Lower Placental Leptin DNA Methylation through Gestational Exposure to Particulate Matter Air Pollution

Abstract

Background: Particulate matter with a diameter ≤ 2.5 µm (PM2.5) affects fetal human development during pregnancy. Oxidative stress is one putative mechanism by which PM2.5 may exert its effects. Leptin (LEP) is an energy regulating hormone involved in fetal growth and development. Objectives: We investigated in placental tissue whether DNA methylation of the LEP promoter is associated with PM2.5 and whether the oxidative/nitrosative stress biomarker 3-nitrotyrosine (3-NTp) is involved. Methods: LEP DNA methylation status of 361 placentas from the ENVIRONAGE birth cohort was assessed using bisulfite-PCR-pyrosequencing. 3-NTp (n = 313) was determined with an ELISA assay. Daily PM2.5 exposure levels were calculated for each mother’s residence using a spatiotemporal interpolation model. Results: After adjustment for a priori chosen covariates, we found a 1.4% lower placental LEP methylation status (p = 0.02) for an interquartile range increment of PM2.5 exposure during the second gestational trimester. For a doubling in placental 3-NTp content, the placental LEP methylation lowered by -0.43% (p = 0.04). Placental 3-NTp mediated the association between second trimester PM2.5 exposure and LEP methylation. Conclusions: The methylation status of the placental LEP region was sensitive to PM2.5 exposure of the second gestational window and to placental oxidative/nitrosative stress. These stressors influenced the PM2.5-LEP methylation association, suggesting an underlying role of oxidative/nitrosative stress in PM2.5-associated placental epigenetic events. The pathophysiological outcomes of these alterations as to newborns’ health and consequences later in life warrant further exploration.