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Chronic Endotoxin Exposure Causes Brain Injury in the Ovine Fetus in the Absence of Hypoxemia

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Abstract

Objective

Intrauterine infection has been linked to brain injury in human infants, although the mechanisms are not fully understood. We recently showed that repeated acute exposure of preterm fetal sheep to bacterial endotoxin (lipopoly saccharide [LPS]) results in fetal hypoxemia, hypotension, increased systemic proinflammatory cytokines, and brain damage, including white matter injury. However, it is not clear whether this injury is caused by reduced cerebral oxygen delivery or inflammatory pathways independent of hypoxia. The aim of the present study was to determine the effects on the fetal brain and placenta of a chronic intrauterine inflammatory state, induced by LPS infusion into the fetal circulation, a model that did not cause hypoxia.

Methods

At 0.65 of term, eight catheterized fetal sheep received intravenous infusions of LPS (5 to 15 μg) over 5 days; control fetuses received saline. Fetal physiologic responses were monitored throughout the infusion. Fetal brain and placental tissues were examined histologically 6 days after the conclusion of the infusion.

Results

LPS infusions did not result in physiologically significant alterations to fetal blood gases or mean arterial pressure; however, plasma proinflammatory cytokine levels were elevated. Following LPS exposure there was no difference in fetal body or brain weights (P >.05); placental weight was reduced (P <.05), consistent with reduced placentome cross-sectional area (P <.05). In the cerebral hemispheres subcortical white matter injury was present in six LPS-exposed fetuses and included axonal damage, microgliosis, oligodendrocyte injury, and increased β amyloid precursor protein (β-APP) expression.

Conclusions

Chronic, systemic exposure of the fetus to LPS resulted in fetal brain damage in the absence of hypoxemia or hypotension, although the resulting injury was less severe than following repeated acute exposure, (J Soc Gynecol Investig 2006;13:87–96) Copyright © 2006 by the Society for Gynecologic Investigation.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria, 3010, Australia

    Jhodie R. Duncan PhD, Megan L. Cock PhD, Keiji Suzuki MD, PhD, Jean-Pierre Y. Scheerlinck PhD, Richard Harding PhD, DSc & Sandra M. Rees PhD

  2. Department of Physiology, Monash University, Melbourne, Victoria, Australia

    Jhodie R. Duncan PhD, Megan L. Cock PhD, Keiji Suzuki MD, PhD, Jean-Pierre Y. Scheerlinck PhD, Richard Harding PhD, DSc & Sandra M. Rees PhD

  3. Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Victoria, Australia

    Jhodie R. Duncan PhD, Megan L. Cock PhD, Keiji Suzuki MD, PhD, Jean-Pierre Y. Scheerlinck PhD, Richard Harding PhD, DSc & Sandra M. Rees PhD

Authors
  1. Jhodie R. Duncan PhD
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  2. Megan L. Cock PhD
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  3. Keiji Suzuki MD, PhD
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  4. Jean-Pierre Y. Scheerlinck PhD
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Corresponding author

Correspondence to Sandra M. Rees PhD.

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Joint senior authors.

Supported by the National Health and Medical Research Council of Australia and the Australian Research Council.

The authors are grateful to Alex Satragno and Todd Briscoe for technical assistance and to Dr Roberto Cappai (University of Melbourne, Parkville, Victoria, Australia) for his kind donation of the β-APP antibody.

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Duncan, J.R., Cock, M.L., Suzuki, K. et al. Chronic Endotoxin Exposure Causes Brain Injury in the Ovine Fetus in the Absence of Hypoxemia. Reprod. Sci. 13, 87–96 (2006). https://doi.org/10.1016/j.jsgi.2005.12.003

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