Paraoxonase-3, a putative circulating antioxidant, is systemically up-regulated in late gestation in the fetal rat, sheep, and human.
BACKGROUND
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.


METHODS
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.
Belteki
Gusztav
G
Department of Obstetrics and Gynaecology, University of Cambridge, and Neonatal Intensive Care Unit, Addenbrooke's Hospital, Box 223, Cambridge CB2 0SW, United Kingdom.
Kempster
Sarah L
SL
Forhead
Alison J
AJ
Giussani
Dino A
DA
Fowden
Abigail L
AL
Curley
Anna
A
Charnock-Jones
D Stephen
DS
Smith
Gordon C S
GC
D000818:Animals; D043303:Aryldialkylphosphatase; D015153:Blotting, Western; D004950:Esterases / Q000235:genetics* / Q000378:metabolism; D005312:Fetal Blood / Q000378:metabolism*; D005333:Fetus / Q000378:metabolism*; D020869:Gene Expression Profiling; D005865:Gestational Age; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D016014:Linear Models; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D015854:Up-Regulation
D004950:Esterases; D043303:Aryldialkylphosphatase; C113656:PON3 protein, human