1931

Background: Current research suggests that short- and intermediate- term exposure to ambient particulate matter is associated with global and gene-specific DNA methylation (DNAm), but little is known regarding the changes in epigenome-wide caused by particulate elements (PEs). Additionally, the potential pathways remain unknown.Objective: We evaluated short- to intermediate-term associations between ambient PEs and DNAm in epigenome-wide and identified potential biological pathways.Method: We collected whole blood samples from 691 elderly men in the Normative Aging Study (1999-2013) and measured epigenome-wide DNAm with the Illumina Infinium HumanMethylation450 BeadChip. Ambient PEs were measured daily at a fixed monitoring station and 5 different moving averages from short- to intermediate-term (current day to 28-day) were considered. Linear quantile mixed models were used to estimate the associations between 15 elements and DNAm (N=1, 262 visits), adjusting for fine particle mass, cell type, batch effects, age, body mass index, smoking, etc. Pathway analysis was also performed to explore the potential biologic mechanisms.Results: Short- to intermediate-term exposure to PEs was significantly associated with epigenome-wide DNAm, especially for 28-d moving average. We observed different Bonferroni significant CpGs for different PE, most of them related with aluminum, iron, silicon, lead, and, calcium. The pathway analyses suggest that the detrimental effects might be relevant to cell cycle, biosynthetic process, and signal transduction. We also found that there were several common genes significantly associated with calcium, silicon and lead, such as, neurodegenerative disease related gene tubulin folding cofactor D.Conclusions: Ours is the first study that find short- to intermediate-term effects on DNAm in epigenome-wide by ambient PEs, especially elements associated with road dust, oil combustion, and wood burning. Our findings provide insight into potential mechanistic pathways.

2277

Background Parabens are detected ubiquitously in human urine samples, but the effects of prenatal exposure are unclear, partially due to inadequate exposure assessment in maternal urine, which may fail to capture fetal exposure. We examined the association of meconium methylparaben detection with preterm birth, gestational age, birthweight, maternal thyroid hormones, and child attention-deficit hyperactivity disorder (ADHD) at 6-7 years. Methods Methylparaben was measured in meconium with ultraperformance liquid chromatography mass spectrometry and dichotomized (detect/non-detect) for 345 children in the Gestation and the Environment cohort in Sherbrooke, Quebec, Canada, Birth outcomes and maternal thyroid hormones (T3, T4, and thyroid stimulating hormone [TSH]) at <20 weeks gestation were measured at the Centre Hospitalier Universitaire de Sherbrooke. ADHD diagnosis at age 6-7 was determined at follow-up or from medical records. Associations were estimated with logistic and linear regressions, and the potential for mediation by birthweight and preterm birth of the effect of methylparaben on ADHD was modeled with causal mediation analysis. Results Meconium methylparaben detection was associated with increased odds of preterm birth (odds ratio [OR]=4.81; 95% CI [2.29, 10.10]), decreased gestational age (beta [β]=-0.61 weeks; 95% CI [-0.93, -0.29]) and decreased birthweight (β=-0.12 kilograms; 95% CI [-0.21, -0.03]). Associations were also found with decreased maternal TSH (relative concentration [RC]=0.76; 95% CI [0.58, 0.99]) and total T3 (RC=0.84; 95% CI [0.75, 0.96]), but increased total T4 (RC=1.10; 95% CI [1.01, 1.19]). Mothers of infants with detectable meconium methylparaben had increased odds of hypothyroxinemia (OR=2.50, 95% CI [1.01, 6.22]), and children were more likely to be diagnosed with ADHD at age 6-7 (OR=2.33, 95% CI [1.45, 3.76]). Preterm birth and birthweight mediated 20% and 13% of the effect of methylparaben on ADHD respectively. Conclusions This adverse association between methylparaben and ADHD, partially mediated by birth outcomes, warrants further research into fetal methylparaben exposure.

2624

Background: Essential and non-essential metal exposure during pregnancy is ubiquitous, influencing maternal and child health. We evaluated associations of prenatal metals with mitochondria DNA abundance (mtDNA) and telomere length (TL) in mothers during pregnancy and their children at birth, as biomarkers of oxidative stress and inflammation. Methods: We measured six nonessential metals (As, Ba, Cd, Cs, Hg, Pb) and four essential metals (Mg, Mn, Se, Zn) in first trimester red blood cells from women in Project Viva, a prospective pre-birth cohort in Massachusetts. We measured mtDNA and TL in second trimester maternal blood (N=893-898) and cord blood (N=408-419). We used multivariable linear regression models and Bayesian Kernel Machine Regression (BKMR) to evaluate their associations, adjusted for confounders. Results: Mean (SD) mtDNA was 1.05 (0.32) in maternal blood and 1.01 (0.25) in cord blood. Mean (SD) TL was 0.68 (0.24) in maternal and 1.24 (0.70) in cord blood. In adjusted models, a two-fold increase in maternal magnesium was associated with decreased maternal mtDNA (β -0.09, 95% CI: -0.15, -0.03) and cord blood mtDNA (β -0.08, 95% CI: -0.14, -0.01). A two-fold increase in maternal lead was associated with increased maternal mtDNA (β 0.04, 95% CI: 0.01, 0.06). Selenium was associated with increased cord blood TL (β 0.26, 95% CI: 0.0, 0.52). When characterizing the overall effect of the mixtures, our BKMR analyses suggested a dose-response association between the metal mixture and cord blood mtDNA relative to the 50^th percentile (25^th percentile of mixture β 0.08, 95% CI: -0.05, 0.20; 75^th percentile of mixture β -0.11, 95% CI: -0.25, 0.03). Conclusion: Our findings suggest that certain prenatal metals are associated with molecular biomarkers of oxidative stress and inflammation in both maternal second trimester and cord blood, and future work will evaluate the extent to which these markers are associated with health outcomes.

2696

Background/Aims: While maternal stress has been linked to adverse child health outcomes, mechanistic links have not been fully elucidated. Maternal microRNAs encapsulated in Extracellular Vesicles (EVs) reach the infant through breastmilk and are a novel biochemical communication pathway for early-life programming. We leverage the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort to investigate associations between maternal stress and breast milk EV-microRNAs. Methods: We assessed maternal lifetime stress using the Life Stressor Checklist-Revised (LSCR) survey and negative life events (NLEs) experienced in the past 6 months during pregnancy using the Crisis in Family Systems-Revised (CRISYS-R) survey. Extracellular vesicles were isolated from N=80 breastmilk samples collected at 6.1±5.9 weeks postnatally. Total RNA was extracted and microRNAs were profiled using the TaqMan OpenArray Human miRNA panel. Logistic regression assessed associations between continuous LSCR and NLE scores and EV-microRNA detection (outcome yes/no);associations with EV-microRNA expression levels were assessed using robust linear regression (N=74 with EV-microRNA and maternal stress data). Models were adjusted for infant sex, maternal race/ethnicity, education, and week of breast milk collection. Results: Among 345 EV-microRNAs detected in >10% of samples, detection of 127 (47%) was associated with LSCR score and detection of 97 (28%) was associated with NLE score (p < 0.05). Among 205 EV-microRNAs detected in >50% of samples, expression of 8 was associated with LSCR scores and expression of 17 was associated with NLE score at our a priori criteria of p < 0.05 and |B_regression| > 0.2. MicroRNAs associated with LSCR and NLE scores were involved in KEGG pathways related to fatty acid metabolism and steroid biosynthesis. Conclusions: Maternal lifetime cumulative stress and stress during pregnancy were associated with EV-microRNAs in breast milk although microRNA profiles differed. Further research is needed to identify biological pathways impacted by differentially expressed microRNAs and investigate relationships with child health outcomes.

2594

Introduction: Exposure to ambient fine particulate matter (PM2.5) is linked to changes in placental mitochondrial DNA (mtDNA) copy number. Whether PM2.5 impacts mitochondrial mutational load in placental tissue-another biomarker of oxidative damage and aging has not been studied. Further, genetic ancestry likely impacts this relationship and may inform health disparities. Methods: We examine the association between PM2.5 and placental mtDNA mutational load in an urban multi-ethnic cohort (N=285). Mothers' daily exposure to PM2.5 over gestation was estimated using a satellite-based spatio-temporally resolved prediction model. Whole mtDNA sequencing was performed and mutations and haplogroups were determined. Bayesian Distributed Lag Interaction regression models (BDLIMs) were used to statistically model and visualize the PM2.5 timing-dependent pattern of associations with mtDNA mutations (total load and gene-specific) and explore effect modification by haplogroup. Results: Overall, increased PM2.5 exposure across pregnancy was not associated with total mutational load. However, results varied by mtDNA haplogroup with increases in PM2.5 being associated with higher total mutational load for African (cumulative effect 1.92, 95%CI 0.46, 3.48) and Asian (cumulative effect: 1.33, 95% CI 0.07, 2.73) haplogroups; a critical window was identified between 29 and 35 weeks gestation for African haplogroups only. Gene-wise analyses suggested that increased PM2.5 exposure during mid pregnancy (20-25 weeks) might have a stronger impact on mutations located in genes coding for ATP synthase subunits regardless of haplogroup. Conclusions: Placental mtDNA mutations, associated with increased PM2.5 exposure mid to late pregnancy, may have consequences on placental energy production, aging, and metabolic regulation that may impact offspring development. Understanding how these associations differ based on ancestry may further elucidate the etiology of environmentally-related disease disparities.

1403

Background: Multiple studies have identified adverse associations between exposures to air pollution and endocrine disrupting chemicals on semen quality. However, few studies have assessed these associations among men from the general population, as opposed to clinical settings. Our objective was to assess these associations in a subset of participants in the US nationwide Growing Up Today Study (GUTS).
Methods: We aim to enroll 200 men from GUTS living in the conterminous US, without a vasectomy, are who have not undergone chemotherapy, and are not taking anabolic steroids. For 90 days, participants use a smartphone application to track GPS location, run an air pollution sampler to collect real-time indoor measurements of NO₂, and wear 3 separate passive wristband samplers each for 30 days. After 90 days of monitoring, participants produce a semen sample, which is analyzed for concentration and morphology at the Massachusetts General Hospital Andrology Laboratory via computer-aided semen analysis. For the first 45 participants, we assessed the interclass correlation (ICC) of exposures and assessed associations between exposures and outcomes using Spearman correlations and linear regressions.
Results: The average NO₂ concentration was 18.11 (SD=10.2) ppb and 21 chemicals were detected in at least 20% of wristbands measured. The ICC for daily NO₂ was 0.71 (95%CI: 0.61, 0.79), the ICCs for the 21 chemicals varied widely, ranging from 0.04 (0.00, 0.97) for dicyclohexyl phthalate to 0.88 (0.78, 0.94) for galaxolide. Ninety-day average exposures to NO₂ were not associated percent normal morphology, but were associated with decreased sperm concentration (-12.09 M/ml per IQR (14.49 ppb) NO₂). There were no clear patterns observed between the EDC exposures and semen parameters.
Conclusions: In an initial subsample of general population men, exposures to NO₂, but not endocrine disrupting chemicals, were associated with lower sperm concentrations.

2693

AbstractBackground: Population aging is a looming global health challenge. New biological aging metrics based on DNA methylation levels have been developed in addition to traditional aging biomarkers. The prospective relationships of aging biomarkers with mitochondrial changes are still not well understood.Aim: to examine the prospective associations of mitochondrial copy number (mtDNAcn) with several aging biomarkers - DNAm-age, DNAm-PhenoAge, DNAm-GrimAge, and leukocyte telomere length.Methods: We analyzed 812 individuals from Veteran Affairs Normative Aging Study (NAS) with available blood samples from 1999-2013. Whole blood mtDNAcn and relative leukocyte telomere length were measured via qPCR. DNA methylation was assessed and used to calculate DNAm-Age, DNAm-GrimAge, and DNAm-PhenoAge. Linear mixed models were used to quantify the associations of mtDNAcn with DNAm-age, DNAm-GrimAge, DNAm-PhenoAge, and leukocyte telomere length.Results: In multivariable cross-sectional analyses, mtDNAcn is negatively associated with DNAm-Age PhenoAge and DNAm-PhenoAge. In contrast, mtDNAcn is associated with prospective measures of higher DNAm-PhenoAge and shorter leukocyte telomere length.Discussion: Our study shows that higher mtDNAcn is associated with prospective measures of greater DNAm-PhenoAge and shorter leukocyte telomere length independent of chronological age. This indicates a role for mitochondrial in aging-related disease and mortality, but not the departure of biological age from chronological age. Methylation, mtDNA and telomere length are sensible to external environmental stressors like air pollution or temperature and this element could determine an influence of these environmental stressor on epigenetic aging biomarkers like DNAm-age, DNAm-PhenoAge, DNAm-GrimAge and how these metrics interact with mtDNAcn.