Obesidade materna induz comportamento semelhante ao autismo, alterações epigenéticas, sinápticas e neuroinflamatórias em descendentes machos

Abstract

Obesity is a chronic metabolic disease that is associated with the development of several comorbidities. Studies have demonstrated the relationship between maternal obesity and impairments in the neurodevelopment of offspring, with one of the most common neurodevelopmental disorders being autism spectrum disorder (ASD). However, the mechanisms associated with these changes have not yet been elucidated. Thus, the aim of this study was to investigate the epigenetic, neuroplastic, synaptic, and astroglial mechanisms associated with autism-like symptoms arising from maternal obesity in male pups. For this, we used the model of maternal obesity by litter reduction where the normal litter (NN - 12 pups) and the reduced litter (NR - 4 pups) in Wistar rats. Weight monitoring, Lee index and quantification of mother and offspring fat were performed to characterize maternal obesity. The offspring were evaluated during the juvenile period (PND28 - PND32) to characterize autism-like symptoms. At the end of the behavioral tests, the animals were euthanized and the brain structures prefrontal cortex and hippocampus were dissected to evaluate epigenetic markers (Line-1, Rest, TETs and DNMTs), and evaluate protein expression by Western Blot (WB) proteins involved in the synaptic transmission (OTR, PSD95 and BDNF) and GFAP, a reactive astrocyte marker. Results: We observed that female rats reared in NR-G1 had an increase in weight gain from the first week of life and this was maintained until adulthood, where obesity was characterized with an increase in peritonadal and retroperitoneal fat and also by an increase in of the Lee index. We also observed that maternal obesity was not able to change the weight gain, Lee Index or the amount of fat in their NR-G2 pups at prepubertal age, however, it altered behavioral parameters that are used to characterize behavior similar to that of TEA: reduced playing time and greater preference for the familiar object. In addition to altering molecular mechanisms. By WB, we observed an increase in GFAP and OTR and a reduction in PSD95 and in the evaluated epigenetic markers, we observed a change in global DNA methylation through Line-1 analysis, with the prefrontal cortex having a tendency to be hypermethylated and the hippocampus was hypomethylated, alteration in the expression of the enzymes that methylate and demethylate the DNA and we observed a reduction both in the expression and in the methylation of Rest. Conclusion: Maternal obesity induces autism-like behavior, astrogliosis, leads to synaptic damage and changes in the epigenetic machinery of prepubertal male offspring.