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Updated: Jun 13, 2026
Instrumentation of Near-term Fetal Sheep for Multivariate Chronic Non-anesthetized Recordings
Published on: October 25, 2015
Paraoxonase-3, a putative circulating antioxidant, is systemically up-regulated in late gestation in the fetal rat,
Gusztav Belteki1, Sarah L Kempster, Alison J Forhead
1Department of Obstetrics and Gynaecology, University of Cambridge, and Neonatal Intensive Care Unit, Addenbrooke's Hospital, Box 223, Cambridge CB2 0SW, United Kingdom.
Insights
Paraoxonase-3 (Pon3), a circulating antioxidant, is naturally increased in late-term fetuses. This finding suggests Pon3 may be a potential therapeutic for preterm infants facing oxidative stress.
Area of Science:
- Biochemistry
- Neonatal Physiology
- Genomics
Background:
- Preterm infants often experience oxidative stress due to insufficient endogenous antioxidant defenses.
- Current surfactant therapy addresses lung immaturity but not oxidative stress.
- There is a need for effective antioxidant therapies for premature neonates.
Purpose of the Study:
- To identify endogenous antioxidants crucial for fetal maturation and preparation for birth.
- To investigate the role of specific antioxidant molecules in late gestation.
- To find potential therapeutic targets for preterm infant complications.
Main Methods:
- Transcript profiling of fetal rat lung and intestine at different gestational ages.
- Gene expression analysis in fetal sheep tissues under varying conditions (gestational age, dexamethasone, adrenalectomy).
- Western blot analysis of protein levels in human umbilical cord serum.
Main Results:
- Paraoxonase-3 (Pon3) mRNA showed significant upregulation (>20-fold) in fetal rat lung and intestine.
- Pon3 mRNA levels increased with gestational age in fetal sheep and correlated with plasma cortisol.
- Dexamethasone increased and adrenalectomy decreased fetal sheep Pon3 expression; term infants had higher cord serum Pon3 than preterm infants.
Conclusions:
- Paraoxonase-3 (Pon3) is identified as a key circulating antioxidant upregulated during late fetal development across species.
- Pon3 levels are influenced by factors related to birth preparation, including cortisol and corticosteroids.
- Pon3 represents a promising candidate for therapeutic intervention in preterm infants to combat oxidative stress.
Context:
Surfactant is a successful therapeutic based on supplementing preterm infants with a substance that would normally have been up-regulated in late gestation. Although prematurity is associated with oxidative stress, no effective antioxidant therapy has yet been identified.
Objective:
Our objective was to identify endogenous antioxidants involved in fetal preparation for birth.
Design:
We performed transcript profiling of fetal rat lung and intestine at 16 d gestational age (dGA) and 20 dGA with out-of-sample validation. Gene expression was then measured in fetal sheep tissues, comparing 1) advancing GA, 2) exogenous maternal dexamethasone (compared with saline, at 130 dGA), and 3) fetal adrenalectomy at 115-118 d on levels at term. Protein levels were compared in human umbilical cord serum using Western blot.
Results:
Four transcripts were up-regulated more than 20-fold on the array in both rat lung and intestine. One of these, paraoxonase-3 (Pon3), had been identified as a putative circulating antioxidant. Up-regulation of Pon3 mRNA in rat lung, intestine, and liver was confirmed in siblings (all P<0.001). Pon3 mRNA levels in fetal sheep lung and intestine increased 5.1- and 5.3-fold, respectively (both P<0.001) between 100 and 145 dGA and were strongly correlated with plasma cortisol (both P<0.001). Fetal sheep pulmonary Pon3 transcript level was increased 55% (P=0.01) by dexamethasone and reduced 74% (P<0.001) by adrenalectomy. Term human infants had more than 6-fold higher umbilical cord serum levels of Pon3 than preterm (24-28 wk GA) infants (P<0.001).
Conclusions:
Pon3, a putative circulating antioxidant, was systemically up-regulated in late-gestation rat, sheep, and human fetuses and is a candidate therapeutic in preterm human infants.
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