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High oxygen prevents fetal lethality due to lack of catecholamines

ABSTRACT: The catecholamine norepinephrine is required for fetal survival, but its essential function is unknown. When catecholamine-deficient [tyrosine hydroxylase (Th) null] mouse fetuses die at E13.5-E14.5, they resemble wild type fetuses exposed to hypoxia. They exhibit bradycardia (28% reduction in heart rate), thin ventricular myocardium (20% reduction in tissue), epicardial detachment, and death with vascular congestion, hemorrhage and edema. At E12.5, prior to the appearance of morphological deficits associated with Th deletion, catecholamine-deficient fetuses are preferentially killed by experimentally-induced hypoxia and have lower tissue pO2 than wild type siblings. Catecholamine-deficient fetuses also induced HIF-1 target genes to a greater extent than wild type siblings, supporting the notion that null fetuses experience greater hypoxia or have an enhanced response to hypoxia. Hypoxia induces a 13-fold increase in plasma norepinephrine levels, which would be expected to increase heart rate, thereby, improving oxygen delivery in wild type mice. Surprisingly, increasing maternal oxygen (FiO2 33% or 63%) prevents the effects of catecholamine-deficiency, restoring heart rate, myocardial mass and survival of Th null fetuses. We suggest that norepinephrine mediates fetal survival by maintaining oxygen homeostasis as vulnerability to constitutive hypoxia increases as fetal growth accelerates during normal development. Keywords: Comparative with respect to genotype and oxygen conditions

ORGANISM(S): Mus musculus

PROVIDER: GSE10341 | GEO | 2008/06/03

SECONDARY ACCESSION(S): PRJNA105581

REPOSITORIES: GEO

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Project description:Although the effects of thyroid hormones (TH) on the brain development have been extensively studied perinatally, effects of TH of maternal origin on the fetal brain development have been largely unexplored. We applied a high throughput study on the mouse models with aberrant TH levels on gestation day (GD) 16, before the onset of fetal thyroid function. Although 3 day treatment with methimazole (MMI) and perchlorate significantly decreased TH levels in fetal cerebral cortex, few changes in the abundance of mRNA were revealed by the microarray analysis. Injection TH to dams 12 hours before sacrifice on GD 16 induced 161 genes significantly changed in fetal cortex. Nine out of 10 selected genes were confirmed with RT-PCR, including known TH responsive gene Klf9 and other novel TH responsive genes such as Appbp2, Ppap2b and Fgfr1op2. TH regulation of the expression of these genes was also confirmed with cultured N2a? cells. Thyroid responsive elements (TREs) in the promoters of these genes were identified using electrophoresis mobility shift assay. TH effect on microRNA (miRNA) expression in developing cortex on GD 16 and postnatal day (PND) 15 was investigated with microarray and RT-PCR. Some of miRNAs and precursors decreased in fetal cortex from the dams injected with TH on GD 16, including miR-16 and miR-106. Using 3’ untranslate region reporter vector, we identified Klf9 is one of the target genes of miR-106, while Ppap2b is the target of miR-16. These results indicated that TH regulation on gene expression could through TR-TRE interaction and through regulating target miRNA expression. This study is the first report to identify TH responsive genes and miRNAs genome wide in the early fetal brain; it provides evidence to further understand the mechanism of TH effect on brain development. Timed-pregnant C57BL/6 mice (n=20; Harlan, Indianapolis, IN) arrived on gestational day (GD) 11 and were housed individually in plastic cages under a 12:12 light cycle (0600 h–1800 h) with food available ad libitum. Mice were divided randomly into one of 4 groups (control, hypo, hypo+ and hyper; 5 per group) . Mice in the control and hyper groups were provided with fresh drinking water containing 2% sucrose from GD 13 to GD 16 until sacrifice. Mice in hypo and hypo+ were provided with fresh drinking water daily containing 1% Perchlorate (Per) and 0.025% Methimazole (MMI) supplemented with 2% sucrose (to mask bitterness) from GD 13 to sacrifice on GD 16. Twelve hours prior to sacrifice on GD 16 all mice received a single subcutaneous injection. Control and hypo mice received vehicle (0.9% saline in 100 µl volume); the hypo+ group received 25.0 µg/100g body weight thyroxine (T4) with 2.5 µg/100g body weight T3 to restore a physiological level of TH; the hyper group received 100.0 µg/100g body weight T4 with 10.0 µg/100g body weight T3 to model hyperthyroidism. Dams were killed by exposure to CO2. Fetuses were dissected from the uterine horn and embryonic membranes then frozen on pulverized dry ice. Tissue samples were taken from the fetuses to determine sex using PCR for SRY (Yang J and RT Zoeller, 2002). Fetal cerebral cortices were removed from each mouse and used for microarray and RT-PCR analysis. Total RNA was extracted from half cortices of individual female fetuses using RNeasy Lipid tissue Mini kits (Qiagen, Germantown, MD) according to the manufacturer's instructions. The quality of total RNA was evaluated by A260/A280 ratio (found to be at least 1.8 for each sample) and by electrophoresis on the Agilent Bioanalyzer. The Yale Center for the Neuroscience Microarray Consortium carried out the Affymetrix microarray analysis using The GeneChip Rat Genome 230 2.0 Array. Preparation of labeled cRNA for hybridization onto Affymetrix GeneChips followed the recommended Affymetrix protocol. Control versus each of the three treatment groups: hyper, hypo, and hypo+. 1 of 20 samples removed due to poor quality.

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High oxygen prevents fetal lethality due to lack of catecholamines

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