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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Effects of perinatal lipopolysaccharide (LPS) exposure on the developing rat brain; modeling the effect of maternal
M Xu1, Z L Sulkowski, P Parekh
1Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Insights
Perinatal exposure to Escherichia coli lipopolysaccharide (LPS) impairs developing rat cerebellum function and structure. These effects are linked to oxidative stress, altered thyroid hormone activity, and gene expression changes, varying by rat strain and sex.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Maternal infections during pregnancy can impact fetal brain development.
- Oxidative stress and thyroid hormone signaling are critical for cerebellar maturation.
- Escherichia coli lipopolysaccharide (LPS) is a potent stimulator of inflammatory responses.
Purpose of the Study:
- To investigate the effects of perinatal LPS exposure on the developing rat cerebellum.
- To test if maternal infections affect brain structure and function via oxidative stress and altered thyroid hormone (TH) pathways.
- To examine strain- and sex-dependent responses in Spontaneously Hypertensive Rats (SHR) and Sprague-Dawley (SD) rats.
Main Methods:
- LPS was administered to pregnant and lactating rat dams (SHR and SD strains).
- Evaluated motor learning, startle response, and cerebellar oxidative stress marker (3-nitrotyrosine) levels in pups.
- Assessed type 2 iodothyronine deiodinase (D2) activity and the expression of TH-responsive genes (DIO2, BDNF, TTR).
Main Results:
- LPS exposure significantly decreased motor learning in SD pups (male and female).
- A trend towards increased cerebellar 3-nitrotyrosine was observed in SD pups, while it decreased in SHR females.
- D2 activity was significantly reduced in LPS-exposed SHR males and SD females; gene expression of DIO2, BDNF, and TTR was altered in a strain- and sex-dependent manner.
Conclusions:
- Perinatal LPS exposure negatively impacts cerebellar development, motor function, and TH homeostasis.
- Mechanisms involve increased oxidative stress and altered expression of genes regulating TH signaling and neuronal growth.
- The observed effects are dependent on the rat strain and the sex of the offspring.
Abstract:
In the present study, we examined the effect of perinatal Escherichia coli lipopolysaccharide (LPS) exposure on the developing rat cerebellum and tested the hypothesis that maternal infections impact brain structure and function by mechanisms involving increase in oxidative stress and changes in brain type 2 iodothyronine deiodinase (D2)- and thyroid hormone (TH)-responsive genes. Spontaneously hypertensive rat (SHR) and Sprague-Dawley (SD) rat dams were challenged with LPS (200 μg/kg body weight) exposure during pregnancy (G10-G15) and lactation (P5-P10), the time periods corresponding, respectively, to the first/second and the third trimesters of human pregnancy. LPS exposure resulted in a significantly decreased motor learning in SD male (29.8 %) and in female (55.0 %) pups (p < 0.05); changes in rollover and startle response showed only a trend. The LPS challenge also resulted in a trend (p = 0.09) toward increased cerebellar levels of the oxidative stress marker 3-nitrotyrosine (3-NT) in SD male (16.2 %) and female (21.2 %) neonates, while 3-NT levels were significantly decreased (p < 0.05) in SHR female pups. D2 activity, responsible for local intra-brain conversion of thyroxine (T4) to the active hormone, 3',3,5-triiodothyronine (T3), was significantly (p < 0.05) decreased in LPS-challenged SHR male (40.3 %) and SD female (47.4 %) pups. Several genes were affected by LPS. Notably, D2 (DIO2) and brain-derived neurotrophic factor (BDNF) were significantly elevated in SHR females, while transthyretin (TTR) expression was decreased in both SD males and females (P < 0.05). In vitro chronic exposure of cerebellar cultures to LPS resulted in decreased arborization of Purkinje cells while D2 was only increased transiently. Our data demonstrate that perinatal LPS exposure impacts the developing cerebellum in strain- and sex-dependent manner via complex mechanisms that involve changes in oxidative stress, enzymes involved in maintaining local TH homeostasis, and downstream gene expression.
