| Large epidemiological and animal studies have revealed a clear association of adverse intrauterine environment with the increased risk of metabolic, cardiovascular and neurological diseases. Maternal smoking is the single most widespread perinatal insult in the world and has been associated with adverse pregnancy outcomes for mother, fetus and the newborn. Our study aims to test the hypothesis that perinatal nicotine exposure induces reprogramming of susceptibility to hypoxic ischemic brain injury in the immature brain, focusing on the roles of AT1R and/or AT2R and trying to reveal the underlying epigenetic mechanisms. Therefore, we established two rat models: perinatal nicotine exposure model in time-dated pregnant rats; hypoxic-ischemic encephalopathy (HIE) in 10-day-old rat pups. In the first part of our study, we demonstrated that nicotine exposure induces aberrant brain development in P10 pups, downregulating AT2R expression in male but upregulating AT2R in female pup brain, enhancing brain vulnerability to HIE in a sex-specific manner. In addition, we observed both AT1R and AT2R are implicated in the pathogenesis of neonatal HIE and confers neuroprotective property; AT2R plays the pivotal and causal role in nicotine induced sex-dependent alteration of vulnerability to HIE in the developing rat brain. Our further study focused on the epigenetic mechanisms involved in nicotine exposure mediated pathological effects in HIE. We demonstrated that perinatal nicotine exposure causes heightened methylation status of a single CpG adjacent to TATA-box at AT2R promoter, inhibiting TBP and recruiting MeCP2 binding, repressing AT2R gene expression, contributing to the enhanced vulnerability to HIE brain injury in male rat pups. All of pathological effects are reversed by administration of 5-Aza, a well-known DNA methylase inhibitor. These findings provide new insights in understanding of the pathogenesis of HIE in newborns and may suggest potential targets for the prevention and treatment of HIE, one of the most common causes of brain damage with severe mortality and long-lasing morbidity in infants and children. |
