ERRγ1 and Aromatase Expression in Human Placental Tissues from Term Deliveries of Large for Gestational Age Newborns

Abstract

<b><i>Introduction:</i></b> Being born either large for gestational age (LGA) or small for gestational age has been associated with an increased risk of developing metabolic syndrome in adulthood. However, the mechanism underlying this early programming remained unclear. Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor with a high expression in the human placenta, particularly ERRγ1. ERRγ has been proposed to play a central role in controlling genes involved in energy metabolism. In the placenta, ERRγ1 acts as an oxygen-responsive transcription factor, regulating aromatase expression during trophoblast differentiation. Aromatase is an enzyme that catalyzes the synthesis of estrogens from androgens and is located in the syncytiotrophoblast. An adequate estrogen-androgen balance is required for normal pregnancy progression. Our aim was to analyze ERRγ1 and aromatase mRNA in human placenta from term LGA newborns. We propose that ERRγ1 and CYP19A1 expressions in the human placenta of LGA newborns are impaired, which would modify the fetal programming of LGA newborns since an imbalance in the intrauterine estrogen-androgen ratio would occur. <b><i>Methods:</i></b> Total RNA was obtained from the placental tissues of LGA (GA: 39–41 weeks, <i>n</i> = 8) and adequate for gestational age (AGA; 39–40 weeks, <i>n</i> = 10) newborns. ERRγ1 and aromatase mRNA variants were analyzed by RT²-PCR. Primers for aromatase analysis were specific for total aromatase (TotalAro) binding in exons 2–3 and for active aromatase (ActAro) in exons 9–10. Aromatase protein was analyzed by Western blot. <b><i>Results:</i></b> ERRγ1 mRNA was significantly higher in LGA compared to AGA. TotalAro mRNA was significantly lower in LGA in comparison with AGA control. Similar results were observed with aromatase protein. In contrast, ActAro/TotalAro ratio was higher in LGA compared to the AGA control. <b><i>Conclusions:</i></b> High expression of ERRγ1 as well as ActAro/TotalAro ratio in LGA suggests that ERRγ1 is involved in ActAro variant expression and hence disrupted estrogen-androgen balance in the intrauterine environment. We propose that dysregulation of ERRγ1 in the placenta might modify the estrogen-androgen balance in the intrauterine environment in LGA newborns, possibly representing one of the key factors in the regulation of fetal programming.