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Oral Concurrent 1 Thursday, February 14 • 1:15 PM - 4:00 PM • Augustus Ballroom 1-2 • Caesars Palace| Volume 220, ISSUE 1, SUPPLEMENT , S10-S11, January 01, 2019

12: Evidence for the crucial role of estrogen signaling with preterm labor and perinatal neuroinflammation

      Objective

      Female offspring are less susceptible to prematurity-related neuroinflammatory injury than males. We hypothesize such differences are attributed to sex-specific hormones, specifically estrogen. Using a murine prematurity model, we evaluated the role of estrogen signaling in the process of perinatal brain injury following exposure to intrauterine inflammation (IUI) by: 1) Characterizing the principle components of signaling (Esr1 and Esr2) and synthesis (Cyp19) and 2) Evaluating the phenotype with Esr1 deletion.

      Study Design

      To simulate IUI, intrauterine lipopolysaccharide (LPS) was used to invoke preterm labor and fetal neuroinflammation and compared to controls. In the set of CD1 dams, fetal brains were collected at 6 hours and analyzed by qRT-PCR, western blot and immunohistochemistry. Additionally, females heterozygous for Esr1 KO allele were bred to heterozygous Esr1 KO males. In this set, dams were monitored for preterm labor and embryo viability.

      Results

      Esr1 and Esr2 transcripts significantly increased with LPS exposure while protein levels declined (Figure 1A-B). Though inverse, the level of Cyp19 did not differ by mRNA or protein analysis. Both Esr1 and Esr2 co-localized to the nuclei of developing neural cells and decreased with LPS (Figure 1C). Dams heterozygous for the Esr1 KO allele did not tolerate LPS with 100% mortality in all exposed offspring (stillborn at gestational days 18-19 of the 21 expected days). These offspring were also significantly smaller, by pup weight as well as head and body size, compared to controls (Figure 2).

      Conclusion

      The reduction of Esr1 and Esr2 by western blot suggests that these proteins may be degraded with neuroinflammation. 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 is disrupted with LPS and upregulation is due to a feedback mechanism. Based on the receptors' nuclear location, it is possible that their transcriptional activity and regulation are altered with neuroinflammation. Correspondingly, lack of fetal viability resulting from Esr1 insufficiency with LPS injury supports the importance of estrogen signaling with preterm labor. Future research will evaluate whether these findings represent an exaggerated maternal response or a susceptible fetal genotype.
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