Prenatal Particulate Matter Exposure Is Associated with Saliva DNA Methylation at Age 15: Applying Cumulative DNA Methylation Scores as an Exposure Biomarker

Abstract

Background: Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. Methods: In the Fragile Families and Child Wellbeing Study, a United States 20-city birth cohort, average residential PM2.5 and PM10 during the three months prior to birth was estimated using air quality monitors with inverse distance weighting. Saliva DNA methylation at ages 9 (n = 749) and 15 (n = 793) was measured using the Illumina HumanMethylation 450 k BeadArray. Cumulative DNA methylation scores for particulate matter were estimated by weighting participant DNA methylation at each site by independent meta-analysis effect estimates and standardizing the sums. Using a mixed-effects regression analysis, we tested the associations between cumulative DNA methylation scores at ages 9 and 15 and PM exposure during pregnancy, adjusted for child sex, age, race/ethnicity, maternal income-to-needs ratio, nonmartial birth status, and saliva cell-type proportions. Results: Our study sample was 50.5% male, 56.3% non-Hispanic Black, and 19.8% Hispanic, with a median income-to-needs ratio of 1.4. Mean exposure levels for PM2.5 were 27.9 μg/m3/day (standard deviation: 7.0; 23.7% of observations exceeded safety standards) and for PM10 were 15.0 μg/m3/day (standard deviation: 3.1). An interquartile range increase in PM2.5 exposure (10.73 μg/m3/day) was associated with a −0.0287 standard deviation lower cumulative DNA methylation score for PM2.5 (95% CI: −0.0732, 0.0158, p = 0.20) across all participants. An interquartile range increase in PM10 exposure (3.20 μg/m3/day) was associated with a −0.1472 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: −0.3038, 0.0095, p = 0.06) across all participants. The PM10 findings were driven by the age 15 subset where an interquartile range increase in PM10 exposure was associated with a −0.024 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: −0.043, −0.005, p = 0.012). Findings were robust to adjustment for PM exposure at ages 1 and 3. Conclusion: In utero PM10-associated DNA methylation differences were identified at age 15 in saliva. Benchmarking the timing and cell-type generalizability is critical for epigenetic exposure biomarker assessment.

Assessment of the Feasibility of a Future Integrated Larger-Scale Epidemiological Study to Evaluate Health Risks of Air Pollution Episodes in Children

“…Ideally, a study should include an integrated investigation combining proteinaceous, genetic and/or epigenetic levels. In recent years, a rapid increase has been observed in the number of studies in which integration was successfully applied, as well as in the number of tools developed to facilitate the integration [ 23 , 101 , 102 , 103 , 104 ]. Such an approach optimizes the use of potential health biomarkers in epidemiological studies to reach an in-depth understanding of interrelated or complementary relationships of the biomarkers and of certain disorders as well as to identify potential risk factors.…”

Immuno-epigenetic signature derived in saliva associates with the encephalopathy of prematurity and perinatal inflammatory disorders

“…Among these developments are the use of poly-epigenetic scores of exposure, which integrate information from multiple CpG sites to provide a record of exposure or to capture a complex trait (93). This approach has been used to examine maternal smoking (94–97) glucocorticoid, and prenatal folate exposure during pregnancy (55,98), alongside environmental exposures such as pollution (98). Examining DNAm proxies of inflammation is uncommon, but given the health associations with inflammatory-related DNAm in adult cohorts (47,48,99), and the shared nature of epigenetic changes between mother and infants (64,100), we hypothesised that variance in the neonatal methylome could reflect a convergence of amassed inflammatory burden from different perinatal origins.…”

“…Given we have now applied this method to buccal-cell DNAm, it is encouraging to see similar associations between DNAm CRP and brain structural outcomes, especially given that DNAm is highly tissue specific (136), and previous research has reported on cross-tissue differences in magnitude and direction of effects for other traits (137). This cross-tissue approach (where weights were originally created from blood-based DNAm, and later applied to saliva-based composite signatures) has also been adopted in other studies (98,138). While future studies would ideally measure CRP directly from serum or blood spots in infants to enable direct cross-tissue comparisons, saliva has the advantage of being one of the most accessible tissue samples for infant populations, and may be more suitable than other peripheral samples (such as blood) when examining brain and cognitive outcomes owing to the brain and buccal cell shared ectodermal origins (139–142).…”

Epigenome-wide association of neonatal methylation and trimester-specific prenatal PM2.5 exposure

“…29,30 Changes in DNAm associated with prenatal exposure to PM 2.5 can even be detected in salivary samples as late as at 15 years of age. 31 Of particular note is a study utilizing a large multisite cohort that identified 14 CpG sites at which infant DNAm was associated with prenatal PM 2.5 exposure averaged across pregnancy. 32 While averaging exposures across pregnancy does provide a robust and powerful marker of total PM 2.5 exposure during pregnancy, it is important to consider that the impact of an exposure on a specific health outcome may depend on the timing of that exposure.…”