards what constitutes healthy living will need to take place before this epidemic can be brought under control.


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[2] M. Axelson, “The cholecalciferol sulphate system in mammals,” J. Steroid Biochem. 26(3), 369-373, 1987.

[3] T. Borisova, N. Krisanova, R. Sivko and A. Borysov, “Cholesterol depletion attenuates tonic release but increases the ambient level of glutamate in rat brain synaptosomes,” Neurochem Int. 2010 Feb;56(3), 466-78, 2010.

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[5] P.A. Dawson, “Sulfate in fetal development,” Seminars in Cell and Developmental Biology in Press, 2011.

[6] P. Good, “Did acetaminophen provoke the autism epidemic?,” Altern Med Rev.
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[7] D.A. Greenberg, S.E. Hodge, J. Sowinski and D. Nicoll, “Excess of Twins among Affected Sibling Pairs with Autism: Implications for the Etiology of Autism,” Am. J. Human Genetics 69, 1062-1067, 2001.

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[9] H. C. Hazlett, M. Poe, G. Gerig, R.G. Smith, J. Provenzale, A. Ross, J. Gilmore and J. Piven, “Magnetic Resonance Imaging and Head Circumference Study of Brain Size in Autism: Birth Through Age 2 Years,” Arch Gen Psychiatry, 62, 1366-1376, 2005.

[10] M. F. Holick, “Environmental factors that influence the cutaneous production of vitamin D,” Am. J. Clin. Nutr. 61(suppl), 638S-45S, 1995.

[11] R.I. Kelley, “Inborn errors of cholesterol biosynthesis,” Adv Pediatr. 47, 1-53, 2000.

[12] H-G Kim, S. Kishikawa, A.W. Higgins, I-S Seong, D.J. Donovan, Y. Shen, E. Lally, L.A. Weiss, J. Najm, K. Kutsche, M. Descartes, L. Holt, S. Braddock, R. Troxell, L. Kaplan, F. Volkmar, A. Klin, K. Tsatsanis, D.J. Harris, I. Noens, D.L. Pauls, M.J. Daly, M.E. MacDonald, C.C. Morton, B.J. Quade and J. F. Gusella1, “Disruption of Neurexin 1 Associated with Autism Spectrum Disorder,” Am J Hum Genet. 82(1), 199-207, 2008.

[13] J. Langlais, M. Zollinger, L. Plante, A. Chapdelaine, G. Bleau, and K.D. Roberts, “Localization of cholesteryl sulfate in human spermatozoa in support of a hypothesis for the mechanism of capacitation,” Proc. Natl Acad. Sci. USA 78(12), Biochemistry, 7266-7270, 1981.

[14] B. Lin, K. Kubushiro, Y. Akiba, Y. Cui, K. Tsukazaki, S. Nozawa and M. Iwamori, “Alteration of acidic lipids in human sera during the course of pregnancy: characteristic increase in the concentration of cholesterol sulfate,” Journal of Chromatography B, 704, 99-104, 1997.

[15] M. Llansola, M-D Minana, C. Montoliu, R. Saez, R. Corbalan, L. Manzo, and V. Felipo, “Prenatal Exposure to Aluminum Reduces Expression of Neuronal Nitric Oxide Synthase and of Soluble Guanylate Cyclase and Impairs Glutamatergic Neurotransmission in Rat Cerebellum,” J. Neurochem., 73(2), 712-718, 1999.

[16] H. Nakae, O. Hanyu, H. Fuda and C.A. Strott “Novel role of cholesterol sulfate in gene regulation during skin development,” The FASEB Journal, 22:782.2, 2008.

[17] C. Napoli, F.P. D'Armiento, F.P. Mancini, A. Postiglione, J.L. Witztum, G. Palumbo and W. Palinski, “Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions,” J Clin Invest. 100:2680 2690, 1997.

[18] W. Palinski, “Maternal Fetal Cholesterol Transport in the Placenta: Good, Bad, and Target for Modulation,” Circ. Res. 104, 569-571, 2009.

[19] W.V. Rodrigueza, J.J. Wheeler, S.K. Klimuk, C. N. Kitson and M.J. Hope, “Transbilayer Movement and Net Flux of Cholesterol and Cholesterol Sulfate between Liposomal Membranes,” Biochemistry 34(18), 6208-6217, 1995.

[20] J. Tong, P.P. Borbat, J.H. Freed and Y-K Shin, ”A scissors mechanism for stimulation of SNARE-mediated lipid mixing by cholesterol,” PNAS 106(13), 5141-5146, 2009.

[21] T. Ylisaukko-oja, K. Rehnstr ̈om, M. Auranen, R. Vanhala, R. Alen, E. Kempas, P. Ellonen, J.A. Turunen, I. Makkonen, R. Riikonen, T. Nieminen-von Wendt, L. von Wendt, L. Peltonen and I. J ̈arvel ̈a, “Analysis of four neuroligin genes as candidates for autism,” European Journal of Human Genetics 13, 1285-1292, 2005.

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