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The proinflammatory potential of Nrf2-deficiency and its influence on fetal growth
06 April 2017 (online)
Increased oxidative stress and intrauterine inflammation are etiological factors for intrauterine growth restriction (IUGR). The transcription factor Nrf2 regulates the expression of multi antioxidative and detoxifying enzymes. The role of Nrf2 in the placental development is not well described. Here, we tested the effect of Nrf2-deletionon on placental and fetal growth.
We mated Nrf2-heterozygote mice to obtain both wild type (WT) embryos and embryos with homozygote gene deletion of Nrf2 (KO) in one litter. Placentas and fetus were collected on day E 13.5, E 15.5 and E18.5 post coitum (p.c). Half of the each placenta was embedded in paraffin and used for histological and immunohistochemistry analyses, the other half were used for molecular biology analyses. Expression of the anti-inflammatory enzyme heme oxygenase-1 (HO-1) and the pro-inflammatory cytokines IL-6, IL-1 und TNF-α were analyzed. Marker of oxidative stress, 4-Hydroxynonenal and cell death (apoptosis) were assessed by immunohistochemical methods.
We determined that 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 reduced placental volume of Nrf2 deleted embryos was reduced (WT 121 ± 4 vs. KO 92.3 ± 5 mm3). Placentas from preterm Nrf2-deleted pups showed increased levels of pro-inflammatory cytokines (IL-6 and TNFa), marker of oxidative stress; 4-hydroxy nonenal, and cell death.
Our results show that a disturbed Nrf2 signaling restricts the function of the placenta and 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 HO-1 in Nrf2 deleted fetuses suggests the intrauterine inflammation as a possible cause of the IUGR in this model.