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Early effects of lipopolysaccharide-induced inflammation on foetal brain development in rat.

ABSTRACT: Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 ?g of LPS (lipopolysaccharide)/kg to timed-pregnant rats at GD15 (gestational day 15) and GD16. Increased thickness of the CP (cortical plate) and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter), and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.

SUBMITTER: Ghiani CA

PROVIDER: S-EPMC3218569 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Early effects of lipopolysaccharide-induced inflammation on foetal brain development in rat.

Ghiani Cristina A CA Mattan Natalia S NS Nobuta Hiroko H Malvar Jemily S JS Boles Julie J Ross Michael G MG Waschek James A JA Carpenter Ellen M EM Fisher Robin S RS de Vellis Jean J

ASN neuro 20111117 4

Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in ...[more]

PMID: 22007738

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Project description:Background:Bacterial infection and inflammation of the testis impairs fertility, yet an understanding of inflammatory responses of the testis is incomplete. We are interested in identifying gene pathways involved in the detection and clearance of infectious microbes in the male reproductive tract. In previous studies in our lab focused on hypoxia-responsive genes of the testis, preliminary experiments suggested that genes classically categorized as hypoxia genes are also activated during antimicrobial responses. The purpose of this study was to identify hypoxia and inflammatory gene pathways that contribute to antimicrobial protection of the testis and to consider possible cross-talk and interactions between these pathways. Inflammation was induced in Sprague-Dawley rats using P. aeruginosa or E. coli lipopolysaccharide (LPS). Levels of hypoxia-inducible factor-1 (HIF-1?) protein and nuclear factor kappa B (NF-?B) were measured, and hypoxia and inflammatory gene expression patterns in testis were analyzed by gene expression profiling using real-time quantitative PCR arrays. Results:In LPS-treated rats, HIF-1? protein increased with no change in Hif-1? mRNA. Western Blot analysis also demonstrated no change in NF-?B and inhibitory NFKB alpha (I?B?) protein levels following LPS treatment. Five hypoxia pathway genes (Angptl4, Egr1, Ier3, Pai1, and Glut1), and 11 inflammatory pathway genes (Ccl12, Cc13, Cd14, Cxcl10, Icam1, Il10, Il1b, Il6, Nfkbia, Tlr2, Tnf) up-regulated after 3 h of inflammation. Angptl4, Ccl12, Cc13, Cd14, Egr1, Nfkbia, Tlr2, and Tnf remained elevated at 6 h. Six genes were up-regulated at 6 h only (Bhlhe40, C3, Jak2, Nlrp3, Slc11a1, Tlr1). One gene (Tlr5) was down-regulated after 3 h and no genes at 6 h. Electrophoretic mobility shift assay results suggest a decrease in NF-?B binding activity following LPS treatment. Conclusions:Testicular HIF-1? is up-regulated following LPS-induced inflammation. In contrast to other tissues, in which HIF-1? is up-regulated through transcriptional activation via NF-?B, we conclude that HIF-1? in the testis is not up-regulated through an increase in Hif-1? mRNA or through NF-?B-dependent mechanisms. Hypoxia pathway genes and genes involved in Toll-like receptor (TLR) and cytokine-mediated signaling comprise major functional categories of up-regulated genes, demonstrating that both hypoxia and classic inflammatory pathways are involved in inflammatory responses of the testis.

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Early effects of lipopolysaccharide-induced inflammation on foetal brain development in rat.

Publications

Early effects of lipopolysaccharide-induced inflammation on foetal brain development in rat.

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