Sex-specific neurotoxicity as possible cause of regressive autism

Autism is a neurodevelopmental disorder with a striking male prevalence and frequent comorbid situations, such as gastrointestinal disorders. Causative genetic variants affect only ~30% of cases and cannot explain the dramatic increase of autism in the last decades. As in other pathologies in which a specific gene-environment interplay triggers the disease, the possible role of environmental factors, such as infections, xenobiotics and drugs in provoking autism in genetically susceptible subjects has been proposed. Among causative genes, we focused on neuroligine3 and neuroligine4X because are involved in synaptic plasticity and, being located on X-chromosome, are hemizygous in males. We analyzed some intronic and 3'UTR SNPS of the two genes in 190 Italian autistic cases. Overall we found 3 SNPs haplotypes statistically significant in autistics comparing to the minor-allele-frequencies (MAF) from the 1000-Genomes Project CEU. Bioinformatics predictive database showed that some SNPs in 3'UTR of neuroligin4X may modify microRNA target sites. Interestingly, mining the literature, we found, among xenobiotics, that ochratoxinA and fumonisin-B1 provoke, in animal models, neurological and immunological damage, especially in males. Recent studies have also demonstrated that in in vitro and in in vivo experiments, these toxins modulated several microRNAs some of which are implicated in autism and in neurologin4X expression. We speculate that a specific neuroligin4X-mycotoxin interplay via 3'UTR SNPS-dysregulated microRNAs cross-talk could trigger autism in patients with gastrointestinal disorders and leaky-gut. Further analyses are required to demonstrate this hypothesis. ACKNOWLEDGEMENTS: Italian Ministry of Health "GR-2009-1570296" project, Italian Ministry of Education, University and Research "InterOmics" Flagship-project.