134 Male Gender Bias and Levels of Male Hormones During Fetal Development
functional connectivity between brain regions may be stronger in ASD chal-
lenging the “under‐connectivity” theory [72]. These inconsistencies may be
explained by taking into account the topographical nature of functional con-
nectivity patterns, rather than their overall strength. We believe that signifi-
cant elongations of axons in NBCs may provide some insight into connectivity
discrepancies found in ASD patients. The significant elongation of axons in
certain parts of brains with associated axonal thinning may result in
increased connectivity but functionally weaker neurons in ASD. If this
occurs in the area of brain that is involved in communication and social
interaction, then the autism communication conundrum may be explained
in morphological terms [67,75,76].
We hypothesize that one of the reasons for the contradictory functional con-
nectivity findings in the literature may be reconciled by taking into account the
fact that a developing fetal brain consists of hundreds of thousands of different
progenitor neurons at 8 weeks of gestation, each destined to become a different
compartment or faculty of an adult brain. However, one cannot expect each of
these progenitor neurons to be equally susceptible to testosterone or other dif-
ferentiation factors. Only the progenitor neurons that either have receptors for
a particular chemical or neurons which are susceptible to the toxic effects of
chemicals would be affected by the external (xenobiotic) or internal (endoge-
nous) chemicals, including hormones [66]. Therefore, only certain progenitor
neurons that express testosterone receptors would respond to higher levels of
testosterone resulting in varied connectivity in different compartments of the
ASD versus normotypic brain. For example, independent component analysis
comparing within‐network connectivity in children with ASD and typically
developing children reveals over‐connectivity of large‐scale brain networks in
ASD, whereas no group differences are observed in similar analyses comparing
adolescents [23] or adults [23,24]. Our in vitro data on elongation of axonal
length may shed light on what may be taking place in vivo. However, we believe
that despite the limitations of the in vitro model, we may be able to clarify the
situation with regards to ASD pathogenesis [2,63–66].Molecular Basis of Gender Bias in ASD
One of the hypotheses to explain potential underlying mechanisms is that in
XX chromosome genes one of the silenced X chromosomes could play a role
in sex ratios if the non‐silenced genes were protective. This means that either
parental X chromosome or the maternal X chromosome could be protective.
One of the hypotheses involves “genomic imprinting,” the process by which
genetic effects are influenced by the father (Xf) or the mother (Xm). Skuse et al.
[77] suggested that an imprinted X locus could explain sex differences in social
and communication skills. Their theory was inspired by the finding that in