Placental endocannabinoid metabolism and gene expression gestational age-related alterations across preterm and term birth.

RESEARCH QUESTION: How does the placental endocannabinoid system (ECS) vary across gestation and in spontaneous preterm birth?

DESIGN

Placental tissue was collected from 102 pregnancies from extremely preterm to very preterm (<32 weeks), moderate to late preterm (32-37 weeks) and term (≥37 weeks) deliveries. Ten ECS-related genes were measured by reverse transcription quantitative real-time PCR, and 20 endocannabinoid-related metabolites by targeted ultra-high performance liquid chromatography-mass spectrometry. Data analyses included univariate and multivariate statistics, linear regression and integrative hierarchical clustering of combined gene-metabolite datasets.

RESULTS

Compared with term placentas, the expression of DAGLB and NAPEPLD was lower in both preterm groups (DAGLB, P < 0.001 for both; NAPEPLD, P = 0.035 for extremely to very preterm, P = 0.045 for moderate to late preterm). ABHD6 expression was lower in extremely to very preterm compared with term placentas (P = 0.010). CNR1 was higher in moderate to late preterm than term placentas (P = 0.009). PTGS2 expression was higher in extremely to very preterm than moderate to late preterm placentas (P = 0.046). Multivariate analyses of metabolites distinguished term from preterm groups, driven mainly by elevated values of monoacylglycerols in preterm placentas. Gestational age was inversely associated with monoacylglycerols (β approximately -0.131 to -0.16; R² approximately 0.49-0.65; P < 0.001 for all). N-Acylethanolamines (NAE) displayed weaker (NAE 14:0: β = -0.034, R2 = 0.18, P < 0.001; NAE 18:1: β = -0.058, R2 = 0.26, P < 0.001) or non-significant associations. Integrative clustering revealed three clusters of preterm placentas differing in gestational age, neonatal birthweight and maternal pregnancy weight gain.

CONCLUSIONS

Placental ECS profiles vary significantly with gestational age. The differences observed in preterm placentas primarily reflect gestational maturation rather than distinct clinical phenotypes.