Prenatal exposure to lipopolysaccharide results in neurodevelopmental damage that is ameliorated by zinc in mice

Joanne S C Chua, Carina J Cowley, Jim Manavis, Allan M Rofe, Peter Coyle

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

There is converging evidence that during pregnancy a maternal immune response to infection can cause neurodevelopmental damage. Lipopolysaccharide (LPS)-mediated induction of metallothionein (MT) and subsequent hypozincaemia has been linked to fetal brain damage. Our group has demonstrated that Zn, when co-administered with LPS in early pregnancy in mice (gestation day (GD) 8), prevents fetal malformations and neurodevelopmental deficits in offspring. Others demonstrating fetal brain lesions have administered LPS much later in gestation (after GD 16), when the influence of LPS-mediated MT-induction on maternal plasma Zn levels, and the effect of Zn co-administration with LPS, are unknown. The aims of this study are firstly to examine whether LPS causes MT induction and maternal hypozincaemia in mid-to-late pregnancy, and secondly to determine if histochemical markers of inflammatory damage in fetal brain are affected by LPS and whether this damage can be alleviated with Zn treatment. Pregnant mice were injected with LPS (5 mg/kgbodywt.) or saline vehicle on GD 16 and then humanely killed at 8, 16 and 24 h for Zn and MT measurements, or concomitantly injected subcutaneously with Zn (2 mg/kgbodywt.) or saline and then killed on GD 18 and immunohistochemistry performed on fetal brain. Maternal hepatic MT was markedly induced after LPS-challenge and this was associated with a 38% reduction in maternal plasma Zn concentrations. Coincidentally, the fetuses of LPS-treated dams showed astrogliosis, extensive cell death and an increased number of cells producing TNF-α which was prevented with concomitant Zn treatment. These results support the premise that in mid-to-late pregnancy, an infection-mediated activation of a maternal immune response can cause MT induction that redistributes Zn in the mother, restricting fetal Zn supply, causing neurodevelopmental damage.

LanguageEnglish
Pages326-36
Number of pages11
JournalBrain, Behavior, and Immunity
Volume26
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Animals
  • Astrocytes
  • Brain
  • Cell Count
  • Female
  • In Situ Nick-End Labeling
  • Lipopolysaccharides
  • Liver
  • Male
  • Metallothionein
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Tumor Necrosis Factor-alpha
  • Zinc
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Chua, Joanne S C ; Cowley, Carina J ; Manavis, Jim ; Rofe, Allan M ; Coyle, Peter. / Prenatal exposure to lipopolysaccharide results in neurodevelopmental damage that is ameliorated by zinc in mice. In: Brain, Behavior, and Immunity. 2012 ; Vol. 26, No. 2. pp. 326-36.
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abstract = "There is converging evidence that during pregnancy a maternal immune response to infection can cause neurodevelopmental damage. Lipopolysaccharide (LPS)-mediated induction of metallothionein (MT) and subsequent hypozincaemia has been linked to fetal brain damage. Our group has demonstrated that Zn, when co-administered with LPS in early pregnancy in mice (gestation day (GD) 8), prevents fetal malformations and neurodevelopmental deficits in offspring. Others demonstrating fetal brain lesions have administered LPS much later in gestation (after GD 16), when the influence of LPS-mediated MT-induction on maternal plasma Zn levels, and the effect of Zn co-administration with LPS, are unknown. The aims of this study are firstly to examine whether LPS causes MT induction and maternal hypozincaemia in mid-to-late pregnancy, and secondly to determine if histochemical markers of inflammatory damage in fetal brain are affected by LPS and whether this damage can be alleviated with Zn treatment. Pregnant mice were injected with LPS (5 mg/kgbodywt.) or saline vehicle on GD 16 and then humanely killed at 8, 16 and 24 h for Zn and MT measurements, or concomitantly injected subcutaneously with Zn (2 mg/kgbodywt.) or saline and then killed on GD 18 and immunohistochemistry performed on fetal brain. Maternal hepatic MT was markedly induced after LPS-challenge and this was associated with a 38{\%} reduction in maternal plasma Zn concentrations. Coincidentally, the fetuses of LPS-treated dams showed astrogliosis, extensive cell death and an increased number of cells producing TNF-α which was prevented with concomitant Zn treatment. These results support the premise that in mid-to-late pregnancy, an infection-mediated activation of a maternal immune response can cause MT induction that redistributes Zn in the mother, restricting fetal Zn supply, causing neurodevelopmental damage.",
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Prenatal exposure to lipopolysaccharide results in neurodevelopmental damage that is ameliorated by zinc in mice. / Chua, Joanne S C; Cowley, Carina J; Manavis, Jim; Rofe, Allan M; Coyle, Peter.

In: Brain, Behavior, and Immunity, Vol. 26, No. 2, 02.2012, p. 326-36.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Prenatal exposure to lipopolysaccharide results in neurodevelopmental damage that is ameliorated by zinc in mice

AU - Chua, Joanne S C

AU - Cowley, Carina J

AU - Manavis, Jim

AU - Rofe, Allan M

AU - Coyle, Peter

N1 - Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

PY - 2012/2

Y1 - 2012/2

N2 - There is converging evidence that during pregnancy a maternal immune response to infection can cause neurodevelopmental damage. Lipopolysaccharide (LPS)-mediated induction of metallothionein (MT) and subsequent hypozincaemia has been linked to fetal brain damage. Our group has demonstrated that Zn, when co-administered with LPS in early pregnancy in mice (gestation day (GD) 8), prevents fetal malformations and neurodevelopmental deficits in offspring. Others demonstrating fetal brain lesions have administered LPS much later in gestation (after GD 16), when the influence of LPS-mediated MT-induction on maternal plasma Zn levels, and the effect of Zn co-administration with LPS, are unknown. The aims of this study are firstly to examine whether LPS causes MT induction and maternal hypozincaemia in mid-to-late pregnancy, and secondly to determine if histochemical markers of inflammatory damage in fetal brain are affected by LPS and whether this damage can be alleviated with Zn treatment. Pregnant mice were injected with LPS (5 mg/kgbodywt.) or saline vehicle on GD 16 and then humanely killed at 8, 16 and 24 h for Zn and MT measurements, or concomitantly injected subcutaneously with Zn (2 mg/kgbodywt.) or saline and then killed on GD 18 and immunohistochemistry performed on fetal brain. Maternal hepatic MT was markedly induced after LPS-challenge and this was associated with a 38% reduction in maternal plasma Zn concentrations. Coincidentally, the fetuses of LPS-treated dams showed astrogliosis, extensive cell death and an increased number of cells producing TNF-α which was prevented with concomitant Zn treatment. These results support the premise that in mid-to-late pregnancy, an infection-mediated activation of a maternal immune response can cause MT induction that redistributes Zn in the mother, restricting fetal Zn supply, causing neurodevelopmental damage.

AB - There is converging evidence that during pregnancy a maternal immune response to infection can cause neurodevelopmental damage. Lipopolysaccharide (LPS)-mediated induction of metallothionein (MT) and subsequent hypozincaemia has been linked to fetal brain damage. Our group has demonstrated that Zn, when co-administered with LPS in early pregnancy in mice (gestation day (GD) 8), prevents fetal malformations and neurodevelopmental deficits in offspring. Others demonstrating fetal brain lesions have administered LPS much later in gestation (after GD 16), when the influence of LPS-mediated MT-induction on maternal plasma Zn levels, and the effect of Zn co-administration with LPS, are unknown. The aims of this study are firstly to examine whether LPS causes MT induction and maternal hypozincaemia in mid-to-late pregnancy, and secondly to determine if histochemical markers of inflammatory damage in fetal brain are affected by LPS and whether this damage can be alleviated with Zn treatment. Pregnant mice were injected with LPS (5 mg/kgbodywt.) or saline vehicle on GD 16 and then humanely killed at 8, 16 and 24 h for Zn and MT measurements, or concomitantly injected subcutaneously with Zn (2 mg/kgbodywt.) or saline and then killed on GD 18 and immunohistochemistry performed on fetal brain. Maternal hepatic MT was markedly induced after LPS-challenge and this was associated with a 38% reduction in maternal plasma Zn concentrations. Coincidentally, the fetuses of LPS-treated dams showed astrogliosis, extensive cell death and an increased number of cells producing TNF-α which was prevented with concomitant Zn treatment. These results support the premise that in mid-to-late pregnancy, an infection-mediated activation of a maternal immune response can cause MT induction that redistributes Zn in the mother, restricting fetal Zn supply, causing neurodevelopmental damage.

KW - Animals

KW - Astrocytes

KW - Brain

KW - Cell Count

KW - Female

KW - In Situ Nick-End Labeling

KW - Lipopolysaccharides

KW - Liver

KW - Male

KW - Metallothionein

KW - Mice

KW - Mice, Inbred C57BL

KW - Pregnancy

KW - Prenatal Exposure Delayed Effects

KW - Tumor Necrosis Factor-alpha

KW - Zinc

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.bbi.2011.10.002

DO - 10.1016/j.bbi.2011.10.002

M3 - Article

VL - 26

SP - 326

EP - 336

JO - Brain, Behavior, and Immunity

T2 - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

SN - 0889-1591

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ER -