Division of Maternal Fetal Medicine, Madigan Army Medical Center, Tacoma, Washington, USA.
Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington, USA.
Am J Reprod Immunol. 2023 Mar;89(3):e13662. doi: 10.1111/aji.13662. Epub 2022 Dec 15.
Protective effects for adult neurological disorders have been attributed to sex hormones. Using a murine model of prematurity, we evaluated the role of estrogen signaling in the process of perinatal brain injury following exposure to intrauterine inflammation.
Intrauterine lipopolysaccharide (LPS) was used to invoke preterm labor and fetal neuroinflammation. Fetal brains were analyzed for changes in Esr1, Esr2 and Cyp19. Dams heterozygous for the Esr1 knockout allele were also given intrauterine LPS to compare delivery and offspring viability to wild type controls.
The upregulation in inflammatory cytokines was accompanied by an increase in Esr1 and Esr2 transcripts, though protein levels declined. Cyp19 did not differ by mRNA or protein abundance. Offspring from Esr1 mutants were larger, had a longer gestation and significantly greater mortality.
Estrogen signaling is altered in the fetal brains of preterm offspring exposed to neuroinflammatory injury. The reduction of Esr1 and Esr2 proteins with LPS suggests that these proteins are degraded. It is possible that transcriptional upregulation of Esr1 and Esr2 occurs to compensate for the loss of these proteins. Alternatively, the translation of Esr1 and Esr2 mRNAs may be disrupted with LPS while a feedback mechanism upregulates transcription. Intact Esr1 signaling is also associated with early preterm delivery following exposure to intrauterine LPS. A loss of one Esr1 allele delays this process, but appears to do so at the cost of fetal viability. These results suggest estrogen signaling plays opposing roles between maternal and fetal responses to preterm birth.
已将保护成年神经疾病的作用归因于性激素。我们使用早产的鼠模型，评估了在宫内炎症暴露后，雌激素信号在围产期脑损伤过程中的作用。
宫内脂多糖（LPS）用于引发早产和胎儿神经炎症。分析胎儿大脑中 Esr1、Esr2 和 Cyp19 的变化。还对 Esr1 敲除等位基因杂合的母体给予宫内 LPS，以比较分娩和后代活力与野生型对照。
炎症细胞因子的上调伴随着 Esr1 和 Esr2 转录本的增加，尽管蛋白水平下降。Cyp19 的 mRNA 或蛋白丰度没有差异。Esr1 突变体的后代更大，妊娠期更长，死亡率显著更高。
暴露于神经炎症损伤的早产儿胎儿大脑中的雌激素信号发生改变。LPS 导致 Esr1 和 Esr2 蛋白减少，表明这些蛋白被降解。可能是 Esr1 和 Esr2 的转录上调以补偿这些蛋白的损失。或者，LPS 可能会破坏 Esr1 和 Esr2 的 mRNA 翻译，而反馈机制则上调转录。完整的 Esr1 信号也与宫内 LPS 暴露后早期早产有关。一个 Esr1 等位基因的缺失会延迟这个过程，但似乎是以牺牲胎儿活力为代价的。这些结果表明，雌激素信号在母体和胎儿对早产的反应之间发挥着相反的作用。
