Lower Placental Leptin Promoter Methylation in Association with Fine Particulate Matter Air Pollution during Pregnancy and Placental Nitrosative Stress at Birth in the ENVIRONAGE Cohort

Abstract

Background: Particulate matter with a diameter ≤ 2.5 μm (PM2.5) affects human fetal development during pregnancy. Oxidative stress is a 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. Placental 3-NTp (n = 313) was determined with an ELISA assay. Daily PM2.5 exposure levels were estimated for each mother's residence, accounting for residential mobility during pregnancy, using a spatiotemporal interpolation model.

Results: After adjustment for a priori chosen covariates, placental LEP methylation was 1.4% lower (95% CI: -2.7, -0.19%) in association with an interquartile range increment (7.5 μg/m3) in second-trimester PM2.5 exposure and 0.43% lower (95% CI: -0.85, -0.02%) in association with a doubling of placental 3-NTp content.

Conclusions: LEP methylation status in the placenta was negatively associated with PM2.5 exposure during the second trimester, and with placental 3-NTp, a marker of oxidative/nitrosative stress. Additional research is needed to confirm our findings and to assess whether oxidative/nitrosative stress might contribute to associations between PM2.5 and placental epigenetic events. Potential consequences for health during the neonatal period and later in life warrant further exploration. Citation: Saenen ND, Vrijens K, Janssen BG, Roels HA, Neven KY, Vanden Berghe W, Gyselaers W, Vanpoucke C, Lefebvre W, De Boever P, Nawrot TS. 2017. Lower placental leptin promoter methylation in association with fine particulate matter air pollution during pregnancy and placental nitrosative stress at birth in the ENVIRONAGE cohort. Environ Health Perspect 125:262-268; http://dx.doi.org/10.1289/EHP38.

Figure 1

Placental LEP promoter DNA methylation in association with PM_2.5 exposure for different time windows of pregnancy (n = 361) or placental 3-nitrotyrosine (3-NTp) at birth (n = 313). Models were adjusted for newborn sex, maternal age, maternal education, maternal smoking status, gestational age, prepregnancy BMI, ethnicity, and season (i.e., gestational trimester-specific season in the PM_2.5 exposure models and season of delivery in the 3-NTp model). The trimester-specific PM_2.5 exposure models were mutually adjusted for the other gestational exposure windows to estimate the independent effect of each trimester of exposure. Estimates are presented as an absolute percentage difference in placental LEP promoter DNA methylation for a trimester-specific interquartile range increment in PM_2.5 exposure (trimester 1: 8.2 μg/m³; trimester 2: 7.5 μg/m³; trimester 3: 9.9 μg/m³) or a doubling in 3-NTp content (nM/mg protein). *p < 0.05.

Figure 2

Placental CpG-specific LEP promoter DNA methylation in association with PM_2.5 exposure for different time windows of pregnancy (n = 361). Models were adjusted for newborn sex, maternal age, maternal education, maternal smoking status, gestational age, prepregnancy BMI, ethnicity, and gestational trimester-specific season. The trimester-specific PM_2.5 exposure models were mutually adjusted for the other gestational exposure windows to estimate the independent effect of each trimester of exposure. Estimates are presented as absolute percentage difference in LEP promoter DNA methylation for a trimester-specific interquartile range increment in PM_2.5 exposure (trimester 1: 8.2 μg/m³; trimester 2: 7.5 μg/m³; trimester 3: 9.9 μg/m³). *p < 0.05.