Exploring microbiota-gut-brain axis biomarkers linked to autism spectrum disorder in prenatally chlorpyrifos-exposed Fmr1 knock-out and wild-type male rats.

Fmr1 (fragile X messenger ribonucleoprotein 1)-knockout (KO) rats, modeling the human Fragile X Syndrome (FXS), are of particular interest for exploring the ASD-like phenotype in preclinical studies. Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents and linked to the microbiota-gut-brain axis. In this study, we have used both Fmr1-KO and wild-type male rats (F2 generation) at postnatal days (PND) 7 and 40 obtained after F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF or vehicle. A nuclear magnetic resonance (NMR) metabolomics approach together with gene expression profiles of these F2 generation rats were employed to analyze different brain regions (such as prefrontal cortex, hippocampus, and cerebellum), whole large intestine (at PND7) and gut content (PND40). The statistical comparison of each matrix spectral profile unveiled tissue-specific metabolic fingerprints. Significant variations in some biomarker levels were detected among brain tissues of different genotypes, including taurine, myo-inositol, and 3-hydroxybutyric acid, and exposure to CPF induced distinct metabolic alterations, particularly in serine and myo-inositol. Additionally, this study provides a set of metabolites associated with gastrointestinal dysfunction in ASD, encompassing several amino acids, choline-derived compounds, bile acids, and sterol molecules. In terms of gene expression, genotype and gestational exposure to CPF had only minimal effects on decarboxylase 2 (gad2) and cholinergic receptor muscarinic 2 (chrm2) genes.

Sociability: Comparing the Effect of Chlorpyrifos with Valproic Acid.

In recent years, exposures to organophosphate pesticide have been highlighted as a possible cause or aggravating factor of autism spectrum disorder (ASD). The present study examined if Wistar rats prenatally exposed to chlorpyrifos (CPF) at a dose of 1 mg/kg in GD 12.5-15.5 could express similar behaviors to those exposed to valproic acid (VPA, 400 mg/kg) during the same administration window, which is an accepted animal model of autism. The 3-chambered test was employed to evaluate sociability and reaction to social novelty in two experiments, the first in adolescence and the second in adulthood. The results obtained in this study show that animals prenatally treated with CPF or VPA show a similar behavioral phenotype compared to the control group (CNT). In adolescence, the CPF animals showed a negative index in the reaction to social novelty, followed closely by the VPA, while both experimental groups showed a recovery in this aspect during adulthood. This study therefore provides evidence to suggest that prenatal exposure to CPF in rats could have similar effects on certain components of sociability to those seen in autistic models.