Persistent organic pollutants (POPs) are toxic chemicals that can adversely affect human health. Efforts have been made to eliminate their production and use, but their long half-lives (which can be more than 10 years)¹ result in nearly ubiquitous exposure, including detection in pregnant women in the United States.² Current US sources of exposure are mostly dietary, including consumption of dairy products and fish. Chemical pollutants can cross the placenta and are present in umbilical cord blood,^3-5 and maternal plasma levels in early pregnancy reflect fetal exposure.⁶

Background: Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies. Results: Our analysis focused on POPs with more than 80% plasma concentrations above the limit of quantification, including 3 organochlorine pesticides (hexachlorobenzene, trans-nonachlor, p,p’-dichlorodiphenyldichloroethylene), 1 polybrominated diphenyl ether (PBDE 47), 3 polychlorinated biphenyls (138/158, 153, 180), and 6 poly- and perfluorinated alkyl substances (PFASs) (perfluorodecanoic acid, perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluoroundecanoic acid (PFUnDA)). Using 5% false discovery rate, POPs were associated with a total of 214 differentially methylated CpG sites (nominal p values ranging from 2.61 × 10⁻²¹ to 2.11 × 10⁻⁷). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated to TUSC3, and increased methylation at those 3 CpG sites was correlated with decreased expression of TUSC3 in the placenta. Increased methylation at cg18145877 (TUSC3) and decreased expression of TUSC3 were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated (p value < 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated (p value < 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs). Conclusions: DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.

Although ambient air pollution may increase hypertension risk through endothelial damage and oxidative stress, evidence is inconsistent regarding its effect on hypertension in pregnancy. Prior research has evaluated a limited scope of pollution species and often not differentiated preeclampsia, which may have a placental origin, from gestational hypertension. Among 49 607 women with at least 2 singleton deliveries in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Consecutive Pregnancies Study (2002–2010), we estimated criteria pollutant and volatile organic compound levels during pregnancy using Community Multiscale Air Quality models and abstracted gestational hypertension and preeclampsia diagnoses from medical records. Generalized estimating equations accounted for repeat pregnancies and adjusted for ambient temperature and maternal age, race/ethnicity, body mass index, smoking, alcohol, parity, insurance, marital status, and asthma. Air pollution levels were low to moderate (eg, median 41.6 ppb [interquartile range, 38.9–43.7 ppb] for ozone and 35.1 ppb [28.9–40.3 ppb] for nitrogen oxides). Higher levels of most criteria pollutants during preconception and the first trimester were associated with lower preeclampsia risk, while higher second-trimester levels were associated with greater gestational hypertension risk. For example, an interquartile increase in first-trimester carbon monoxide was associated with a relative risk of 0.88 (95% CI, 0.81–0.95) for preeclampsia and second-trimester carbon monoxide a relative risk of 1.14 (95% CI, 1.07–1.22) for gestational hypertension. Volatile organic compounds, conversely, were not associated with gestational hypertension but consistently associated with higher preeclampsia risk. These findings further suggest air pollution may affect the development of hypertension in pregnancy, although differing causes of preeclampsia and gestational hypertension may alter these relationships.

Background: Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. Results: We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. Conclusion: We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. Clinical trial registration: ClinicalTrials.gov, NCT00912132