TitleCord blood DNA methylation of DNMT3A mediates the association between in utero arsenic exposure and birth outcomes: Results from a prospective birth cohort in Bangladesh.
Publication TypeJournal Article
Year of Publication2020
AuthorsBozack, AK, Cardenas, A, Geldhof, J, Quamruzzaman, Q, Rahman, M, Mostofa, G, Christiani, DC, Kile, ML
JournalEnviron Res
Date Published2020 04
KeywordsArsenic, Bangladesh, Birth Weight, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA Methyltransferase 3A, Female, Fetal Blood, Humans, Infant, Newborn, Male, Maternal Exposure, Pregnancy, Prospective Studies

BACKGROUND: Fetal epigenetic programming plays a critical role in development. DNA methyltransferase 3 alpha (DNMT3A), which is involved in de novo DNA methylation (DNAm), is a prime candidate gene as a mediator between prenatal exposures and birth outcomes. We evaluated the relationships between in utero arsenic (As) exposure, birth outcomes, and DNMT3A DNAm.

METHODS: In a prospective Bangladeshi birth cohort, cord blood DNAm of three DNMT3A CpGs was measured using bisulfite pyrosequencing. Maternal toenail As concentrations at birth were measured to estimate in utero exposure. Among vaginal births (N = 413), structural equation models (SEMs) were used to evaluate relationships between DNMT3A methylation, log (toenail As), birth weight, and gestational age.

RESULTS: In an adjusted SEM including birth weight and gestational age, maternal toenail As levels were associated with DNMT3A DNAm (B = 0.40; 95% CI: 0.15, 0.66) and gestational age (B = -0.19 weeks; 95% CI: 0.36, -0.03). DNMT3A DNAm was associated with gestational age (B = -0.10 weeks; 95% CI: 0.16, -0.04) and birth weight (B = -11.0 g; 95% CI: 21.5, 0.4). There was an indirect effect of As on gestational age mediated through DNMT3A DNAm (B = -0.04; 95% CI: 0.08, -0.01), and there were indirect effects of maternal toenail As levels on birth weight through pathways including gestational age (B = -14.4 g; 95% CI: 29.2, -1.9), DNMT3A DNAm and gestational age (B = -3.1 g; 95% CI: 6.6, -0.8), and maternal weight gain and gestational age (B = -5.1 g; 95% CI: 9.6, -1.5). The total effect of a doubling in maternal toenail As concentration is a decrease in gestational age of 2.1 days (95% CI: 0.9, 3.3) and a decrease in birth weight of 29 g (95% CI: 14, 46).

CONCLUSIONS: DNMT3A plays a critical role in fetal epigenetic programming. In utero arsenic exposure was associated with greater methylation of CpGs in DNMT3A which partially mediated associations between prenatal As exposure and birth outcomes. Additional studies are needed to verify this finding.

Alternate JournalEnviron Res
PubMed ID32018205
PubMed Central IDPMC7167334
Grant ListF31 ES029019 / ES / NIEHS NIH HHS / United States
P42 ES010349 / ES / NIEHS NIH HHS / United States
R01 ES015533 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
TL1 TR001875 / TR / NCATS NIH HHS / United States
R01 ES023441 / ES / NIEHS NIH HHS / United States