Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Maternal immune activation (MIA)puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through the maternal, placental, and fetal compartments contribute to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, pregnant rat dams were treated with the clinically available 11β-hydroxylase inhibitor metyrapone, alongside administration of the bacterial mimetic lipopolysaccharide (LPS), on gestational day 15. Maternal, placental, and fetal CNS levels of corticosterone and placental 11ßHSD enzymes type 1 and 2 were measured 3-hrs post treatment. Subsequently, offspring social behaviors were measured across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11ßHSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure protected against MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Transcriptomic analyses revealed that metyrapone-exposure triggered opposing effects on gene expression to combat MIA-exposure in males, but not among females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinical drug already provided to pregnant people and neonates for the treatment of hypercortisolism, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.母体免疫激活（Maternal immune activation, MIA）会使子代罹患与社交行为受损相关的神经发育障碍的风险升高。目前已知，通过母体、胎盘及胎儿腔室的免疫信号通路参与了上述表型改变，但尚不清楚疾病相关应激反应在其中发挥的作用程度，以及如何利用该应激反应开发潜在干预手段。为此，研究人员在妊娠第15天对孕鼠给予临床可用的11β-羟化酶抑制剂（11β-hydroxylase inhibitor）美替拉酮（metyrapone），同时辅以细菌模拟物脂多糖（lipopolysaccharide, LPS）给药。于给药后3小时检测母体、胎盘及胎儿中枢神经系统的皮质酮水平，以及胎盘11β-羟类固醇脱氢酶（11β-hydroxysteroid dehydrogenase, 11βHSD）1型和2型的表达水平。随后，在发育的关键阶段检测子代的社交行为。研究发现，MIA会升高母体、胎盘及胎儿中枢神经系统的皮质酮浓度，而美替拉酮给药可缓解这一现象。美替拉酮仅能抵御雄性胎盘中11βHSD2的表达下调，这提示雌性胎盘中未被灭活的皮质酮水平更高。行为学实验结果显示，美替拉酮可抵御MIA诱导的幼年、青春期及成年雄性子代的社交行为紊乱，但雌性子代未受保护甚至表现更差。转录组分析（transcriptomic analyses）表明，美替拉酮给药可在雄性子代中触发与对抗MIA暴露相关的相反基因表达变化，而雌性子代未出现该现象。综上，本研究结果表明，MIA诱导的下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal, HPA）轴应答与免疫系统协同作用，引发行为缺陷。作为一种已被用于孕妇及新生儿治疗皮质醇增多症（hypercortisolism）的临床药物，美替拉酮的性别特异性获益与局限应被进一步研究，以探索其作为降低妊娠MIA所致神经发育风险的潜在手段。