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.

Dietary zinc supplementation ameliorates LPS-induced teratogenicity in mice.

Maternal infection during the first trimester of pregnancy has been associated with preterm birth, spontaneous abortion, growth retardation, and congenital anomalies. Previously, our group has shown that subcutaneous injection of zinc prevents endotoxin [lipopolysaccharide (LPS)]-induced teratogenicity. The purpose of this study was to investigate whether increasing or decreasing dietary zinc alters the teratogenic effects of LPS. Female C57BL6 mice were mated and fed diets containing 5, 35, or 100 mg/kg zinc. On gestational day (GD) 8, pregnant dams were injected with either LPS (0.5 mg/kg s.c.) or saline and killed on GD18. LPS-treated fetuses from dams fed 5 and 35 mg/kg zinc diet had a significantly higher number of abnormalities per litter (2- and 1- fold saline controls, respectively) compared with those from LPS + zinc supplemented dams, which were not significantly different from the saline control groups. The beneficial effect and importance of zinc was also reflected in the larger size of fetuses (weight and crown-rump length) from the LPS + zinc-supplemented treatment group. We have demonstrated that low dietary zinc during exposure to infection (i.e. LPS) in pregnancy augments the negative impact of LPS alone, and that dietary zinc supplementation throughout pregnancy ameliorates LPS-induced teratogenicity.