Maternal immune activation elicits rapid and sex-dependent changes in gene expression and vascular dysfunction in the rat placenta

Introduction: Maternal immune activation (MIA), characterized by increased circulating inflammatory mediators during pregnancy, is associated with adverse pregnancy outcomes and neurodevelopmental deficits in offspring. These health outcomes often manifest differently depending on fetal-placental sex. A well-established model of MIA involves administration of a viral mimetic, polyinosinic:polycytidilic acid (PolyI:C), to pregnant rodents. Placental responses to PolyI:C contribute to the detrimental effects of MIA on offspring, but these responses have not yet been well characterized. In the present study, we profiled acute gene expression changes in male and female placentas following PolyI:C administration to pregnant rats. Methods: Pregnant rats received 4 mg/kg PolyI:C or saline intravenously on gestational day 18.5, and tissues were harvested 4-5 hours later. Gene expression profiling on placental tissue was performed. Enzyme immunoassays and immunohistochemistry were conducted to determine levels of select proteins in maternal blood and placental tissue, respectively. Results: Maternal PolyI:C exposure caused a robust increase in levels of inflammatory markers in maternal blood and placental tissue. There were more genes differentially expressed in female placentas after PolyI:C exposure (765) than male placentas (221), including reduced expression of genes associated with maternal-fetal communication. Placentas also had increased expression of genes linked with vascular dysfunction after PolyI:C-induced MIA. Discussion: PolyI:C elicited a powerful inflammatory response in the placenta along with vascular dysfunction, likely contributing to the adverse pregnancy outcomes triggered by MIA. Female placentas responded to PolyI:C more vigorously than male placentas, which could underlie the differential outcomes of MIA depending on sex.Introduction: 母体免疫激活（Maternal immune activation, MIA）以妊娠期间循环炎症介质水平升高为核心特征，与不良妊娠结局及子代神经发育缺陷显著相关。此类健康结局的表型通常会因胎儿-胎盘的性别差异而有所不同。目前构建MIA模型的经典方法是向妊娠啮齿类动物注射病毒模拟物聚肌胞苷酸（polyinosinic:polycytidilic acid, PolyI:C）。胎盘对PolyI:C的应答是MIA对子代产生有害影响的关键环节，但目前此类应答的分子特征尚未得到充分阐释。本研究在妊娠大鼠注射PolyI:C后，对雌雄胎盘的急性基因表达变化进行了基因表达谱分析。 Methods: 于妊娠第18.5天向妊娠大鼠静脉注射4 mg/kg的PolyI:C或生理盐水，并在给药后4-5小时采集组织样本。对胎盘组织开展基因表达谱分析。分别采用酶联免疫吸附实验和免疫组织化学技术，检测母体外周血及胎盘组织中特定蛋白的表达水平。 Results: 母体PolyI:C暴露可显著升高母体外周血及胎盘组织中的炎症标志物水平。PolyI:C暴露后，雌性胎盘中的差异表达基因数量（765个）多于雄性胎盘（221个），其中包括与母胎通信相关的基因表达下调。在PolyI:C诱导的MIA模型中，胎盘组织中与血管功能障碍相关的基因表达同样出现上调。 Discussion: PolyI:C可在胎盘中诱发强烈的炎症反应，并伴随血管功能障碍，这可能是MIA诱发不良妊娠结局的核心机制。雌性胎盘对PolyI:C的应答强度高于雄性胎盘，这或许是MIA相关健康结局存在性别差异的潜在原因。