Untangling the most probable role for vitamin D3 in autism.

DERMATO-ENDOCRINOLOGY 2018, VOL. 9, NO. 1, e1387702 (13 pages) https://doi.org/10.1080/19381980.2017.1387702 REVIEW Untangling the most probable role for vitamin D3 in autism Dianne E. Godar, PhDa and Stephen J. Merrill, PhDb a Body of Knowledge, Inc., Division of Human Disease Research Worldwide, Racine, WI, USA ; bMarquette University, Department of Mathematics, Statistics, and Computer Science, Milwaukee, WI, USA ABSTRACT ARTICLE HISTORY Recent studies indicate an important role for vitamin D3 in autism spectrum disorder (ASD), although its mechanism is not completely understood. The most puzzling aspect of ASD is that identical twins, who share identical DNA, do not have 100% concordance rates (»88% for identical and »31% for fraternal twins). These findings provide major clues into the etiology: ASD must involve an environmental factor present in the prenatal milieu that both identical twins are not always exposed to because they do not always share it (i.e., placentas). Combined with the exponential increasing rates of ASD around the world, these observations suggest a contagious disease is probably transferred to the fetus via the placenta becoming infected by a cervical virus. Vitamin D3 boosts immune responses clearing viral infections and increases serotonin and estrogen brain levels. Here we review the different roles and untangle the most probable one vitamin D3 plays in ASD. Received 15 June 2017 Revised 2 September 2017 Accepted 29 September 2017 The most puzzling aspect of autism spectrum disorder (ASD) is that identical twins, who share identical DNA, do not have 100% concordance rates. Identical, monozygotic twins only have concordance rates of »88%, while fraternal, dizygotic twins have concordance rates of »31%.1,2 These twin observations alone provide clues into the etiology: ASD must involve something present in the prenatal environment that both identical twins are not always exposed to because they do not always share it. Identical twins can share the same placenta and amniotic sac (occurrence »1%) or they can share the same placenta but not their amniotic sac (occurrence »69%) or they can have their own placentas and amniotic sacs (occurrence »30%), while fraternal twins always have their own placentas and amniotic sacs3 (see Fig. 1). The subtle differences between the prenatal environments of identical twins, especially their placentas, might explain why a 100% concordance rate of ASD does not exist for them. Thus, we need to closely examine the prenatal environment of twins. KEYWORDS autism spectrum disorder; cervix; cerebral spinal fluids; choroid plexus; estrogen; human papillomavirus; learning disabilities; placenta; prenatal environment; serotonin; vitamin D3 Prenatal soluble factors Many soluble factors exist in the prenatal environment that can possibly affect the developing fetus: vitamins, hormones, cytokines, chemicals, alcohol, drugs, medications, etc. A prenatal environment with low levels of vitamin D3, measured as 25-hydroxyvitamin D3, was hypothesized to cause ASD.4 Recent investigations confirm low maternal 25-hydroxyvitamin D3 levels during gestation are associated with ASD-related traits in a large population-based sample5 and supplementing children with vitamin D3 improve the signs and symptoms of ASD.6 However, although vitamin D3 treatment is beneficial for improving and possibly preventing some of the symptoms of ASD or even lowering its occurrence, those observations do not prove a causal relationship exists because low 25-hydroxyvitamin D3 levels are shared between twins in their prenatal environment whether they are identical or not. In fact, any circulating soluble factor like cytokines, medications, alcohol, drugs, or exposure to any chemical in our environment would give a 100% concordance rate CONTACT Dianne E. Godar, PhD , Inc., 326 Main Street, Racine, WI 53403, USA. Division of Human Disease Research Worldwide, Body of Knowledge, © 2018 Dianne E Godar and Stephen J. Merrill. Published with license by Taylor & Francis This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/ 4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. e1387702-2 D. E GODAR AND S. J. MERRILL 25-dihydroxyvitamin D3, on ASD is its ability to raise both estrogen and serotonin levels during fetal brain development.20 Another important biological function of vitamin D3 is its ability to activate the mother’s immune system,21 especially T cells22 that remove infected cells and infectious agents like bacteria and viruses in the mother, especially from her cervix. Thus, if ASD is caused by an infectious agent, boosting the immune system with vitamin D3 might also help to explain its positive effects. Figure 1. Identical and fraternal twin placenta and amniotic sac possibilities and percent occurrences: shared placentas (monochorionic), separate placentas (dichorionic), shared amniotic sacs (monoamniotic) and separate amniotic sacs (diamniotic). The placenta is represented by an oval with a large dark disc in the middle. for either identical or fraternal twins, but this is not observed. Thus, something else must be awry that vitamin D3 somehow differentially affects. Vitamin D3 – estrogen, serotonin and immune function The hormonal form of vitamin D3, 1, 25-dihydroxyvitamin D3, affects over 200 genes through the vitamin D3 receptor,7 but more importantly it increases estrogen levels in the placenta8 and the brain9 and is probably necessary for regulating serotonin production.10 Estrogen brain levels might help to somewhat explain why males are 4 to 5 times more likely to become autistic than females11 because estrogen is extremely important in brain development.12 Of note, ASD subjects displayed dysregulation of the estrogen receptor beta, aromatase, and estrogen receptor co-activators in the middle frontal gyrus region of their brains.13 Racial disparity supports a causal role for estrogen rather than vitamin D3 in ASD because African-American blacks have lower vitamin D3 status than whites14 but instead of having higher incidences of ASD their incidences are actually lower15–17 probably because their male’s estrogen levels are significantly higher than white males.18 Estrogen increases the synthesis of tryptophan hydroxylase-2, the rate-limiting enzyme in the production of serotonin,19 and vitamin D3 also increases tryptophan hydroxylase-2.10 Apparently some of the positive effects of vitamin D3, or 1, Infectious placental and cervical diseases The increase in the incidence of ASD is much faster than that predicted from genetic inheritance or from exposure to environmental pollutants23 but rather displays characteristics of an infectious disease because it is increasing a (...truncated)