Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment

Charles E Wood, Maria Belen Rabaglino, Elaine Richards, Nancy Denslow, Miguel A Zarate, Eileen I Chang, Maureen Keller-Wood

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Estradiol (E2) is a well-known modulator of fetal neuroendocrine activity and has been proposed as a critical endocrine signal readying the fetus for birth and postnatal life. To investigate the modulatory role of E2 on fetal stress responsiveness and the response of the fetal brain to asphyxic stress, we subjected chronically catheterized fetal sheep to a transient (10 min) brachiocephalic artery occlusion (BCO) or sham occlusion. Half of the fetuses received subcutaneous pellets that increased plasma E2 concentrations within the physiological range. Hypothalamic mRNA was analyzed using the Agilent 8x15k ovine array (019921), processed and annotated as previously reported by our laboratory. Analysis of the data by ANOVA revealed that E2 differentially regulated (DR) 561 genes, and BCO DR 894 genes compared with control and E2+BCO DR 1,153 genes compared with BCO alone (all P < 0.05). E2 upregulated epigenetic pathways and downregulated local steroid biosynthesis but did not significantly involve genes known to directly respond to the estrogen receptor. Brachiocephalic occlusion upregulated kinase pathways as well as genes associated with lymphocyte infiltration into the brain and downregulated neuropeptide synthesis. E2 upregulated immune- and apoptosis-related pathways after BCO and reduced kinase and epigenetic pathway responses to the BCO. Responses to BCO are different from responses to hypoxic hypoxia suggesting that mechanisms of responses to these two forms of brain hypoxia are distinct. We conclude that cerebral ischemia caused by BCO might stimulate lymphocyte infiltration into the brain and that this response appears to be modified by estradiol.

Original languageEnglish
Pages (from-to)523-32
Number of pages10
JournalPhysiological Genomics
Volume46
Issue number14
DOIs
Publication statusPublished - 15 Jul 2014
Externally publishedYes

Keywords

  • Animals
  • Brachiocephalic Trunk/drug effects
  • Brain/drug effects
  • Brain Ischemia/genetics
  • Down-Regulation/drug effects
  • Epigenesis, Genetic/drug effects
  • Estradiol/pharmacology
  • Fetus/drug effects
  • Hypothalamus/drug effects
  • Hypoxia/embryology
  • Lymphocytes/drug effects
  • Neuropeptides/genetics
  • RNA, Messenger/genetics
  • Receptors, Estrogen/genetics
  • Sheep/metabolism
  • Transcriptome/drug effects
  • Up-Regulation/drug effects

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