OP 24 Nrf2 deficiency induces placental TNF- α expression and influences the fetal growth in mice

Abstract

Introduction and objectives Increased oxidative stress and intrauterine inflammation are etiological factors for intrauterine growth restriction (IUGR). The transcription of many antioxidative genes is mediated mainly through the transcription factor Nrf2. A link between Nrf2 and the vascular haemeostasis in preeclampsia has been discussed. The influence of Nrf2 deficiency on fetal growth has not been well described. Here, we studied the effect of Nrf2-deletion on fetal and placental development in the knockout mice model. Materials and methods We paired Nrf2 heterozygote mice to conditionally induce gene deletion in the coming embryos. Placentas from Nrf2 −/− and Nrf2 +/+ fetuses were collected on days 13.5, 15.5 and 18.5 post coitum . One fixed half was processed into paraffin wax, exhaustively sectioned and then stained with Periodic Acid Schiff (PAS).The total volume of each placenta was estimated using the Cavalieri estimator of volume. The other half was used for molecular biology analyses. Expression of the pro-inflammatory cytokines IL-6, IL-1, TNF- α , the anti-inflammatory enzyme Heme oxygenase-1 and VEGF were analyzed. Results The Nrf2-deficient pups presented reduced birth weight (0.7 ± 0.06 g) when compared to the wild type pups (0.95 ± 0.03 g). In addition the placental volume of Nrf2 deleted embryos was significantly reduced in comparison to the wild type placentas (Nrf2 +/+ 121 ± 4 vs. Nrf2 −/− 92 ± 5 mm 3 ). Placentas from preterm Nrf2-deleted pups showed increased levels of the pro-inflammatory cytokines (IL-6 and TNF- α ), and decreased expression of HO-1 and VEGF. Conclusion Our results show that a disturbed Nrf2 signaling leads to a significant reduction in the growth of the fetuses. The increased expression of the pro-inflammatory cytokines IL-6 and TNF- α as well as the reduced expression of the anti-inflammatory enzyme HO-1 and VEGF in Nrf2 deleted placentas suggest that intrauterine inflammation may be a cause for the IUGR in this model.