Cui et al. (2007) have determined t

Cui et al. (2007) have determined that vitamin D is important for neural development and its deficiency negatively alters the brain structure and function. As mentioned, vitamin D, a neurosteroid, is considered to be an important regulator of cell proliferation in the developing brain, while calcitriol, an activated form of vitamin D, is an up-regulator of nerve growth factor and its receptor is found in a variety of brain tissues early in embryogenesis (McGrath et al. 2001). A deficiency of vitamin D may result from inheritance of polymorphisms in cytochrome P450 gene, CYP27B1, which is required for vitamin D activation (Cannell 2008). CYP27B1 is an enzyme of interest in the study of autism, but, to date, no research has been conducted and/or published analyzing this potential correlation. Approximately 0.5% of the human genome, which represents only 200 genes, is targeted by calcitriol (Kalueff et al. 2006). It is remarkable that 90.0% of the human vitamin D supply comes from skin production and not from oral intake (Holick 1987). Taking into consideration that sun avoidance has become more common in recent times due to the fear of skin cancer, the increase in autism is steadily increasing, specifically after 1989, when the American Medical Association (1989) warned about the risks of sun exposure and advised mothers to keep infants out of the sun as much as possible. See Fig. 4 for details. In
fact, abnormalities in immune responses have been implicated in both autism and vitamin D deficiency (Cannell 2008). Autistic individuals have T cell abnormalities and
cytokine excess, which is similar to immune functions affected by vitamin D (Ashwood et al. 2006). Another interesting function of vitamin D (calcitriol) is its ability to increase cellular glutathione levels (Garcion et al. 2002). Other investigators discovered that estrogen has the capability of increasing neural and cellular calcitriol levels (Epstein and Schneider 2005), while testosterone does not. It is, indeed, well documented that autism occurs much for frequently in males than females. Cannell (2008) concludes that estrogen shields female brains from calcitriol defi- ciencies, providing strong evidence to clarify this discrepancy. Moreover, as previously mentioned, autism occurs more frequently in African-Americans as opposed to
Caucasians (Bhasin and Scendel 2007). African-Americans have a darker pigmented skin color and, therefore, require an elevated exposure to sunlight in order to compensate for the deficiency of vitamin D. Bodnar et al. (2007) also finds that only 4.0% of black women and 37.0% of white women were vitamin D sufficient during gestation. This is very significant in light of the fact that experimental research demonstrates that vitamin D functions as a potent regulator of neuroprogenitor formation in the developing brain (Cui et al. 2007). The potential involvement of vitamin D and folic acid supplementation, therefore, strongly supports the interest of gene–environment interplay. The results of investigations on the role of vitamin D are very interesting because they may explain specific discrepancies regarding occurrence of autism, such as the higher occurrence in African-Americans and males. Most African-Americans, especially those living in colder climates with less exposure to sunlight, are vitamin D deficient. In general, African-Americans, due to their dark pigmentation of the skin, require more sun to satisfy their vitamin D requirements. Furthermore, CYP27B1 mutants have been linked to the inability of efficiently metabolizing vitamin D, potentially leading to neurological regression. Vitamin D may be directly involved in the gender disparity between males and females, as autism has a 4 to 1 male to female occurrence. Estrogen has the capability to increase neural calcitriol (active vitamin D) levels, as opposed to testosterone that does not. Both of these facts present compelling evidence that CYP27B1 and vitamin D levels are important mediators of normal neurological functions, and may explain these discrepancies. In light of the fact that polymorphisms of CYP27B1 have been implicated in other neurodevelopmental diseases, they may prove to play a major or principal role in the development of autism. Emerging research strongly suggests environmental changes that have occurred within the past 30 years are influencing our genetic makeup, leading to the conception of children with an increased risk of developing neurological disorders. Alterations in MTHFR and CYP27B1 follow this conjecture.