The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes

• Environmental influences (industrial and agrochemical pollutants and endocrine disruptors) may be partly to blame for the autism epidemic.
• The entry of such chemicals to the mother, foetus or child is regulated by placental, intestinal, skin, airway and blood-brain barriers.
• Autism susceptibility genes are anatomically and functionally related to barrier systems and intestinal permeability is affected in autism.
• The same genes also control neurodevelopment and are an interface between upstream environmental cause and downstream physiological effect.
• Environmental control of the compounds that cross these barriers may be the key to halting and reversing the autism epidemic.

Even taking problems of diagnosis into account, a five-fold increase in the incidence of autism in recent decades, in the absence of any known changes in the human gene pool suggests a strong environmental influence. Numerous pollutants have been implicated in epidemiological studies, including pesticides, heavy metals, industrial solvents, air pollutants, particulate matter, bisphenol A, phthalates and flame retardants. Many genes have been implicated in autism, some of which are directly related to detoxification processes. Many are also expressed prenatally in the frontal cortex when the effects of such toxins on neurodevelopment are most relevant. To gain access to the foetal brain, toxins must pass placental and blood/brain barriers and access to maternal or children’s blood necessitates passage across skin, airway and intestinal barriers. Literature survey of a subset of 206 genes, defined as prime autism susceptibility candidates from an Autworks/Genotator analysis, revealed that most could be related to barrier function at blood/brain, skin, intestinal, placental or other interfaces. These genes were highly enriched in proteome datasets from blood/brain and placental trophoblast barriers and many localised to skin, intestinal, lung, umbilical and placental compartments. Many were also components of the exosomal/transcytosis pathway that is involved in the transfer of compounds across cells themselves, rather than between them. Several are involved in the control of respiratory cilia that sweep mucus and noxious particles from the airways. A key role of autism susceptibility genes may thus relate to their ability to modulate the access of numerous toxins to children, and adults and, during gestation, to the developing foetal brain.