Transcriptomics Modeling of the Late-Gestation Fetal Pituitary Response to Transient Hypoxia

Abstract

BackgroundThe late-gestation fetal sheep responds to hypoxia with physiological, neuroendocrine, and cellular responses that aid in fetal survival. The response of the fetus to hypoxia represents a coordinated effort to maximize oxygen transfer from the mother and minimize wasteful oxygen consumption by the fetus. While there have been many studies aimed at investigating the coordinated physiological and endocrine responses to hypoxia, and while immunohistochemical or in situ hybridization studies have revealed pathways supporting the endocrine function of the pituitary, there is little known about the coordinated cellular response of the pituitary to the hypoxia.ResultsThirty min hypoxia (from 17.0±1.7 to 8.0±0.8 mm Hg, followed by 30 min normoxia) upregulated 595 and downregulated 790 genes in fetal pituitary (123–132 days’ gestation; term = 147 days). Network inference of up- and down- regulated genes revealed a high degree of functional relatedness amongst the gene sets. Gene ontology analysis revealed upregulation of cellular metabolic processes (e.g., RNA synthesis, response to estrogens) and downregulation of protein phosphorylation, protein metabolism, and mitosis. Genes found to be at the center of the network of upregulated genes included genes important for purine binding and signaling. At the center of the downregulated network were genes involved in mRNA processing, DNA repair, sumoylation, and vesicular trafficking. Transcription factor analysis revealed that both up- and down-regulated gene sets are enriched for control by several transcription factors (e.g., SP1, MAZ, LEF1, NRF1, ELK1, NFAT, E12, PAX4) but not for HIF-1, which is known to be an important controller of genomic responses to hypoxia.ConclusionsThe multiple analytical approaches used in this study suggests that the acute response to 30 min of transient hypoxia in the late-gestation fetus results in reduced cellular metabolism and a pattern of gene expression that is consistent with cellular oxygen and ATP starvation. In this early time point, we see a vigorous gene response. But, like the hypothalamus, the transcriptomic response is not consistent with mediation by HIF-1. If HIF-1 is a significant controller of gene expression in the fetal pituitary after hypoxia, it must be at a later time.

Chronic hypoxemia induces mitochondrial respiratory complex gene expression in the fetal sheep brain

“…Previous efforts have largely focused on the effects of acute hypoxemic injury to fetal and neonatal animal models. Limited studies have shown the effects of acute hypoxemia on fetal and neonatal brain transcriptomic profiles including upregulation of chemokines, 17 purine binding and signaling, 18 and hypoxia-inducible transcription factor–dependent genes and apoptosis-promoting factors. 16 However, these studies were not designed to accurately model the effects of chronic hypoxemia in a fetus with CHD.…”

“…In this study, we compared the brain transcriptome of fetal sheep in the EXTEND system supported under normoxemic versus chronically hypoxemic conditions, which are similar to those found in a human fetus with CHD. While there have been previous fetal brain transcriptome studies looking at the effects of acute hypoxemia on fetal brains in multiple animal models, 16 , 17 , 18 to our knowledge this is the first transcriptomics study investigating the effects of chronic hypoxemia at levels similar to those seen in severe CHD on the fetal brain ( Video 1 ).…”

Effects of ketamine on the fetal transcriptomic response to umbilical cord occlusion: comparison with hypoxic hypoxia in the cerebral cortex

“…All of these responses have been described previously as the primary early cellular response to other fetal hypoxia models in the pituitary gland (Wood et al . ) and hypothalamus (Wood et al . ) at 1 h post stimulus.…”

Downregulation of the Vitamin D Receptor Regulated Gene Set in the Hippocampus After MDMA Treatment

“…Among transcription factors regulating the significantly altered sets several could be related to hypoxia/ischemia, a known consequence of MDMA administration (Ferrington et al, 2006). For example, the Pax4 regulated gene set was downregulated after transient hypoxic condition in the fetal pituitary of sheep (Wood et al, 2016). FoxO1 and FoxO4 were implicated in antioxidant mechanisms after brain ischemia (Abbas et al, 2009; Fukunaga and Shioda, 2009; Araujo et al, 2011; Jenwitheesuk et al, 2017).…”