Late-gestational intrauterine hypoxia represents is a well known risk factor of acquired perinatal brain injury. Cell type- and age-specific sensitivity of hypoxia-responsive genes to low oxygen partial pressure is to be considered in the screening for early indicators of feto-placental tissue hypoxia. To identify early hypoxia-induced alterations in gene expression during late-gestational hypoxia (6 % O(2), 6 h; gestational day 20) we compared primary mouse placenta and brain transcriptomes using high-density oligonucleotide microarrays. Up-regulation of candidate marker genes for hypoxia was confirmed by quantitative RT PCR and immunohistochemistry. Both developing brain and placenta were highly responsive to systemic hypoxia at the level of gene expression involving hypoxia-inducible transcription factor (HIF)-dependent genes and immediate early genes (IEG) (Fos, Jun, Egr1, Bhlhb2), apoptosis-promoting factors (Bnip3, Dusp1, Ier3) which were all up-regulated, and genes modulating RNA binding and translation (Rbm3, Thap2, Lig4, Rbm12b) which mainly were down-regulated. Functional activity of the HIF system was obvious from elevated expression of various known HIF target genes (Adm, Vegf, Hk2, Pdk1, Bnip3, Ier3, Dusp-1) indicating immediate availability among early response to acute hypoxia. In addition, genes not yet described as being hypoxia-related were identified that are involved in angiogenesis/cell differentiation (Gna13, Gab2), mRNA processing and embryonic development. RT PCR of placenta and brain tissues confirmed up-regulation of selected HIF target genes and IEG. These data indicate that the early hypoxia-induced genomic response of the placenta mirrors that of developing brain in a temporally parallel manner. Our observations implicate future diagnostic options to identify fetal and cerebral tissue hypoxia.
Abstract
Late-gestational intrauterine hypoxia represents is a well known risk factor of acquired perinatal brain injury. Cell type- and age-specific sensitivity of hypoxia-responsive genes to low oxygen partial pressure is to be considered in the screening for early indicators of feto-placental tissue hypoxia. To identify early hypoxia-induced alterations in gene expression during late-gestational hypoxia (6 % O(2), 6 h; gestational day 20) we compared primary mouse placenta and brain transcriptomes using high-density oligonucleotide microarrays. Up-regulation of candidate marker genes for hypoxia was confirmed by quantitative RT PCR and immunohistochemistry. Both developing brain and placenta were highly responsive to systemic hypoxia at the level of gene expression involving hypoxia-inducible transcription factor (HIF)-dependent genes and immediate early genes (IEG) (Fos, Jun, Egr1, Bhlhb2), apoptosis-promoting factors (Bnip3, Dusp1, Ier3) which were all up-regulated, and genes modulating RNA binding and translation (Rbm3, Thap2, Lig4, Rbm12b) which mainly were down-regulated. Functional activity of the HIF system was obvious from elevated expression of various known HIF target genes (Adm, Vegf, Hk2, Pdk1, Bnip3, Ier3, Dusp-1) indicating immediate availability among early response to acute hypoxia. In addition, genes not yet described as being hypoxia-related were identified that are involved in angiogenesis/cell differentiation (Gna13, Gab2), mRNA processing and embryonic development. RT PCR of placenta and brain tissues confirmed up-regulation of selected HIF target genes and IEG. These data indicate that the early hypoxia-induced genomic response of the placenta mirrors that of developing brain in a temporally parallel manner. Our observations implicate future diagnostic options to identify fetal and cerebral tissue hypoxia.
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