Epigenetic regulation in the offspring of gestationally stressed rats?

ANTONELLI, MC

Cuenca

Simposio; VII Biennial Neurotoxicity Meeting.; 2015

International Society for Neurochemistry (ISN)

 The period of intrauterinedevelopment represents a sensitive window during which disruption ormodification of the environment can influence fetal development and might leadto altered health throughout life course. Moderate to severe stressfullife?events, in combination with inadequate social network, are closelyassociated with increased child morbidity, neurological dysfunction,attention-deficit hyperactivity disorder (ADHD) and sleep disturbance duringinfancy, which if persist in adulthood might result in depression andvulnerability to psychotic disorders. The process of ?fetal programming? ismediated by the impact of prenatal experience on the developinghypothalamic-pituitary-adrenal (HPA) axis, a dynamic metabolic system thatregulates homeostatic mechanisms, including the ability to respond tostressors, and which is highly sensitive to adverse early life experiences.Several studies support the hypothesis that parental programming is mediated byepigenetic mechanisms that stably alter gene transcription affecting physiologyand behavior. In this study, we analyzed the effect of prenatal stress (PS) on gpm6a expressionand the epigenetic mechanism involved. gpm6aencodes the neuronal glycoprotein M6a involved in filopodium extension. Hippocampusand prefrontal cortex (PFC) samples were analyzed for gene expression (qPCR formRNAs and microRNAs), methylation status (bisulfite conversion) and proteinlevels in male offspring at postnatal days 28 and 60. Hippocampal neurons inculture were used to analyze microRNA over expression effects. Prenatal stressinduced changes in gpm6a levels inboth tissues and at both ages analyzed, indicating a persistent effect. Two CpGislands in the gpm6a gene wereidentified. Variations in the methylation pattern at three specific CpGs werefound in hippocampus, but not in PFC samples from PS offspring. MicroRNAspredicted to target gpm6a wereidentified in silico. qPCR measurements showed that PS modified the expressionof several microRNAs in both tissues, being microRNA-133b the mostsignificantly altered. Further studies overexpressing this microRNA in neuronalcultures showed a reduction in gmp6a mRNAand protein level. Moreover filopodium density was also reduced, suggestingthat GPM6a function was affected. Gestational stress affected gpm6a gene expression in offspringlikely through changes in methylation status and in posttranscriptionalregulation by microRNAs. Thus, our findings propose gpm6a as a novel target for epigenetic regulation during prenatalstress.