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116: Exposure to prenatal inflammation and fetal brain injury: Does route of exposure and gestational age matter?

      Objective

      Exposure to prenatal inflammation either from a systemic illness or with chorioamnionitis is associated with adverse neurodevelopment in offspring. This study was performed to elucidate whether systemic or localized (in utero) inflammation has differential effects on the fetal brain and whether the gestational age at the time of inflammatory insult modulates the effect

      Study Design

      CD-1 mice on E15 and E18 were randomized to either systemic iinflammation (IP administration of LPS) or to localized intrauterine inflammation (LIUI)). 6-10 dams per treatment group per gestational age were used. 6 hrs after LPS, amniotic fluid (AF) and fetal brains were collected. Cytokine and genes implicated in neurobehavioral disoders were assessed by QPCR. Cytokine expression in AF was assessed by ELISA.

      Results

      See table. AF IL-6 levels were 5-fold and 25-fold increased from LIUI on E15 and 18. To systemic inflammation, AF IL-6 was 15-fold and 5-fold increased on E15 and E18. Cytokine mRNA expression was most dramatically increased in setting of LIUI. In response to LIUI, 2/8 neurobehavioral genes assessed were differentially regulated on E15 and 1/8 on E18. To systemic inflammation, 3/8 on E15 were differentially regulated and 2/8 on E18. Pattern of gene expression was divergent between the groups.
      Tabled 1Fetal Brain Cytokine Response (fold change)
      Mode of InflammationGestational Day of ExposureIL-1BTNF-alphaIL-6IL-10
      LocalE1552*3.1*2.5*5.7*
      LocalE1812.4*2.8*3.2*1.2
      SystemicE152.3−2.81.7−1.8
      SystemicE187.7*−1.51.52.2

      Conclusion

      Exposure to prenatal inflammation, whether systemic or intrauterine, has dramatic effects on gene expression in the fetal brain. Altered gene expression in the fetal brain is varied by the mode of the inflammatory challenge and gestational age of exposure. These studies provide a mechanism by which prenatal inflammation promotes adverse neurodevelopmental outcomes in exposed offspring.