What elements could potentially trigger autism?

The prevalence of ASD is steadily increasing over the past 20 years. The Centers for Disease Control & Prevention (CDC) reported that 1 in 110 children were diagnosed with ASD in 2006 while this number increased to 1 in 68 in 2010 ( CDC Website). If the genetic causes of ASD are indisputable, environmental agents that impact the expression of factors involved in brain development could be a target of choice.

Vitamin D deficiency

Role of vitamin D in brain development:

Autism is a neurodevelopmental disorder, where biologically active substances induce brain dysfunction, most likely during brain development in utero or in the very early years of life.

Neurosteroids are hormones that could be sensitive to environmental factors and could regulate protein of the nervous system (1).

Several studies have associated vitamin D deficiency to several mental pathologies such as autism or schizophrenia through its role during brain development (2-4).

After sun exposure or vitamin D dietary complement intake, vitamin D3 (precursor) is metabolized by the liver then the kidney to generate calcitriol (or 1, 25 dihydroxycholecalciferol), the active form of vitamin D.

Calcitriol regulates over 200 genes in human and play a crucial role in brain development by modulating 36 proteins involved in neurotransmission, synapse plasticity and provides neuroprotection at multiple levels (5-7):

  • Calcitriol induces the secretion of neurotropin, a key factor in neuroprotection.
  • Calcitriol increases brain glutathione production, a very powerful anti-oxidant that gets rid of heavy-metal, which are neurotoxic to brain.
  • Calcitriol represses the production of inflammatory cytokines production in the brain and induces anti-inflammatory IL-10 production.
  • Calcitriol plays a key role in the establishment of immunological self-tolerance thus preventing autoimmunity by inducing Treg cells.
  • Calcitriol protects DNA from mutation.

Study in animals showed that a severe vitamin D deficiency during pregnancy leads to anatomical abnormalities in pups similar to those found in autism including changes in its volume, shape (8-9). In addition, vitamin D deficiency induces inflammatory cytokines production that impact neural development and leads to brain damage (10).

If vitamin D deficiency has dramatic effects on brain development, it is also involved in a certain autoimmune disorder present in a subgroup of autistic patients. In some autistic children, brain specific auto-antibodies called anti-MAG (anti-myelin associated protein) could attack the brain and alter neural activity. In recent studies, up to 70% of autistic children showed a seropositivity for anti-MAG autoantibodies that correlates with low level of vitamin D (5).

What are the causes of a vitamin D deficiency?

  • Less sun exposure:

90% of human vitamin D stock come from sun exposure (11). Vitamin D production is linked to photoperiod (UVB light) that varies among season and latitude. Urban areas, high air pollution, high precipitation could limit the UVB light penetration. Sun avoidance campaign to prevent skin cancer, sun protection, an urban life with limited outdoor activities could explain a vitamin D deficiency.

  • Sexual differences:

Vitamin D deficiency is more prone to affect male as estrogen has a positive effect on vitamin D production while testosterone has none (12). Therefore, a lower vitamin D level might alter the control of immune activation as seen in male pregnancy. This could explain the differences observed in autism prevalence between male and female.

  • Ethnic differences

Darker skin have a higher level of cutaneous melanin which is a potent sunscreen therefore children born from dark-skinned mother should be more prone to develop autism. This fact is perfectly illustrated by a Swedish study showing that black children from mother who emigrates from Uganda develop autism up to 200 times more than the fair-skinned general population (13). Indeed, an American study showed than 45% of black women but only 2% of white women have a severe vitamin D deficiency during pregnancy explaining, in part, the prevalence of autism in black-American children (14).

How can I have sufficient vitamin D levels?

Optimal serum vitamin D level (25-OH vitamin D3) has been estimated around 30-40 ng/mL which is equivalent to a daily intake of thousand unit (15). 20mn exposure to sun is equivalent to 50 prenatal vitamin (400UI/tablet) or 200 glasses of milk (100IU/glass).

Most pregnant women have a deficiency in vitamin D that could have harmful consequences on their child brain development despite taking prenatal vitamin D (96% of pregnant black women vs. 63% of pregnant white women). Furthermore, autistic children seem to benefit from sun exposure during summer camp where improvement of their behavior has been noticed (16).

Therefore, sun exposure might be the easiest, cheapest way to significantly increase vitamin D level.

Maternal Diet

Folic acid deficiency and genetic predisposition
Maternal nutrition is a key component of fetal development. The crucial role of folic acid in minimizing the risks of defect during neural tube formation has been clearly demonstrated (17).

We, as mammals, are not able to synthesize folate and must rely on dietary supplements.

Folate is essential to DNA synthesis and to methylation, a process that regulates gene expression. If an error occur in DNA synthesis or during methylation (epigenetic alteration), abnormal fetal development could happen.

Several studies have shown that folic acid intake prior conception and during pregnancy could significantly lower the risks of developing autistic disorder in the offspring (18).

Maternal genetic variant (allele) can regulate and affect folate intrauterine availabilities therefore leading to alteration of DNA synthesis and/or DNA methylation. RFC1 is a gene that encodes for a protein playing a key role in folate intracellular transport. If this gene is homozygous for the G allele, lower folate will be available despite dietary complement intake and mothers will have a 46% risk increase of having a child with autism (19).

High fat diet

One third of pregnant women are obese in USA (20). A maternal high trans-fat diet consumption during embryo development could have dramatic consequences on fetal health as intra uterine environment is highly influenced by hyperlipidemia, hyperglycemia or hyperinsulinemia. Several animal studies showed that a high fat maternal diet during pregnancy impacts cognition function in the offspring that is revealed by the presence of inflammation in areas of brain responsible for cognitive function (21-23). Moreover, maternal obesity is associated with a greater risk of ASD in offspring, most likely due to the higher level of inflammatory cytokines (such as IL-1β) in obese women that impact neural development (24). A high fat diet suppresses the serotonin system that:

  • Regulates key functions during brain development.
  • Prevents allogenic rejection of the fetus by modulating the immune function.

On the other hand, a high maternal intake of polyunsaturated fat such as ω-3 or ω-6 could be protective during brain development in utero. A retrospective study showed that the risk associated with ASD development decreases of 34% when pregnant women consume a rich ω-3 diet (25).

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