LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation

Highlights

• Maternal LPS up regulates placental IL-1β and reduced HSD11B2 in late gestation.

• No effect of 48 h exposure to maternal LPS on fetal weight and crown-rump length.

• Exposure to maternal LPS in late gestation impairs neuronal growth in offspring.

Abstract

Introduction

During pregnancy, maternal infection at different stages of gestation increases the risk of developing several psychiatric and neurological disorders later in life for affected offspring. As placental health is intrinsically linked to neurodevelopmental outcome, maternal infection may adversely affect the placenta at or before the gestational stages it affects fetal neurodevelopment. Here we examined this premise.

Methods

Pregnant-Sprague Dawley rats were administered saline or lipopolysaccharide by intraperitoneal injection on embryonic days 12–18. We then examined a number of key placental inflammatory and endocrine mediators, along with fetal, birth and neuronal characteristics at different stages of development.

Results

Maternal exposure to lipopolysaccharide at later gestational ages significantly increased pro-inflammatory IL-1β expression and reduced placental HSD11B2 expression. This was accompanied by a reduction in placental weight and embryo number without an effect on embryo weight or crown-rump length. In utero lipopolysaccharide exposure at later gestational ages also impaired the growth of neurons from affected offspring.

Discussion

These data show that maternal infection at later gestational ages modifies placental inflammatory and endocrine mediators that may adversely affect the growth of developing neurons in affected offspring.

Introduction

Fetal programming describes how in utero adversity influences later disease risk [1]. Many epidemiological studies have now shown that maternal infection increases the risk for neurodevelopmental and neuropsychiatric disorders in affected offspring including schizophrenia [2], [3], autism spectrum disorders [4], [5] and cerebral palsy [6] (for reviews see Refs. [7], [8]). Critical to these outcomes, is the role of the placenta at the maternal–fetal interface in regulating fetal growth and development [9]. There is increasing evidence that placental health plays a key role in determining fetal neurodevelopmental outcome (for review see Refs. [10], [11], [12]). This was directly assessed in a recent retrospective cohort study that showed that neurodevelopmental impairment was significantly more frequent in infants with distinct signs of placenta dysfunction compared to those with normal placental function [12]. These data show that placental health during pregnancy is likely to be intrinsically linked to neurodevelopmental outcome, thus infection-induced changes in the placenta may contribute to the molecular sequela of how these affect the developing fetal nervous system.

The increase in risk for adverse neurodevelopmental outcome for affected offspring following maternal infection has been shown to be dependent on the stage at which the infection occurs during pregnancy. For example, bacterial infection in the second, but not the first trimester of human pregnancy was found to increase the risk for autism spectrum disorders and schizophrenia in the offspring [13], [14], [15]. This has been confirmed by a large body of work in pre-clinical models that have confirmed the presence of “critical developmental periods” during which the developing nervous system is susceptible to the effects of maternal immune activation [8], [16]. In agreement with this, we have recently shown, using the well-characterised superior cervical ganglion (SCG) in vitro model [17], that the growth of fetal neurons can be inhibited by the pro-inflammatory cytokine, interleukin (IL)-1β, at late embryonic and early postnatal stages of development, but not before or after this developmental window of sensitivity [18]. This suggests that maternal infection during this window of sensitivity may impair fetal neurite growth and/or affect the placenta. Here we use the lipopolysaccharide (LPS) rat model to examine the effects of maternal infection on placental expression of pro-inflammatory cytokines and 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) which plays a critical role in protecting the fetus against excessive exposure to maternal cortisol [19], [20], [21], and determine its effects on the developing fetus and the growth of fetal neurons at different stages of gestation.