Molecular Basis of Gender Bias in ASD 135individuals with Turner syndrome), the rate of social difficulties varied accord-
ing to whether their single X chromosome was Xf or Xm [77,78]. In Turner
syndrome one of the X chromosomes is missing and a female could have
acquired either the father’s or mother’s X chromosome. Typical females inherit
an X chromosome from both parents (XfXm), but typical males have only a
maternal X chromosome (XmY). Skuse et al. hypothesized that a gene expressed
on the maternal Xm acts as a protective factor against the social problems seen
in Turner syndrome and, by extrapolation, as a protective factor against ASD
[1,2,77]. However, recent data from Creswell and Skuse [78], who reported five
cases of ASD within an unselected sample of 150 subjects with Turner syn-
drome, showed that all cases were Xm, strongly suggesting that the maternal X
chromosome is not protective. Also, given that 77% of Turner syndrome
females are XmO, while only 23% are Xf [1,2,78], then, by probability one would
expect to find ASD more often associated with Xm than with Xf, making the Xm
hypothesis unlikely.
It is well documented that ASD children have bigger overall brain size and
larger amygdala and frontal lobes of the brains [1,63] than normally developing
children. Also, many autistic children’s brains tend to grow faster, prenatally,
than the typical child’s brain, and later brain growth is more normal, or even
relatively slower, during childhood [1,63]. Therefore, it is possible that use of
certain fragrances may be neuromodulatory to fetal brains, especially early in
gestation. It is also probable that the neuromodulatory effects initiated during
gestation may persist after birth. We are most intrigued by the observations
that certain fragrances at fentomolar concentrations can be neuromodulatory
considering the amount of fragrance that will reach a developing fetal brain
during 8–24 weeks of gestation (the most vulnerable time of fetal brain devel-
opment with regard to ASD) [1,2,63,64,66]. Expectant women may be exposed
to fragrance not only from their own use (e.g., dermal application and inhala-
tion), but also from the environment. The levels of fragrance components that
would reach fetal brain neurons would be at fentomolar or even lower concen-
trations and unlikely to be at levels where cytotoxic effects would occur.
However, these chemicals may interfere with the normal development of a fetal
brain. Of note, the most vulnerable brain areas, where this excessively rapid
growth seems to be most common, are the areas that are the foundations of
superior cognitive specialization development [1,2,63,66].
We analyzed the male and female NBCs to determine if exposure to fen-
tomolar concentrations of fragrances adversely affected these cell lines.
Specifically, we examined OXY‐receptor (OXYR) and AVPR1‐receptor posi-
tive neurons to assess whether the fragrances had differential neurotoxic
effects on female versus male neuroblastoma cells. In both cell types, 1:10^6
dilutions of three selected fragrances induced profound and significant neuro-
modulations and caused central chromatolysis, enlargement of the neuronal
cell body, shortening or abnormal increase and thinning of axonal length and