| Description |
Fetal exposure to maternal tobacco smoke (MTS) causes growth restriction and alters lung development in humans and animal models. Lung development depends upon molecular mechanisms including PPARγ and Wnt signaling. Recent reports suggest that chromatin-mediated negative cross-talk between PPARγ and Wnt signaling reduces transcription of Wnt output genes. This chromatin-mediated cross-talk is initiated by the lysine histone methyltransferase, and PPARγ target gene, Setd8. We previously showed that lung protein abundance of PPARγ is decreased by MTS exposure in both male and female rat pups. However, the effect of MTS exposure on Setd8 abundance, Wnt signaling, and expression of Wnt target genes in the rat lung is unknown. We hypothesize that MTS exposure decreases Setd8 protein abundance in newborn rat lung. We also hypothesize that MTS exposure decreases transcription of Wnt output genes, in the context of increased Wnt signaling, in newborn rat lung. Pregnant rats were exposed to room air (Control) or tobacco smoke (MTS) from gestational day 11.5 to term (day 22.5). Newborn pups were euthanized and lung tissue collected. We used western blot to measure β-catenin and Setd8 protein abundance in newborn female and male rat pup lung. We used real-time RT-PCR to measure mRNA transcript levels of Lef1, Tcf4, Axin2, MMP-9, and MMP-12 in newborn female and male rat lung. Setd8 protein abundance did not change in MTS exposed female rat lung and was significantly decreased in MTS exposed male rat lung compared to sex-matched controls. β-catenin protein abundance was increased in both female and male MTS exposed rat lung compared to sex-matched controls. mRNA transcript levels of Wnt transducer Lef1 were unchanged in MTS exposed female and male newborn rat lung compared to sex- matched controls. Tcf4 mRNA transcript levels significantly increased in MTS exposed female and male newborn rat pup lung compared to sex-matched controls. Axin2 mRNA transcript levels significantly decreased in only female newborn rat lung, while male Axin2 mRNA transcript levels were unchanged compared to sex-matched controls. mRNA transcript levels of Wnt target gene MMP-9 were significantly decreased in MTS exposed female and male newborn rat lung compared to sex-matched controls. MMP-12 mRNA transcript levels were increased in both female and male newborn rat lung compared with sex-matched controls. Our results demonstrated that MTS exposure causes changes in Setd8 protein abundance as well as mRNA transcript levels of Wnt transducers and target genes in newborn rat lung. We speculate that the interaction of MTS exposure, the PPARγ-Setd8- H4K20me1 pathway, and Wnt signaling pathway contribute to these changes. |
