Prenatal Stress-Induced Increases in Placental Inflammation and Offspring Hyperactivity Are Male-Specific and Ameliorated by Maternal Antiinflammatory Treatment
Prenatal Stress-Induced Increases in Placental Inflammation and Offspring Hyperactivity Are Male-Specific and Ameliorated by Maternal Antiinflammatory Treatment
复制标题
DOI：
10.1210/en.2014-1040
复制
发表时间：
2014-07-01
期刊：
影响因子：
4.8
通讯作者：
Bale, Tracy L.
中科院分区：
文献类型：
--
作者：
Bronson, Stefanie L.;Bale, Tracy L.
孕期的不良经历，如母亲的压力和感染，是神经发育障碍（包括精神分裂症、自闭症和注意缺陷/多动障碍）的已知风险因素。尽管可能涉及母胎界面的压力和免疫反应共有的通路，但这些不同的暴露因素如何导致相似的精神易感性的机制仍不清楚。我们假设母亲压力诱导的胎盘（具有性别特异性的母胎中介）内免疫通路的激活可能有助于产前压力对后代的编程效应。因此，我们评估了指示压力诱导的胎盘炎症的标志物，并研究了母亲使用非甾体抗炎药（NSAID）治疗改善胎盘效应从而挽救在我们已建立的早期产前压力（EPS）小鼠模型中观察到的压力失调表型的能力。正如预期的那样，胎盘基因表达分析显示免疫反应基因水平升高，包括促炎细胞因子白细胞介素 - 6和白细胞介素 - 1β，特别是在雄性胎盘中。NSAID治疗部分改善了这些EPS效应。同样，在成年后代中，雄性表现出压力诱导的运动亢进，这是多巴胺能失调的一个标志，母亲使用NSAID治疗可改善这种情况。与这些结果相符且支持多巴胺通路参与其中的是，雄性中多巴胺D1和D2受体的表达因EPS而改变。这些研究支持母亲压力与促炎状态在母亲压力的长期编程效应中存在重要的相互作用。
Adverse experiences during gestation such as maternal stress and infection are known risk factors for neurodevelopmental disorders, including schizophrenia, autism, and attention deficit/hyperactivity disorder. The mechanisms by which these distinct exposures may confer similar psychiatric vulnerability remain unclear, although likely involve pathways common to both stress and immune responses at the maternal-fetal interface. We hypothesized that maternal stress-induced activation of immune pathways within the placenta, the sex-specific maternal-fetal intermediary, may contribute to prenatal stress programming effects on the offspring. Therefore, we assessed for markers indicative of stress-induced placental inflammation, and examined the ability of maternal nonsteroidal antiinflammatory drug (NSAID) treatment to ameliorate placental effects and thereby rescue the stress-dysregulation phenotype observed in our established mouse model of early prenatal stress (EPS). As expected, placental gene expression analyses revealed increased levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1 beta, specifically in male placentas. NSAID treatment partially ameliorated these EPS effects. Similarly, in adult offspring, males displayed stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal NSAID treatment. Fitting with these outcomes and supportive of dopamine pathway involvement, expression of dopamine D1 and D2 receptors was altered by EPS in males. These studies support an important interaction between maternal stress and a proinflammatory state in the long-term programming effects of maternal stress.