Exposure to Propionic Acid Induces Autistic-Like Gene Expression Profiles in Lymphoblastoid Cell Lines From Non-Autistic Individuals

Background: Genetic and environmental factors, including dietary substances and chemical toxins, are believed to contribute to the etiology and pathobiology of autism spectrum disorders (ASD). There is evidence that some individuals with ASD exhibit increased symptoms after ingesting foods containing high levels of propionic acid (PPA). PPA is a short chain fatty acid known to be an intermediate product of fatty acid metabolism and a metabolic end product of enteric bacteria in the GI tract. MacFabe, D.F. and colleagues (2007) reported that intracerebroventricular (ICV) injection of PPA in rats resulted in altered neuroinflammatory response, social impairment, and repetitive behaviors, all of which are consistent with clinical symptoms observed in autism. However, the effects of PPA on gene expression profiles in cells from autistic cases and controls have not yet been elucidated. We therefore hypothesize that PPA exposure causes deregulation in gene expression which may reflect that which is seen in autism.

Objectives: To investigate dysregulation of gene expression mediated by PPA exposure in lymphoblastoid cell lines (LCLs) derived from non-autistic individuals, which may contribute to pathological conditions observed in autism.

Methods: LCLs from non-autistic individuals (n=5) and their autistic siblings (n=5) were employed in this study. Each of the non-autistic cell lines was split into 3 groups and treated with PPA, propanol, or PBS, while each autistic LCL was split into 2 groups and treated with propanol or PBS. Gene expression profiling for each sample was performed using a TIGR40K human cDNA microarray containing 41,472 probes. Pavlidis Template Matching (PTM) and the Significance Analysis for Microarrays (SAM) analyses were employed to identify genes that were significantly differentially expressed and matched to expression in autistic samples. Ingenuity Pathway Analysis (IPA) and Pathway Studio 5 programs were employed for identification of biological functions and pathways associated with PPA-responsive genes.

Results: The PTM-SAM analyses revealed that a total of 177 genes in non-autistic LCLs were significantly differentially expressed, and exhibited autism-related gene expression profiles after 24 hr exposure to PPA (p<0.05; %FDR<5). Novel network prediction analyses of these PPA-responsive genes reveal significant association with autism and other co-morbid disorders, including cognitive impairment, epilepsy, bipolar affective disorder, muscular dystrophy, altered immunological response, and gastrointestinal diseases. Many interesting biological functions implicated in autism, such as memory and synaptic plasticity, were also highlighted.

Conclusions: Findings from this study indicate that PPA exposure leads to global changes in gene expression profiles of non-autistic LCLs toward autistic-like expression patterns. The PPA-responsive genes are associated with autism and co-morbid disorders, suggesting that PPA exposure may contribute to pathological conditions observed in autism.

Reference: MacFabe DF, et al (2007) Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 176, 149-169.

Supports: National Institute of Mental Health (R21 MH073393) and Autism Speaks (2381) to VWH.