Prenatal inflammation represents a significant risk factor for adverse neurodevelopment. Intrauterine inflammation occurs in approximately 20% of all pregnancies with a much higher prevalence in preterm births. The objective of this study was to determine if in utero exposure to inflammation results in genetic and epigenetic modifications in the prepubescent mouse brain.
CD-1 timed-pregnant mice on E18. 5 were randomized to intrauterine infusion with saline or LPS (n=18 per group). Number of live pups and maternal morbidity was recorded. On PND 2, litters were culled. On PND 21, brains from pups were harvested and processed for QPCR, IHC or epigenetic studies. QPCR was performed to assess expression of genes involved in an immune response, glial differentiation, neurogenesis, and neurotransmission. IHC was performed for H&E and markers of glial development.
Intrauterine inflammation on E18 resulted in 20% maternal mortality and a live pup rate of 65%. LPS-exposed dams had smaller litter sizes (P=.02) compared to controls. On PND 7, neonatal weights were not significantly different. On PND 21, cytokine mRNA expression was not different in LPS vs. saline exposed pups. However, several genes in the studied gene pathways were differentially regulated in LPS-exposed pups: dopamine beta hydroxlase (P=0.013), GFAP (P=0.04), MAG (0.04), MBP (0.04), PLP (<0.001), auts2 (0.03) and MeCP2 (0.005). H&E did not demonstrated structural abnormalities. GFAP staining was increased in periventricular regions. Global hypermethylation was present in both male and female pups exposed to LPS in utero (P<0.0001).
Exposure to intrauterine inflammation results in significant alterations in gene expression and epigenetic modifications in the prepubescent mouse brain, in the absence of overt structural injury. These abnormalities are not secondary to a persistent immune response. Epigenetic modifications from prenatal inflammation may be a critical mechanisms for the observed increased in cognitive and neurobehavioral outcomes in ex-preterm infants.
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.