Abstract
Autism spectrum disorders (ASDs) are increasingly being diagnosed. Hypotheses link ASD to genetic, epigenetic, or environmental factors. The role of oxidative stress and the imbalance between excitatory and inhibitory neurotransmission in the pathogenesis of ASD has been suggested. Rats in which ASD symptoms are induced by valproate (VPA) or thalidomide (THAL) application in utero are useful models in ASD studies. Our study investigated whether rats in ASD models show changes in metabolite levels in the brain consistent with the hypothetical pathomechanisms of ASD. Female rats were fed one dose of 800 mg/kg VPA or 500 mg/kg THAL orally on the 11th day of gestation, and 1-month offspring were used for the experiments. Metabolic profiles from proton nuclear magnetic resonance spectroscopy of hydrophilic and hydrophobic extracts of rat hippocampi were subjected to OPLS-DA statistical analysis. Large differences between both models in the content of several metabolites in the rat hippocampus were noticed. The following metabolic pathways were identified as being disturbed in both ASD models: steroid hormone biosynthesis; fatty acid biosynthesis; the synthesis and degradation of ketone bodies; glycerophospholipid metabolism; cholesterol metabolism; purine metabolism; arginine and proline metabolism; valine, leucine, and isoleucine biosynthesis and degradation. These results indicate disorders of energy metabolism, altered structure of cell membranes, changes in neurotransmission, and the induction of oxidative stress in the hippocampus. Our data, consistent with hypotheses of ASD pathomechanisms, may be useful in future ASD studies, especially for the interpretation of the results of metabolomics analysis of body fluids in rat ASD models.
Highlights
Autism spectrum disorder (ASD) is an increasingly emerging disease that appears worldwide, and the prevalence of Autism spectrum disorders (ASDs) ranges from 25 to 110 cases per 10,000 children, depending on the country [1]
Our discussion of the results obtained in this study mainly focuses on the role of the substances identified in the nuclear magnetic resonance (NMR) spectra whose content in rat hippocampus homogenates from experimental groups proved to be significantly (VIP > 1) different from that in the control group in the multivariate analyses (MVAs) and whose changes can be related to hypothetical mechanisms implicated in the pathogenesis of ASD
It is known that very similar behavioral symptoms that correspond to symptoms in autistic patients are observed in the two ASD rat models used in these studies, our NMR spectroscopic analysis showed large differences between these models in the content of several metabolites in the hippocampi
Summary
Autism spectrum disorder (ASD) is an increasingly emerging disease that appears worldwide, and the prevalence of ASD ranges from 25 to 110 cases per 10,000 children, depending on the country [1]. It seems that ASD occurs 2–3 times more often in boys than that in girls [2]. There are hypotheses linking symptoms of ASD with genetic [3,4,5], epigenetic, or environmental factors [1]. Epigenetic factors could modify the expression of mRNA or miRNA, which could affect the conformation and content of proteins involved in body functions [6].
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