https://www.tandfonline.com/doi/full/10.1080/19381980.2017.1387702
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.
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.
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.
Prenatal soluble factors
Vitamin D3 – estrogen, serotonin and immune function
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 at an exponential rate in the United States (see Fig. 2, plotted from the data in reference 24) and around the world.24 This infectious disease is probably either a bacterium or a virus.25 We can rule out bacterial infections because they would have been noticed on hematoxylin and eosin stained slides of different tissues and would have produced other health problems. So, if it is an infection, it is most likely a viral infection.26 Human immunodeficiency virus was a candidate over two decades ago that did not pan out27 but co-infections are common so that other viruses should be considered. Evidently, the virus that may cause ASD does not cause any obvious symptoms or it would have been discovered years ago.
Figure 2. Incidence ASD/1,000 children over time in the United States. Plotted from the data in reference 24. Note that an exponential increase over time for ASD occurs around the world primarily in developed countries.
Which viral infection?
We know viral infections can affect the developing fetal brain from the Zika virus that causes microencephaly. Evidence that ASD might be caused by a virus is obtained from affected children's increased levels of the virally-induced enzyme, alpha-N- acetylgalactosaminidase,28 similar to women with cervical cancer whose enzyme levels are elevated by the Human Papillomavirus (HPV).29
HPV is vertically transmitted from the mother's infected cervix to her placenta and then to her fetus rather than through her blood.30,31 Further proof of placental transmission of HPV rather than blood is obtained from the prevalence of HPV DNA, which was found to be considerably lower in newborns (∼1.5% or ∼1/68) of infected mother's (∼30% population of pregnant women).32 Coincidentally, this infection rate matches the incidence of 1 in 68 children with ASD eight years later. HPV is known to infect the trophoblasts of the placenta33 where inclusions in it have been found to be predictive of ASD.34 Moreover, the discordant rates of identical twins might be explained by the initial location of one of their placentas being juxtapose to the cervix, where HPV infection occurs; a low-lying placenta, which is a fairly common occurrence, moves back up 90% of the time during the second trimester35 and can sometimes take HPV with it. Fraternal twins with only a 31% concordant rate of ASD might be explained by one twin having its placenta in closer proximity to the cervix than the other twin whether or not it moves back up (placenta previa if it remains low). And besides the differences in estrogen levels, the higher male to female ratio of ASD might be explained by the male fetuses' tendency to implant their placentas lower in the uterus during the first trimester, as demonstrated by male fetuses having a higher incidence of placenta previa (the reason is unknown).36,37 Twins also have a higher rate of placenta previa than singletons38 and they have a higher rate of ASD as well.39,40 Furthermore, cesarean births increase the risk for placenta previa41 and they also increase the risk for ASD.42 Finally, the increase in ASD with increasing age of the mother might be explained by the increasing incidence of placenta previa as women age.43 Thus, timing of HPV infection during pregnancy might be important because HPV probably has to be replicating in the cervix during the first trimester while the placenta is low-lying in the uterus prior to moving back up;44,45 however, if placenta previa occurs or if the infection travels higher into the uterus, then transfer of the infection can occur at any time during pregnancy.
