Prenatal Stress Induces Epigenetic Changes in the Rat Offspring

ANTONELLI, MC.; MONTELEONE, MC.; PALLARES, ME.; ADROVER, E.; FRASCH, AC; BROCCO, MA.

Chicago.

Congreso; 45th Annual Meeting of the Society for Neurocience; 2015

Society of Neurociences

The period of intrauterine development represents a sensitive window during whichdisruption or modification of the environment can influence fetal developmentand might lead to altered health throughout life course. Moderate to severestressful life-events, in combination with inadequate social network, areclosely associated 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 developing hypothalamic-pituitary-adrenal(HPA) axis, a dynamic metabolic system that regulates homeostatic mechanisms,including the ability to respond to stressors, and which is highly sensitive toadverse early life experiences. Several studies support the hypothesis thatparental programming is mediated by epigenetic mechanisms that stably altergene transcription affecting physiology and behavior. In this study, weanalyzed the effect of prenatal stress (PS) on gpm6aexpression and theepigenetic mechanism involvedgpm6aencodesthe neuronal glycoprotein M6ainvolved in filopodium extension. Hippocampus and prefrontal cortex (PFC)samples were analyzed for gene expression (qPCR for mRNAs and microRNAs),methylation status (bisulfite conversion) and protein levels in male offspringat postnatal days 28 and 60.Hippocampal neurons in culture were used to analyzemicroRNAoverexpression effects. Prenatal stress induced changes in gpm6alevelsin both tissues and at both ages analyzed, indicating a persistent effect. TwoCpG islands in the gpm6agene were identified. Variations in the methylationpattern at three specific CpGs were found in hippocampus, but not in PFCsamplesfrom PS offspring. MicroRNAs predicted to target gpm6awere identified insilico. qPCR measurements showed that PS modified the expression of severalmicroRNAs in both tissues, being microRNA-133b the most significantly altered.Further studies overexpressing this microRNAin neuronal cultures showed areduction in gmp6amRNAand protein level. Moreover filopodium density was alsoreduced, suggesting that GPM6afunction was affected. Gestational stressaffected gpm6agene expression in offspring likely through changes inmethylation status and in posttranscriptional regulation by microRNAs. Thus,our findings propose gpm6aas a novel target for epigenetic regulation duringprenatal stress.