THE MECHANISM OF CADMIUM-INDUCED FETAL GROWTH RESTRICTION: ROLE OF PLACENTAL 11 ß - HYDROXY STEROID DEHYDROGENASE 2 (llß-HSD2) AND METALLOTHIONEIN PROTEINS I & H.

Maternal cadmium exposure induces fetal growth restriction (FGR), but the underlying mechanisms remain largely unknown. Placental llß-hydroxysteroid dehydrogenase type 2 (llß-HSD2) has been implicated as a potential molecular target by which cadmium induces FGR. Furthermore, metallothionein-I and II (MT-I/II) sequester cadmium in the placenta, thereby reducing its toxicity on the developing fetus. The present study was undertaken to examine the role of MT- I/II in cadmium-induced FGR using the MT-I/IIA mouse model. Maternal cadmium administration led to FGR and reductions in placental llß- HSD2 activity in MT-I/II1\u27 but not MT-I/lf/+ mice. Although it did not alter placental weight or structure, maternal cadmium administration increased placental cell death in MT-I/lf/+ and MT-I/lf\u27 mice. Together, these results demonstrate that MT-I/II/_ mice are vulnerable to cadmium-induced FGR and reductions in placental llß-HSD2 activity, suggesting that MT-I/II proteins protect the fetus from adverse effects of cadmium on fetal growth and development

Hypoxia-inducible factor-1 stimulates postnatal lung development but does not prevent o2-induced alveolar injury

This study investigated whether hypoxia-inducible factor (HIF)-1 influences postnatal vascularization and alveologenesis in mice and whether stable (constitutive-active) HIF could prevent hyperoxia-induced lung injury. We assessed postnatal vessel and alveolar formation in transgenic mice, expressing a stable, constitutive-active, HIF1a-subunit (HIF-1aDODD) in the distal lung epithelium. In addition,we compared lung function, histology, and morphometry of neonatal transgenic and wild-type mice subjected to hyperoxia. We found that postnatal lungs of HIF-1aDODDmice had a greater peripheral vessel density and displayed advanced alveolarization compared with control lungs. Stable HIF-1a expression was associated with increased postnatal expression of angiogenic factors, including vascular endothelial growth factor, angiopoietins 1 and 2, Tie2, and Ephrin B2 and B4. Hyperoxiaexposed neonatal HIF-1aDODD mice exhibited worse lung function but had similar histological and surfactant abnormalities compared with hyperoxia-exposed wild-type controls. In conclusion, expression of constitutive-active HIF-1a in the lung epithelium was associated with increased postnatal vessel growth via up-regulation of angiogenic factors. The increase in postnatal vasculature was accompanied by enhanced alveolar formation. However, stable HIF-1a expression in the distal lung did not prevent hyperoxia-induced lung injury in neonates but instead worsened lung function