Environmental risk factors for autism: do they help cause de novo genetic mutations that contribute to the disorder?
Recent research has discovered that a number of genetic risk factors for autism are de novo mutations. Advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations. We investigated the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations. A survey of the research literature identified 9 environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of these factors—mercury, cadmium, nickel, trichloroethylene, and vinyl chloride—are established mutagens. Another four—including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation—are associated with decreased sun exposure and increased risk for vitamin D deficiency. Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress—a key cause of DNA damage. Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA. We note how de novo mutations may also help explain why the concordance rate for autism is so markedly higher in monozygotic than dizygotic twins. De novo mutations may also explain in part why the prevalence of autism is so remarkably high, given the evidence for a strong role of genetic factors and the low fertility of individuals with autism—and resultant selection pressure against autism susceptibility genes. These several lines of evidence provide support for the hypothesis, and warrant new research approaches—which we suggest—to address limitations in existing studies. The hypothesis has implications for understanding possible etiologic roles of de novo mutations in autism, and it suggests possible approaches to primary prevention of the disorder, such as addressing widespread vitamin D deficiency and exposure to known mutagens.
Med Hypotheses. 2010 Jan;74(1):102-6.
Autism and vitamin D.
Any theory of autism’s etiology must take into account its strong genetic basis while explaining its striking epidemiology. The apparent increase in the prevalence of autism over the last 20 years corresponds with increasing medical advice to avoid the sun, advice that has probably lowered vitamin D levels and would theoretically greatly lower activated vitamin D (calcitriol) levels in developing brains. Animal data has repeatedly shown that severe vitamin D deficiency during gestation dysregulates dozens of proteins involved in brain development and leads to rat pups with increased brain size and enlarged ventricles, abnormalities similar to those found in autistic children. Children with the Williams Syndrome, who can have greatly elevated calcitriol levels in early infancy, usually have phenotypes that are the opposite of autism. Children with vitamin D deficient rickets have several autistic markers that apparently disappear with high-dose vitamin D treatment. Estrogen and testosterone have very different effects on calcitriol’s metabolism, differences that may explain the striking male/female sex ratios in autism. Calcitriol down-regulates production of inflammatory cytokines in the brain, cytokines that have been associated with autism. Consumption of vitamin D containing fish during pregnancy reduces autistic symptoms in offspring. Autism is more common in areas of impaired UVB penetration such as poleward latitudes, urban areas, areas with high air pollution, and areas of high precipitation. Autism is more common in dark-skinned persons and severe maternal vitamin D deficiency is exceptionally common the dark-skinned. Conclusion: simple Gaussian distributions of the enzyme that activates neural calcitriol combined with widespread gestational and/or early childhood vitamin D deficiency may explain both the genetics and epidemiology of autism. If so, much of the disease is iatrogenic, brought on by medical advice to avoid the sun. Several types of studies could easily test the theory.
Med Hypotheses. 2008;70(4):750-9
Vitamin D and autism: clinical review.
BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with multiple genetic and environmental risk factors. The interplay between genetic and environmental factors has become the subject of intensified research in the last several years. Vitamin D deficiency has recently been proposed as a possible environmental risk factor for ASD. OBJECTIVE: The aim of the current paper is to systematically review the research regarding the possible connection between ASD and vitamin D, and to provide a narrative review of the literature regarding the role of vitamin D in various biological processes in order to generate hypotheses for future research. RESULTS: Systematic data obtained by different research groups provide some, albeit very limited, support for the possible role of vitamin D deficiency in the pathogenesis of ASD. There are two main areas of involvement of vitamin D in the human body that could potentially have direct impact on the development of ASD: (1) the brain (its homeostasis, immune system and neurodevelopment) and (2) gene regulation. CONCLUSION: Vitamin D deficiency—either during pregnancy or early childhood—may be an environmental trigger for ASD in individuals genetically predisposed for the broad phenotype of autism. On the basis of the results of the present review, we argue for the recognition of this possibly important role of vitamin D in ASD, and for urgent research in the field.
Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50
Primary vitamin D target genes allow a categorization of possible benefits of vitamin D3 supplementation.
Vitamin D deficiency has been associated with an increased risk of developing a number of diseases. Here we investigated samples from 71 pre-diabetic individuals of the VitDmet study, a 5-month high dose vitamin D3 intervention trial during Finnish winter, for their changes in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations and the expression of primary vitamin D target genes in peripheral blood mononuclear cells and adipose tissue. A negative correlation between serum concentrations of parathyroid hormone and 25(OH)D3 suggested an overall normal physiological vitamin D response among the participants. The genes CD14 and thrombomodulin (THBD) are up-regulated primary vitamin D targets and showed to be suitable gene expression markers for vitamin D signaling in both primary tissues. However, in a ranking of the samples concerning their expected response to vitamin D only the top half showed a positive correlation between the changes of CD14 or THBD mRNA and serum 25(OH)D3 concentrations. Interestingly, this categorization allows unmasking a negative correlation between changes in serum concentrations of 25(OH)D3 and the inflammation marker interleukin 6. We propose the genes CD14 and THBD as transcriptomic biomarkers, from which the effects of a vitamin D3 supplementation can be evaluated. These biomarkers allow the classification of subjects into those, who might benefit from a vitamin D3 supplementation, and others who do not.
PLoS One. 2013 Jul 29;8(7):e71042
Vitamin D deficiency: universal risk factor for multifactorial diseases?
In the Western world, the majority of morbidity and mortality are caused by multifactorial diseases. Some risk factors are related to more than one type of disease. These so-called universal risk factors are highly relevant to the population, as reduction of universal risk factors may reduce the prevalence of several types of multifactorial disease simultaneously. Vitamin D deficiency is traditionally seen as an etiological factor in bone disorders such as rickets and osteomalacia. Recent studies also suggest a role for vitamin D deficiency in multifactorial disorders, including progressive renal function loss and cardiovascular disease; it is also a risk factor for frailty. The potentially pleiotropic effects of vitamin D analogues support the hypothesis that vitamin D deficiency is a universal risk factor. Here we review molecular actions of the vitamin D receptor (VDR), to identify mechanisms and pathways for vitamin D deficiency as a universal risk factor. To identify genes directly regulated by the VDR, we searched for genes containing vitamin D response elements (VDREs). A further refinement was made by selecting only VDRE-containing genes with documented modulation by VDR analogues in vivo. Our search yielded a limited number of factors possibly related to pleiotropic effects of vitamin D, including growth factors, hormones, inflammatory factors and factors related to calcium homeostasis. Results from observational, intervention and mechanistic studies indicate that vitamin D is a universal risk factor involved in diverse multifactorial conditions. Further exploration of the multifaceted actions of vitamin D may pave the way for disease-overriding intervention strategies.
Curr Drug Targets. 2011 Jan;12(1):97-106
The neurobiology of lipid metabolism in autism spectrum disorders.
Autism is a neurodevelopmental disorder characterized by impairments in communication and reciprocal social interaction, coupled with repetitive behavior, which typically manifests by 3 years of age. Multiple genes and early exposure to environmental factors are the etiological determinants of the disorder that contribute to variable expression of autism-related traits. Increasing evidence indicates that altered fatty acid metabolic pathways may affect proper function of the nervous system and contribute to autism spectrum disorders. This review provides an overview of the reported abnormalities associated with the synthesis of membrane fatty acids in individuals with autism as a result of insufficient dietary supplementation or genetic defects. Moreover, we discuss deficits associated with the release of arachidonic acid from the membrane phospholipids and its subsequent metabolism to bioactive prostaglandins via phospholipase A(2)-cyclooxygenase biosynthetic pathway in autism spectrum disorders. The existing evidence for the involvement of lipid neurobiology in the pathology of neurodevelopmental disorders such as autism is compelling and opens up an interesting possibility for further investigation of this metabolic pathway.
Prevalence of serum antibodies to caudate nucleus in autistic children.
Autism may involve autoimmunity to brain. We studied regional distribution of antibodies to rat caudate nucleus, cerebral cortex, cerebellum, brain stem and hippocampus. The study included 30 normal and 68 autistic children. Antibodies were assayed by immunoblotting. Autistic children, but not normal children, had antibodies to caudate nucleus (49% positive sera), cerebral cortex (18% positive sera) and cerebellum (9% positive sera). Brain stem and hippocampus were negative. Antibodies to caudate nucleus were directed towards three proteins having 160, 115 and 49 kD molecular weights. Since a significant number of autistic children had antibodies to caudate nucleus, we propose that an autoimmune reaction to this brain region may cause neurological impairments in autistic children. Thus, the caudate nucleus might be involved in the neurobiology of autism.
Neurosci Lett. 2004 Jan 23;355(1-2):53-6
Increased serum levels of anti-ganglioside M1 auto-antibodies in autistic children: relation to the disease severity.
BACKGROUND: Autoimm-unity to the central nervous system (CNS) may play a pathogenic role in a subgroup of patients with autism. This study aimed to investigate the frequency of serum anti-ganglioside M1 auto-antibodies, as indicators of the presence of autoimmunity to CNS, in a group of autistic children. We are the first to measure the relationship between these antibodies and the degree of the severity of autism. METHODS: Serum anti-ganglioside M1 antibodies were measured, by ELISA, in 54 autistic children, aged between 4 and 12 years, in comparison to 54 healthy-matched children. Autistic severity was assessed by using the Childhood Autism Rating Scale (CARS). RESULTS: Autistic children had significantly higher serum levels of anti-ganglioside M1 antibodies than healthy children (P < 0.001). The seropositivity of anti-ganglioside M1 antibodies was found in 74% (40/54) of autistic children. Serum levels of anti-ganglioside M1 antibodies were significantly higher in autistic children with severe autism (63%) than those with mild to moderate autism (37%), P = 0.001. Moreover, serum anti-ganglioside M1 antibodies had significant positive correlations with CARS (P < 0.001). CONCLUSIONS: Serum levels of anti-ganglioside M1 antibodies were increased in many autistic children. Also, their levels had significant positive correlations with the degree of the severity of autism. Thus, autism may be, in part, one of the pediatric autoimmune neuropsychiatric disorders. Further wide-scale studies are warranted to shed light on the possible etiopathogenic role of anti-ganglioside M1 auto-antibodies in autism. The role of immunotherapy in autistic patients who have increased serum levels of anti-ganglioside M1 antibodies should also be studied.
J Neuroinflammation. 2011 Apr 25;8:39
Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors.
Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used for years as a preservative in many infant vaccines and in flu vaccines. Environmental methyl mercury has been shown to be highly neurotoxic, especially to the developing brain. Because mercury has a high affinity for thiol (sulfhydryl (-SH)) groups, the thiol-containing antioxidant, glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. Cultured neuroblastoma cells were found to have lower levels of GSH and increased sensitivity to thimerosol toxicity compared to glioblastoma cells that have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC), but not methionine, resulted in a significant increase in intracellular GSH in both cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC prevented cytotoxicity with exposure to 15 microM Thimerosal. Although Thimerosal has been recently removed from most children’s vaccines, it is still present in flu vaccines given to pregnant women, the elderly, and to children in developing countries. The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations.
Neurotoxicology. 2005 Jan;26(1):1-8
Assessing vitamin D status.
PURPOSE OF REVIEW: To characterize methods evaluating and to summarize studies linking various serum 25-hydroxyvitamin D [25(OH)D] concentrations with health status. RECENT FINDINGS: Elucidation of the cell-biologic mechanism of vitamin D action, and numerous clinical trials and observational studies relating vitamin D status to health and disease. CONCLUSION: The distinction between deficiency and insufficiency is not useful or necessary. Serum 25(OH)D values below 120 nmol/l (48 ng/mL) are associated with preventable disease and are therefore indicative of deficiency. The upper limit of the normal range can be set at 225 nmol/l (90 ng/mL), although toxicity is rare below 500 nmol/l (200 ng/mL).
Curr Opin Clin Nutr Metab Care. 2011 Sep;14(5):440-4