On 2013 Dec 06, John Cannell commented:

I congratulate the authors on their intresting paper. I found my self wondering however, how can they explain the dramatic increase in incidence in this centruy? Didn't Tylenol use remain fairly constant from the year 2000 to the present time?

The question is why do some children exposed to Tylenol may develop autism and some do not? The answer must lie in their immune system. Some mothers and fetuses have enough antioxidant reserve to protect themselves from the oxidative damage induced by paracetamol exposure and some do not.

Certainly, a controlling factor in such reserve is the amount of the key antioxidants superoxide dismutase and thioredoxin reductase expressed by the mother or fetus. It has been known for some time that both of these antioxidants have been shown to be upregulated rather dramatically by the neurosteroid calcitriol or activated vitamin D. Although it is not clear from the papers below, it is probable that a vitamin D response element is involved in directly or indirectly controlling the genetic expression of both antioxidants.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25-dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol. 2004;92:131–141.

Swami S, Raghavachari N, Muller UR, Bao YP, Feldman D. Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. Breast Cancer Res Treat. 2003;80:49–62.

Palmer HG, Sanchez-Carbayo M, Ordonez-Moran P, Larriba MJ, Cordon-Cardo C, Munoz A. Genetic signatures of differentiation induced by 1α,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res. 2003;63:7799–7806.

I propose that much of the autism epidemic is caused by the meeting of a dysfunctional antioxidant reserve with paracetamol. That is, gestational or early childhood vitamin D deficiency causes down-regulation of key antioxidants, which leave the fetus vulnerable to the oxidative damage induced by paracetamol. Thus a combination of vitamin D deficiency and paracetamol exposure is both a necessary and sufficient condition to trigger an unkown percentage of autism and explains the rapid rise in the prevalence of the disorder, at least in the 1980s and 90s.

As far as vitamin D deficiency is concerned, three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with autism. Two of the studies below (Mostafa et al and Gong et al) also found autism severity, as rated on standard autism rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with autism severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1.

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5.

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201.

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely affect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57.

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84.

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64.

Furthermore, the vitamin D theory of autism explains many of the epidemiological facts of autism.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug; 99(8):1128-30.

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9.

It is likely that much of the autism epidemic is caused by the perfect storm of paracetamol meeting a vitamin D deficient immune system.

John Cannell, MD

Vitamin D Council

http://www.vitamindcouncil.org/

On 2013 Dec 06, John Cannell commented:

I congratulate the authors on their intresting paper. I found my self wondering however, how can they explain the dramatic increase in incidence in this centruy? Didn't Tylenol use remain fairly constant from the year 2000 to the present time?

The question is why do some children exposed to Tylenol may develop autism and some do not? The answer must lie in their immune system. Some mothers and fetuses have enough antioxidant reserve to protect themselves from the oxidative damage induced by paracetamol exposure and some do not.

Certainly, a controlling factor in such reserve is the amount of the key antioxidants superoxide dismutase and thioredoxin reductase expressed by the mother or fetus. It has been known for some time that both of these antioxidants have been shown to be upregulated rather dramatically by the neurosteroid calcitriol or activated vitamin D. Although it is not clear from the papers below, it is probable that a vitamin D response element is involved in directly or indirectly controlling the genetic expression of both antioxidants.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25-dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol. 2004;92:131–141.

Swami S, Raghavachari N, Muller UR, Bao YP, Feldman D. Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. Breast Cancer Res Treat. 2003;80:49–62.

Palmer HG, Sanchez-Carbayo M, Ordonez-Moran P, Larriba MJ, Cordon-Cardo C, Munoz A. Genetic signatures of differentiation induced by 1α,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res. 2003;63:7799–7806.

I propose that much of the autism epidemic is caused by the meeting of a dysfunctional antioxidant reserve with paracetamol. That is, gestational or early childhood vitamin D deficiency causes down-regulation of key antioxidants, which leave the fetus vulnerable to the oxidative damage induced by paracetamol. Thus a combination of vitamin D deficiency and paracetamol exposure is both a necessary and sufficient condition to trigger an unkown percentage of autism and explains the rapid rise in the prevalence of the disorder, at least in the 1980s and 90s.

As far as vitamin D deficiency is concerned, three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with autism. Two of the studies below (Mostafa et al and Gong et al) also found autism severity, as rated on standard autism rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with autism severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1.

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5.

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201.

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely affect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57.

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84.

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64.

Furthermore, the vitamin D theory of autism explains many of the epidemiological facts of autism.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug; 99(8):1128-30.

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9.

It is likely that much of the autism epidemic is caused by the perfect storm of paracetamol meeting a vitamin D deficient immune system.

John Cannell, MD

Vitamin D Council

http://www.vitamindcouncil.org/