Phenotypic Overlap between Atopic Dermatitis and Autism

Abstract

Background: Though multifactorial in etiology, approximately 10% of autism spectrum disorders (ASD) are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in hairless mice.Methods: We performed our studies in valproic acid (VPA)-treated hairless mice. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5, and these mice were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various post-natal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels.Results: AD-like changes in ceramide content occurred by day one post-partum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with the early appearance of Th2 markers (i.e., interleukin [IL]-4, 5, & 13, mast cells) both in the skin and brain. The high levels of interferon (IFN)g not only in skin, but also in brain likely account for a significant decrease in very-long-chain N-acyl fatty acids in brain ceramides that again mimicked known IFNg-induced changes in AD.Conclusion: The baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both the epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, and suggest further that ASD could be included within the atopic diathesis.