11 beta-hydroxysteroid dehydrogenase 2 promoter methylation is associated with placental protein expression in small for gestational age newborns

- 11β-HSD2 protein expression is lower in placentas of SGA newborns.
- Placental 11β-HSD2 expression is directly correlated to birthweight.
- HSD11B2 promoter methylation is higher in SGA placentas.
- AGA and SGA placentas have no variation in global placental methylation.
- Reduced 11β-HSD2 protein expression may be modulated by methylation of the HSD11B2 promoter.

Small for gestational age infants have greater risk of developing metabolic diseases in adult life. It has been suggested that low birth weight may result from glucocorticoid excess in utero, a key mechanism in fetal programming. The placental enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2, HSD11B2 gene) acts as a barrier protecting the fetus from maternal corticosteroid deleterious effects. Low placental 11β-HSD2 transcription and activity have been associated with low birth weight, yet the mechanism regulating its protein expression is not fully understood. In the present study we aimed to analyze 11β-HSD2 protein expression in placentas of adequate and small for gestational age (AGA and SGA, respectively) newborns from healthy mothers, and to explore whether 11β-HSD2 protein expression could be modulated by DNA methylation. 11β-HSD2 protein levels were measured by western blot in placental biopsies from term AGA and SGA infants (n = 10 per group). DNA methylation was profiled both globally and in the HSD11B2 promoter by liquid chromatography with UV detection and methylation-specific melting curve analysis, respectively. We found lower placental 11β-HSD2 protein expression and higher HSD11B2 promoter methylation in SGA compared to AGA. Promoter methylation was inversely correlated with both protein expression and, importantly, birth weight. No changes in global placental methylation were found. In conclusion, lower 11β-HSD2 protein expression is associated with higher HSD11B2 promoter methylation, correlating with birth weight in healthy pregnancy. Our data support the role of 11β-HSD2 in determining birth weight, providing evidence of its regulation by epigenetic mechanisms, which may affect postnatal metabolic disease risk.