Prenatal exposure to lipopolysaccharide results in neurodevelopmental damage that is ameliorated by zinc in mice.
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.
Hanson Institute, SA Pathology, Adelaide, SA 5000, Australia.
Joanne S C
JS
Chua
Carina J
CJ
Cowley
Jim
J
Manavis
Allan M
AM
Rofe
Peter
P
Coyle
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D002452:Cell Count; D005260:Female; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry; D008297:Male; D008668:Metallothionein / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015032:Zinc / Q000032:analysis / Q000097:blood / Q000494:pharmacology*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D008668:Metallothionein; D015032:Zinc