Anne Bozack

All Publications

• Associations of prenatal one-carbon metabolism nutrients and metals with epigenetic aging biomarkers at birth and in childhood in a US cohort. Aging Bozack, A. K., Rifas-Shiman, S. L., Baccarelli, A. A., Wright, R. O., Gold, D. R., Oken, E., Hivert, M. F., Cardenas, A. 2024; 16

  Abstract

  Epigenetic gestational age acceleration (EGAA) at birth and epigenetic age acceleration (EAA) in childhood may be biomarkers of the intrauterine environment. We investigated the extent to which first-trimester folate, B12, 5 essential, and 7 non-essential metals in maternal circulation are associated with EGAA and EAA in early life. Bohlin EGAA and Horvath pan-tissue and skin and blood EAA were calculated using DNA methylation measured in cord blood (N=351) and mid-childhood blood (N=326; median age = 7.7 years) in the Project Viva pre-birth cohort. A one standard deviation increase in individual essential metals (copper, manganese, and zinc) was associated with 0.94-1.2 weeks lower Horvath EAA at birth, and patterns of exposures identified by exploratory factor analysis suggested that a common source of essential metals was associated with Horvath EAA. We also observed evidence nonlinear associations of zinc with Bohlin EGAA, magnesium and lead with Horvath EAA, and cesium with skin and blood EAA at birth. Overall, associations at birth did not persist in mid-childhood; however, arsenic was associated with greater EAA at birth and in childhood. Prenatal metals, including essential metals and arsenic, are associated with epigenetic aging in early life, which might be associated with future health.

  View details for DOI 10.18632/aging.205602

  View details for PubMedID 38412256

• DNA Methylation-Based Biomarkers of Protein Levels and Cardiovascular Disease Risk: Opportunities and Challenges for Precision Cardiology. Circulation. Genomic and precision medicine Bozack, A. K., Navas-Acien, A., Cardenas, A. 2024: e004571

  View details for DOI 10.1161/CIRCGEN.124.004571

  View details for PubMedID 38348680

• COVID-19 subphenotypes at hospital admission are associated with mortality: a cross-sectional study ANNALS OF MEDICINE Dubowski, K., Braganza, G. T., Bozack, A., Colicino, E., DeFelice, N., McGuinn, L., Maru, D., Lee, A. G. 2023; 55 (1): 12-23

  Abstract

  We have an incomplete understanding of COVID-19 characteristics at hospital presentation and whether underlying subphenotypes are associated with clinical outcomes and therapeutic responses.For this cross-sectional study, we extracted electronic health data from adults hospitalized between 1 March and 30 August 2020 with a PCR-confirmed diagnosis of COVID-19 at five New York City Hospitals. We obtained clinical and laboratory data from the first 24 h of the patient's hospitalization. Treatment with tocilizumab and convalescent plasma was assessed over hospitalization. The primary outcome was mortality; secondary outcomes included intubation, intensive care unit (ICU) admission and length of stay (LOS). First, we employed latent class analysis (LCA) to identify COVID-19 subphenotypes on admission without consideration of outcomes and assigned each patient to a subphenotype. We then performed robust Poisson regression to examine associations between COVID-19 subphenotype assignment and outcome. We explored whether the COVID-19 subphenotypes had a differential response to tocilizumab and convalescent plasma therapies.A total of 4620 patients were included. LCA identified six subphenotypes, which were distinct by level of inflammation, clinical and laboratory derangements and ranged from a hypoinflammatory subphenotype with the fewest derangements to a hyperinflammatory with multiorgan dysfunction subphenotypes. Multivariable regression analyses found differences in risk for mortality, intubation, ICU admission and LOS, as compared to the hypoinflammatory subphenotype. For example, in multivariable analyses the moderate inflammation with fever subphenotype had 3.29 times the risk of mortality (95% CI 2.05, 5.28), while the hyperinflammatory with multiorgan failure subphenotype had 17.87 times the risk of mortality (95% CI 11.56, 27.63), as compared to the hypoinflammatory subphenotype. Exploratory analyses suggested that subphenotypes may differential respond to convalescent plasma or tocilizumab therapy.COVID-19 subphenotype at hospital admission may predict risk for mortality, ICU admission and intubation and differential response to treatment.KEY MESSAGEThis cross-sectional study of COVID patients admitted to the Mount Sinai Health System, identified six distinct COVID subphenotypes on admission. Subphenotypes correlated with ICU admission, intubation, mortality and differential response to treatment.

  View details for DOI 10.1080/07853890.2022.2148733

  View details for Web of Science ID 000892039900001

  View details for PubMedID 36444856

  View details for PubMedCentralID PMC10795648

• Maternal adverse childhood experiences (ACEs) and DNA methylation of newborns in cord blood. Clinical epigenetics Collender, P., Bozack, A. K., Veazie, S., Nwanaji-Enwerem, J. C., Van Der Laan, L., Kogut, K., Riddell, C., Eskenazi, B., Holland, N., Deardorff, J., Cardenas, A. 2023; 15 (1): 162

  Abstract

  Adverse childhood experiences (ACEs) increase the risk of poor health outcomes later in life. Psychosocial stressors may also have intergenerational health effects by which parental ACEs are associated with mental and physical health of children. Epigenetic programming may be one mechanism linking parental ACEs to child health. This study aimed to investigate epigenome-wide associations of maternal preconception ACEs with DNA methylation patterns of children. In the Center for the Health Assessment of Mothers and Children of Salinas study, cord blood DNA methylation was measured using the Illumina HumanMethylation450 BeadChip. Preconception ACEs, which occurred during the mothers' childhoods, were collected using a standard ACE questionnaire including 10 ACE indicators. Maternal ACE exposures were defined in this study as (1) the total number of ACEs; (2) the total number of ACEs categorized as 0, 1-3, and > 4; and (3) individual ACEs. Associations of ACE exposures with differential methylated positions, regions, and CpG modules determined using weighted gene co-expression network analysis were evaluated adjusting for covariates.Data on maternal ACEs and cord blood DNA methylation were available for 196 mother/newborn pairs. One differential methylated position was associated with maternal experience of emotional abuse (cg05486260/FAM135B gene; q value < 0.05). Five differential methylated regions were significantly associated with the total number of ACEs, and 36 unique differential methylated regions were associated with individual ACEs (Šidák p value < 0.05). Fifteen CpG modules were significantly correlated with the total number of ACEs or individual ACEs, of which 8 remained significant in fully adjusted models (p value < 0.05). Significant modules were enriched for pathways related to neurological and immune development and function.Maternal ACEs prior to conception were associated with cord blood DNA methylation of offspring at birth. Although there was limited overlap between differential methylated regions and CpGs in modules associated with ACE exposures, statistically significant regions and networks were related to genes involved in neurological and immune function. Findings may provide insights to pathways linking psychosocial stressors to health. Further research is needed to understand the relationship between changes in DNA methylation and child health.

  View details for DOI 10.1186/s13148-023-01581-y

  View details for PubMedID 37845746

  View details for PubMedCentralID PMC10577922

• Maternal prenatal social experiences and offspring epigenetic aging from birth to mid-childhood. Annals of epidemiology Laubach, Z. M., Bozack, A., Aris, I. M., Slopen, N., Tiemeier, H., Hivert, M. F., Cardenas, A., Perng, W. 2023

  Abstract

  Investigate associations of maternal social experiences with offspring epigenetic age acceleration (EAA) from birth through mid-childhood among 205 mother-offspring dyads of minoritized racial and ethnic groups.We used linear regression to examine associations of maternal experiences of racial bias or discrimination (0=none, 1-2=intermediate, or 3+=high), social support (tertile 1=low, 2=intermediate, 3=high), and socioeconomic status index (tertile 1=low, 2=intermediate, 3=high) during the prenatal period with offspring EAA according to Horvath's Pan-Tissue, Horvath's Skin & Blood, and Intrinsic EAA clocks at birth, 3 years, and 7 years.In comparison to children of women who did not experience any racial bias or discrimination, those whose mothers reported highest levels of racial bias or discrimination had lower Pan-Tissue clock EAA in early (-0.50 years; 90% CI: -0.91, -0.09) and mid-childhood (-0.75 years; -1.41, -0.08). We observed similar associations for the Skin & Blood clock and Intrinsic EAA. Maternal experiences of discrimination were not associated with Pan-Tissue EAA at birth. Neither maternal social support nor socioeconomic status predicted offspring EAA.Children whose mothers experienced racial bias or discrimination exhibited slower EAA. Future studies are warranted to confirm these findings and establish associations of early-life EAA with long-term health outcomes.

  View details for DOI 10.1016/j.annepidem.2023.10.003

  View details for PubMedID 37839726

• Parenting Practices May Buffer the Impact of Adversity on Epigenetic Age Acceleration Among Young Children With Developmental Delays. Psychological science Sullivan, A. D., Bozack, A. K., Cardenas, A., Comer, J. S., Bagner, D. M., Forehand, R., Parent, J. 2023: 9567976231194221

  Abstract

  This study examined whether children exposed to adversity would exhibit lower epigenetic age acceleration in the context of improved parenting. Children with developmental delays and externalizing behavior problems (N = 62; Mage = 36.26 months; 70.97% boys, 29.03% girls; 71% Latinx, 22.6% Black) were drawn from a larger randomized controlled trial (RCT), which randomized them to receive Internet-delivered parent-child interaction therapy (iPCIT; n = 30) or community referrals as usual (RAU; n = 32). Epigenetic age acceleration was estimated with the pediatric buccal epigenetic clock, using saliva. Adversity was assessed using parent, family, and neighborhood-level cumulative-risk indicators. Adversity interacted with Time 2 (T2) observations of positive and negative-parenting practices to predict epigenetic age acceleration 1.5 years later, regardless of treatment assignment. Children exposed to more adversity displayed lower epigenetic age acceleration when parents evidenced increased positive (b = -0.15, p = .001) and decreased negative (b = -0.12, p = .01) parenting practices.

  View details for DOI 10.1177/09567976231194221

  View details for PubMedID 37733001

• Household air pollution and epigenetic aging in Xuanwei, China. Environment international Blechter, B., Cardenas, A., Shi, J., Wong, J. Y., Hu, W., Rahman, M. L., Breeze, C., Downward, G. S., Portengen, L., Zhang, Y., Ning, B., Ji, B. T., Cawthon, R., Li, J., Yang, K., Bozack, A., Dean Hosgood, H., Silverman, D. T., Huang, Y., Rothman, N., Vermeulen, R., Lan, Q. 2023; 178: 108041

  Abstract

  Household air pollution (HAP) from indoor combustion of solid fuel is a global health burden linked to lung cancer. In Xuanwei, China, lung cancer rate for nonsmoking women is among the highest in the world and largely attributed to high levels of polycyclic aromatic hydrocarbons (PAHs) that are produced from combustion of smoky (bituminous) coal used for cooking and heating. Epigenetic age acceleration (EAA), a DNA methylation-based biomarker of aging, has been shown to be highly correlated with biological processes underlying the susceptibility of age-related diseases. We aim to assess the association between HAP exposure and EAA.We analyzed data from 106 never-smoking women from Xuanwei, China. Information on fuel type was collected using a questionnaire, and validated exposure models were used to predict levels of 43 HAP constituents. Exposure clusters were identified using hierarchical clustering. EAA was derived for five epigenetic clocks defined as the residuals resulting from regressing each clock on chronological age. We used generalized estimating equations to test associations between exposure clusters derived from predicted levels of HAP exposure, ambient 5-methylchrysene (5-MC), a PAH previously found to be associated with risk of lung cancer, and EAA, while accounting for repeated-measurements and confounders.We observed an increase in GrimAge EAA for clusters with 31 and 33 PAHs reflecting current (β = 0.77 y per standard deviation (SD) increase, 95 % CI:0.36,1.19) and childhood (β = 0.92 y per SD, 95 % CI:0.40,1.45) exposure, respectively. 5-MC (ng/m3-year) was found to be associated with GrimAge EAA for current (β = 0.15 y, 95 % CI:0.05,0.25) and childhood (β = 0.30 y, 95 % CI:0.13,0.47) exposure.Our findings suggest that exposure to PAHs from indoor smoky coal combustion, particularly 5-MC, is associated with GrimAge EAA, a biomarker of mortality.

  View details for DOI 10.1016/j.envint.2023.108041

  View details for PubMedID 37354880

• DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort. Clinical epigenetics Bozack, A. K., Rifas-Shiman, S. L., Gold, D. R., Laubach, Z. M., Perng, W., Hivert, M. F., Cardenas, A. 2023; 15 (1): 62

  Abstract

  Epigenetic age acceleration (EAA) and epigenetic gestational age acceleration (EGAA) are biomarkers of physiological development and may be affected by the perinatal environment. The aim of this study was to evaluate performance of epigenetic clocks and to identify biological and sociodemographic correlates of EGAA and EAA at birth and in childhood. In the Project Viva pre-birth cohort, DNA methylation was measured in nucleated cells in cord blood (leukocytes and nucleated red blood cells, N = 485) and leukocytes in early (N = 120, median age = 3.2 years) and mid-childhood (N = 460, median age = 7.7 years). We calculated epigenetic gestational age (EGA; Bohlin and Knight clocks) and epigenetic age (EA; Horvath and skin & blood clocks), and respective measures of EGAA and EAA. We evaluated the performance of clocks relative to chronological age using correlations and median absolute error. We tested for associations of maternal-child characteristics with EGAA and EAA using mutually adjusted linear models controlling for estimated cell type proportions. We also tested associations of Horvath EA at birth with childhood EAA.Bohlin EGA was strongly correlated with chronological gestational age (Bohlin EGA r = 0.82, p < 0.001). Horvath and skin & blood EA were weakly correlated with gestational age, but moderately correlated with chronological age in childhood (r = 0.45-0.65). Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males. When comparing self-reported Asian, Black, Hispanic, and more than one race or other racial/ethnic groups to White, we identified significant differences in EGAA and EAA at birth and in mid-childhood, but associations varied across clocks. Horvath EA at birth was positively associated with childhood Horvath and skin & blood EAA.Maternal smoking during pregnancy and child sex were associated with EGAA and EAA at multiple timepoints. Further research may provide insight into the relationship between perinatal factors, pediatric epigenetic aging, and health and development across the lifespan.

  View details for DOI 10.1186/s13148-023-01480-2

  View details for PubMedID 37046280

  View details for PubMedCentralID 8901047

• Prenatal trimester-specific intake of micronutrients: global DNA methylation and hydroxymethylation at birth and persistence in childhood. Journal of developmental origins of health and disease Parsons, E., Rifas-Shiman, S. L., Bozack, A. K., Baccarelli, A. A., DeMeo, D. L., Hivert, M., Godderis, L., Duca, R., Oken, E., Cardenas, A. 2022: 1-8

  Abstract

  The prenatal environment may program health and disease susceptibility via epigenetic mechanisms. We evaluated associations of maternal trimester-specific intake of micronutrients with global DNA methylation (%5mC) and 5-hydroxymethylation (%5hmC) at birth in cord blood and tested for persistence into childhood. We quantified global %5mC and %5hmC in cord blood cells (n = 434) and in leukocytes collected in early (n = 108) and mid-childhood (n = 390) from children in Project Viva, a pre-birth cohort from Boston, MA. Validated food frequency questionnaires estimated maternal first- and second-trimester intakes of vitamin B2, vitamin B6, vitamin B12, folate, betaine, choline, methionine, iron, and zinc. Mean (SD) cord blood %5mC and %5hmC was 5.62% (2.04) and 0.25% (0.15), respectively. Each mug increase in first-trimester B12 intake was associated with 0.002 lower %5hmC in cord blood (95% CI: -0.005, -0.0003), and this association persisted in early childhood (beta = -0.007; 95% CI: -0.01, -0.001) but not mid-childhood. Second-trimester iron (mg) was associated with 0.01 lower %5mC (95% CI: -0.02, -0.002) and 0.001 lower %5hmC (95% CI: -0.01, -0.00001) in cord blood only. Increased second-trimester zinc (mg) intake was associated with 0.003 greater %5hmC in early childhood (beta = 0.003; 95% CI: 0.0004, 0.006). Second-trimester folate was positively associated with %5hmC in early childhood only (beta = 0.08, 95% CI: 0.003, 0.16). Associations did not survive multiple testing adjustment; future replication is needed. Trimester-specific nutrients may impact various sensitive windows of epigenetic programming some with lasting effects in childhood. Further research is needed to understand the role of gene-specific epigenetic changes and how global DNA methylation measures relate to child health.

  View details for DOI 10.1017/S2040174422000642

  View details for PubMedID 36515010

• Associations between antenatal maternal asthma status and placental DNA methylation PLACENTA Lee, A. G., Tignor, N., Cowell, W., Colicino, E., Bozack, A., Baccarelli, A., Wang, P., Wright, R. J. 2022; 126: 184-195

  Abstract

  Maternal asthma in pregnancy is associated with adverse perinatal and child health outcomes; however, mechanisms are poorly understood.The PRogramming of Intergenerational Stress Mechanisms (PRISM) prospective pregnancy cohort characterized asthma history during pregnancy via questionnaires and quantified placental DNAm using the Illumina Infinium HumanMethylation450 BeadChip. We performed epigenome-wide association analyses (n = 223) to estimate associations between maternal active or inactive asthma, as compared to never asthma, and placental differentially methylated positions (DMPs) and differentially variable positions (DVPs). Models adjusted for maternal pre-pregnancy body mass index, smoking status, parity, age and education level and child sex. P-values were FDR-adjusted.One hundred and fifty-nine (71.3%) pregnant women reported no history of asthma (never asthma), 15 (6.7%) reported inactive, and 49 (22%) reported active antenatal asthma. Women predominantly self-identified as Black/Hispanic Black [88 (39.5%)] and Hispanic/non-Black [42 (18.8%)]. We identified 10 probes at FDR<0.05 and 4 probes at FDR<0.10 characterized by higher variability in maternal active asthma compared to never asthma mapping to GPX3, LHPP, PECAM1, ATAD3C, and ARHGEF4 and 2 probes characterized by lower variation mapping to CHMP4A and C5orf24. Amongst women with inactive asthma, we identified 52 probes, 41 at FDR<0.05 and an additional 11 at FDR <0.10, with higher variability compared to never asthma; BMP4, LHPP, PHYHIPL, and ZSCAN23 were associated with multiple DVPs. No associations were observed with DMPs.We observed alterations in placental DNAm in women with antenatal asthma, as compared to women without a history of asthma. Further research is needed to understand the impact on fetal development.

  View details for DOI 10.1016/j.placenta.2022.06.008

  View details for Web of Science ID 000841901300002

  View details for PubMedID 35858526

  View details for PubMedCentralID PMC9679966

• Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease CIRCULATION RESEARCH Domingo-Relloso, A., Makhani, K., Riffo-Campos, A. L., Tellez-Plaza, M., Klein, K., Subedi, P., Zhao, J., Moon, K. A., Bozack, A. K., Haack, K., Goessler, W., Umans, J. G., Best, L. G., Zhang, Y., Herreros-Martinez, M., Glabonjat, R. A., Schilling, K., Galvez-Fernandez, M., Kent, J. W., Sanchez, T. R., Taylor, K. D., Johnson, W., Durda, P., Tracy, R. P., Rotter, J. I., Rich, S. S., Van Den Berg, D., Kasela, S., Lappalainen, T., Vasan, R. S., Joehanes, R., Howard, B. V., Levy, D., Lohman, K., Liu, Y., Fallin, M., Cole, S. A., Mann, K. K., Navas-Acien, A. 2022; 131 (2): E51-E69

  Abstract

  Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD.Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis.A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic.Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

  View details for DOI 10.1161/CIRCRESAHA.122.320991

  View details for Web of Science ID 000821208900004

  View details for PubMedID 35658476

  View details for PubMedCentralID PMC10203287

• The impact of prenatal and early-life arsenic exposure on epigenetic age acceleration among adults in Northern Chile ENVIRONMENTAL EPIGENETICS Bozack, A. K., Boileau, P., Hubbard, A. E., Sille, F. M., Ferreccio, C., Steinmaus, C. M., Smith, M. T., Cardenas, A. 2022; 8 (1): dvac014

  Abstract

  Exposure to arsenic affects millions of people globally. Changes in the epigenome may be involved in pathways linking arsenic to health or serve as biomarkers of exposure. This study investigated associations between prenatal and early-life arsenic exposure and epigenetic age acceleration (EAA) in adults, a biomarker of morbidity and mortality. DNA methylation was measured in peripheral blood mononuclear cells (PBMCs) and buccal cells from 40 adults (median age = 49 years) in Chile with and without high prenatal and early-life arsenic exposure. EAA was calculated using the Horvath, Hannum, PhenoAge, skin and blood, GrimAge, and DNA methylation telomere length clocks. We evaluated associations between arsenic exposure and EAA using robust linear models. Participants classified as with and without arsenic exposure had a median drinking water arsenic concentration at birth of 555 and 2 μg/l, respectively. In PBMCs, adjusting for sex and smoking, exposure was associated with a 6-year PhenoAge acceleration [B (95% CI) = 6.01 (2.60, 9.42)]. After adjusting for cell-type composition, we found positive associations with Hannum EAA [B (95% CI) = 3.11 (0.13, 6.10)], skin and blood EAA [B (95% CI) = 1.77 (0.51, 3.03)], and extrinsic EAA [B (95% CI) = 4.90 (1.22, 8.57)]. The association with PhenoAge acceleration in buccal cells was positive but not statistically significant [B (95% CI) = 4.88 (-1.60, 11.36)]. Arsenic exposure limited to early-life stages may be associated with biological aging in adulthood. Future research may provide information on how EAA programmed in early life is related to health.

  View details for DOI 10.1093/eep/dvac014

  View details for Web of Science ID 000816745100001

  View details for PubMedID 35769198

  View details for PubMedCentralID PMC9235373

• Breast milk-derived extracellular vesicle miRNAs are associated with maternal asthma and atopy EPIGENOMICS Bozack, A. K., Colicino, E., Rodosthenous, R. S., Bloomquist, T. R., Baccarelli, A. A., Wright, R. O., Wright, R. J., Lee, A. G. 2022; 14 (12): 727-739

  Abstract

  Background: Breast milk-derived extracellular vesicle (EV) miRNAs may program child health outcomes associated with maternal asthma and atopy. The authors investigated associations between maternal asthma/atopy and EV miRNAs in the Programming of Intergenerational Stress Mechanisms cohort. Methods: Breast milk-derived EV miRNAs collected 6.1 ± 5.9 weeks postnatally (n = 80 mothers) were profiled using the TaqMan OpenArray Human MicroRNA Panel. The authors assessed associations using adjusted robust regression. Results: Nine EV miRNAs were associated with asthma during pregnancy (a priori criteria: nominal p < 0.05; |Bregression| >0.2). miR-1290 was associated with asthma and atopy during pregnancy (p < 0.05; |Bregression| >0.2). Enriched Kyoto Encyclopedia of Genes and Genomes pathways included TGF-β signaling and extracellular matrix-receptor interaction (false discovery rate <0.05). Conclusion: In this study, maternal asthma and atopy were associated with breast milk-derived EV miRNAs. Additional studies are needed to understand whether EV miRNAs have direct effects on infant and child health.

  View details for DOI 10.2217/epi-2022-0090

  View details for Web of Science ID 000803030200001

  View details for PubMedID 35638388

  View details for PubMedCentralID PMC9280402

• Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals CLINICAL EPIGENETICS Bozack, A. K., Rifas-Shiman, S. L., Coull, B. A., Baccarelli, A. A., Wright, R. O., Amarasiriwardena, C., Gold, D. R., Oken, E., Hivert, M., Cardenas, A. 2021; 13 (1): 208

  Abstract

  Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses.Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10-6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn.Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.

  View details for DOI 10.1186/s13148-021-01198-z

  View details for Web of Science ID 000720641900001

  View details for PubMedID 34798907

  View details for PubMedCentralID PMC8605513

• Associations between infant sex and DNA methylation across umbilical cord blood, artery, and placenta samples EPIGENETICS Bozack, A. K., Colicino, E., Just, A. C., Wright, R. O., Baccarelli, A. A., Wright, R. J., Lee, A. G. 2022; 17 (10): 1080-1097

  Abstract

  DNA methylation (DNAm) is vulnerable to dysregulation by environmental exposures during epigenetic reprogramming that occurs in embryogenesis. Sexual dimorphism in environmentally induced DNAm dysregulation has been identified and therefore it is important to understand sex-specific DNAm patterns. DNAm at several autosomal sites has been consistently associated with sex in cord blood and placental foetal tissues. However, there is limited research comparing sex-specific DNAm across tissues, particularly differentially methylated regions (DMRs). This study leverages DNAm data measured using the Illumina HumanMethylation450 BeadChip in cord blood (N = 179), placenta (N = 229), and umbilical artery samples (N = 229) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort to identify autosomal DMRs and differentially methylated positions (DMPs). A replication analyses was conducted in an independent cohort (GEO Accession GSE129841). We identified 183, 257, and 419 DMRs and 2119, 2281, and 3405 DMPs (pBonferroni < 0.05) in cord blood, placenta, and artery samples, respectively. Thirty-nine DMRs overlapped in all three tissues, overlapping with genes involved in spermatogenesis (NKAPL, PIWIL2 and AURKC) and X-inactivation (LRIF1). In replication analysis, 85% of DMRs overlapped with those identified in PRISM. Overall, DMRs and DMPs had higher methylation levels among females in cord blood and artery samples, but higher methylation levels among males in placenta samples. Further research is necessary to understand biological mechanisms that contribute to differences in sex-specific DNAm signatures across tissues, as well as to determine if sexual dimorphism in the epigenome impacts response to environmental stressors.

  View details for DOI 10.1080/15592294.2021.1985300

  View details for Web of Science ID 000710028900001

  View details for PubMedID 34569420

  View details for PubMedCentralID PMC9542631

• Arsenic exposure and human blood DNA methylation and hydroxymethylation profiles in two diverse populations from Bangladesh and Spain ENVIRONMENTAL RESEARCH Domingo-Relloso, A., Bozack, A., Kiihl, S., Rodriguez-Hernandez, Z., Rentero-Garrido, P., Antonio Casasnovas, J., Leon-Latre, M., Garcia-Barrera, T., Luis Gomez-Ariza, J., Moreno, B., Cenarro, A., de Marco, G., Parvez, F., Siddique, A. B., Shahriar, H., Uddin, M. N., Islam, T., Navas-Acien, A., Gamble, M., Tellez-Plaza, M. 2022; 204: 112021

  Abstract

  Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported; however, As exposure-related differences of the separated 5-mC and 5-hmC markers have rarely been studied.In this study, we evaluated the association of arsenic exposure biomarkers and 5-mC and 5-hmC in 30 healthy men (43-55 years) from the Aragon Workers Health Study (AWHS) (Spain) and 31 healthy men (31-50 years) from the Folic Acid and Creatinine Trial (FACT) (Bangladesh). We conducted 5-mC and 5-hmC profiling using Infinium MethylationEPIC arrays, on paired standard and modified (ox-BS in AWHS and TAB in FACT) bisulfite converted blood DNA samples.The median for the sum of urine inorganic and methylated As species (ΣAs) (μg/L) was 12.5 for AWHS and 89.6 for FACT. The median of blood As (μg/L) was 8.8 for AWHS and 10.2 for FACT. At a statistical significance p-value cut-off of 0.01, the differentially methylated (DMP) and hydroxymethylated (DHP) positions were mostly located in different genomic sites. Several DMPs and DHPs were consistently found in AWHS and FACT both for urine ΣAs and blood models, being of special interest those attributed to the DIP2C gene. Three DMPs (annotated to CLEC12A) for AWHS and one DHP (annotated to NPLOC4) for FACT remained statistically significant after false discovery rate (FDR) correction. Pathways related to chronic diseases including cardiovascular, cancer and neurological were enriched.While we identified common 5-hmC and 5-mC signatures in two populations exposed to varying levels of inorganic As, differences in As-related epigenetic sites across the study populations may additionally reflect low and high As-specific associations. This work contributes a deeper understanding of potential epigenetic dysregulations of As. However, further research is needed to confirm biological consequences associated with DIP2C epigenetic regulation and to investigate the role of 5-hmC and 5-mC separately in As-induced health disorders at different exposure levels.

  View details for DOI 10.1016/j.envres.2021.112021

  View details for Web of Science ID 000704709600003

  View details for PubMedID 34516978

  View details for PubMedCentralID PMC8734953

• Exposure to arsenic at different life-stages and DNA methylation meta-analysis in buccal cells and leukocytes ENVIRONMENTAL HEALTH Bozack, A. K., Boileau, P., Wei, L., Hubbard, A. E., Sille, F. M., Ferreccio, C., Acevedo, J., Hou, L., Ilievski, V., Steinmaus, C. M., Smith, M. T., Navas-Acien, A., Gamble, M., Cardenas, A. 2021; 20 (1): 79

  Abstract

  Arsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS.DNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs.In a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR < 0.05). Using meta-analyzed results, we identified 11 DMRs and 11 DVRs in PBMC samples, and 16 DMRs and 19 DVRs in PBMC and buccal cell samples. One region annotated to LRRC27 was identified as a DMR and DVR. Arsenic-associated KEGG pathways included lysosome, autophagy, and mTOR signaling, AMPK signaling, and one carbon pool by folate.Using a two-step process of (1) harmonized data processing and analysis and (2) meta-analysis, we leverage four DNAm datasets from two continents of individuals exposed to high levels of As prenatally and during adulthood to identify DMPs and DVPs associated with arsenic exposure. Our approach suggests that standardizing analytical pipelines can aid in identifying biological meaningful signals.

  View details for DOI 10.1186/s12940-021-00754-7

  View details for Web of Science ID 000671560400001

  View details for PubMedID 34243768

  View details for PubMedCentralID PMC8272372

• Nutrition, one-carbon metabolism and arsenic methylation TOXICOLOGY Abuawad, A., Bozack, A. K., Saxena, R., Gamble, M. 2021; 457: 152803

  Abstract

  Exposure to arsenic (As) is a major public health concern globally. Inorganic As (InAs) undergoes hepatic methylation to form monomethyl (MMAs)- and dimethyl (DMAs)-arsenical species, facilitating urinary As elimination. MMAsIII is considerably more toxic than either InAsIII or DMAsV, and a higher proportion of MMAs in urine has been associated with risk for a wide range of adverse health outcomes. Efficiency of As methylation differs substantially between species, between individuals, and across populations. One-carbon metabolism (OCM) is a biochemical pathway that provides methyl groups for the methylation of As, and is influenced by folate and other micronutrients, such as vitamin B12, choline, betaine and creatine. A growing body of evidence has demonstrated that OCM-related micronutrients play a critical role in As methylation. This review will summarize observational epidemiological studies, interventions, and relevant experimental evidence examining the role that OCM-related micronutrients have on As methylation, toxicity of As, and risk for associated adverse health-related outcomes. There is fairly robust evidence supporting the impact of folate on As methylation, and some evidence from case-control studies indicating that folate nutritional status influences risk for As-induced skin lesions and bladder cancer. However, the potential for folate to be protective for other As-related health outcomes, and the potential beneficial effects of other OCM-related micronutrients on As methylation and risk for health outcomes are less well studied and warrant additional research.

  View details for DOI 10.1016/j.tox.2021.152803

  View details for Web of Science ID 000664290000007

  View details for PubMedID 33905762

  View details for PubMedCentralID PMC8349595

• Association between prenatal immune phenotyping and cord blood leukocyte telomere length in the PRISM pregnancy cohort ENVIRONMENTAL RESEARCH Colicino, E., Cowell, W., Bozack, A., Pedretti, N., Joshi, A., Niedzwiecki, M. M., Bollati, Berin, C., Wright, R. O., Wright, R. J. 2020; 191: 110113

  Abstract

  Environmental exposures including air pollutants, toxic metals, and psychosocial stress have been associated with shorter telomere length (TL) in newborns. These exposures have in turn been linked to an enhanced inflammatory immune response. Increased inflammation during pregnancy may be a central biological pathway linking environmental factors with reduced TL at birth. Approaches that more comprehensively characterize the prenatal inflammatory milieu rather than targeting specific individual cytokines in relation to newborn TL may better elucidate inflammatory mechanisms.Analyses included 129 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured 92 inflammation related proteins during pregnancy in maternal serum using the Olink protein array and quantified cord blood relative leukocyte TL (rLTL) via qPCR. We leveraged a tree-based machine learning algorithm to select the most important inflammatory related proteins jointly associated with rLTL. We then evaluated the combined association between the selected proteins with rLTL using Bayesian Weighted Quantile Sum (BWQS) Regression. Analyses were adjusted for gestational week of serum collection, maternal race/ethnicity, age, and education, and fetal sex. We evaluated major biological function of the identified proteins by using the UniProtKB, a centralized repository of curated functional information.Three proteins were negatively and linearly associated with rLTL (CASP8 β: -0.22 p = 0.008, BNGF β: -0.43 p = 0.033, TRANCE β: 0.38 p = 0.004). Results from BWQS regression showed a significant overall decrease in rLTL (β: -0.26 95%CrI: -0.43, -0.07) per quartile increase of the mixture, with CASP8 contributing the greatest weight (CASP8 50%; BNGF 27%, and TRANCE 23%). The identified proteins were involved in the regulation of apoptotic processes and cell proliferation.This proteomics approach identifies novel maternal prenatal inflammatory protein biomarkers associated with shortened rLTL in newborns.

  View details for DOI 10.1016/j.envres.2020.110113

  View details for Web of Science ID 000587971600081

  View details for PubMedID 32841635

  View details for PubMedCentralID PMC7883408

• Betaine and choline status modify the effects of folic acid and creatine supplementation on arsenic methylation in a randomized controlled trial of Bangladeshi adults EUROPEAN JOURNAL OF NUTRITION Bozack, A. K., Howe, C. G., Hall, M. N., Liu, X., Slavkovich, V., Ilievski, V., Lomax-Luu, A. M., Parvez, F., Siddique, A. B., Shahriar, H., Uddin, M. N., Islam, T., Graziano, J. H., Gamble, M. V. 2021; 60 (4): 1921-1934

  Abstract

  Methylation of ingested inorganic arsenic (InAs) to monomethyl- (MMAs) and dimethyl-arsenical species (DMAs) facilitates urinary arsenic elimination. Folate and creatine supplementation influenced arsenic methylation in a randomized controlled trial. Here, we examine if baseline status of one-carbon metabolism nutrients (folate, choline, betaine, and vitamin B12) modified the effects of FA and creatine supplementation on changes in homocysteine, guanidinoacetate (GAA), total blood arsenic, and urinary arsenic metabolite proportions and indices.Study participants (N = 622) received 400 or 800 μg FA, 3 g creatine, 400 μg FA + 3 g creatine, or placebo daily for 12 weeks.Relative to placebo, FA supplementation was associated with greater mean increases in %DMAs among participants with betaine concentrations below the median than those with levels above the median (FDR < 0.05). 400 μg FA/day was associated with a greater decrease in homocysteine among participants with plasma folate concentrations below, compared with those above, the median (FDR < 0.03). Creatine treatment was associated with a significant decrease in %MMAs among participants with choline concentrations below the median (P = 0.04), but not among participants above the median (P = 0.94); this effect did not significantly differ between strata (P = 0.10).Effects of FA and creatine supplementation on arsenic methylation capacity were greater among individuals with low betaine and choline status, respectively. The efficacy of FA and creatine interventions to facilitate arsenic methylation may be modified by choline and betaine nutritional status.Clinical Trial Registry Identifier: NCT01050556, U.S. National Library of Medicine, https://clinicaltrials.gov ; registered January 15, 2010.

  View details for DOI 10.1007/s00394-020-02377-z

  View details for Web of Science ID 000568585200002

  View details for PubMedID 32918135

  View details for PubMedCentralID PMC7947037

• Associations between maternal lifetime stressors and negative events in pregnancy and breast milk-derived extracellular vesicle microRNAs in the programming of intergenerational stress mechanisms (PRISM) pregnancy cohort EPIGENETICS Bozack, A. K., Colicino, E., Rodosthenous, R., Bloomquist, T. R., Baccarelli, A. A., Wright, R. O., Wright, R. J., Lee, A. G. 2021; 16 (4): 389-404

  Abstract

  Maternal stress is associated with adverse child health. Breast milk microRNAs encapsulated in extracellular vesicles (EVs) are involved in mother-infant biochemical communication during 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. Lifetime stress and negative life events (NLEs) during pregnancy were assessed using the Life Stressor Checklist-Revised (LSCR) and the Crisis in Family Systems-Revised surveys, respectively. RNA was extracted from breast milk EVs (N = 80; collected 6.1 ± 5.9 weeks postnatally), and microRNAs were profiled using the TaqMan OpenArray Human miRNA panel. Associations between stress scores and detection (yes/no) of 173 microRNAs identified in 20-80% of samples were assessed using logistic regression; associations with expression levels of 205 EV-microRNAs identified in >50% of samples were assessed using linear regression. In adjusted models, detection of 60 and 44 EV-microRNAs was associated with higher LSCR and NLE scores, respectively (p < 0.05). Expression level of 8 and 17 EV-microRNAs was associated with LSCR and NLE scores, respectively, at our a priori criteria of p < 0.05 and |Bregression|>0.2. Enriched KEGG pathways for microRNAs associated with stress scores included fatty acid metabolism and the Hippo signaling pathway. Maternal lifetime stress and NLEs during pregnancy were both associated with detection and expression level of breast milk EV-microRNAs, although associations with microRNA profiles differed between stress measures. Further research is needed to identify biological pathways impacted by associated microRNAs and investigate relationships with child health outcomes.Abbreviations: EV: extracellular vesicle; PRISM: PRogramming of Intergenerational Stress Mechanisms pregnancy cohort; LSCR: Life Stressor Checklist-Revised survey; NLE: negative life event; CRISYS-R: Crisis in Family Systems-Revised survey; KEGG: Kyoto Encyclopaedia of Genes and Genomes; NYC: New York City; SD: standard deviation; IQR: interquartile range; Cq: relative cycle threshold values; PCA: principal component analysis.

  View details for DOI 10.1080/15592294.2020.1805677

  View details for Web of Science ID 000562655600001

  View details for PubMedID 32777999

  View details for PubMedCentralID PMC7996083

• Locus -Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low -to -Moderate Arsenic Exposure ENVIRONMENTAL HEALTH PERSPECTIVES Bozack, A. K., Domingo-Relloso, A., Haack, K., Gamble, M. V., Tellez-Plaza, M., Umans, J. G., Best, L. G., Yracheta, J., Gribble, M. O., Cardenas, A., Francesconi, K. A., Goessler, W., Tang, W., Fallin, M., Cole, S. A., Navas-Acien, A. 2020; 128 (6): 67015

  Abstract

  Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes.We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, mean (±SD) μg/g creatinine: 11.7 (10.6)].DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species.In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (FDR< 0.05). After Bonferroni correction, 5 CpGs remained associated with total urinary As (pBonferroni<0.05), located in SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to C11orf2; TSPAN32 genes.This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in SLC7A11A, a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. https://doi.org/10.1289/EHP6263.

  View details for DOI 10.1289/EHP6263

  View details for Web of Science ID 000548216800007

  View details for PubMedID 32603190

  View details for PubMedCentralID PMC7534587

• Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study ENVIRONMENTAL HEALTH PERSPECTIVES Domingo-Relloso, A., Riffo-Campos, A. L., Haack, K., Rentero-Garrido, P., Ladd-Acosta, C., Fallin, D. M., Tang, W., Herreros-Martinez, M., Gonzalez, J. R., Bozack, A. K., Cole, S. A., Navas-Acien, A., Tellez-Plaza, M. 2020; 128 (6): 67005

  Abstract

  The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals.We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm.We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein-protein interaction networks to explore the biological relevance of the findings.At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm.Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345.

  View details for DOI 10.1289/EHP6345

  View details for Web of Science ID 000548216800018

  View details for PubMedID 32484362

  View details for PubMedCentralID PMC7265996

• Cord blood DNA methylation of DNMT3A mediates the association between in utero arsenic exposure and birth outcomes: Results from a prospective birth cohort in Bangladesh ENVIRONMENTAL RESEARCH Bozack, A. K., Cardenas, A., Geldhof, J., Quamruzzaman, Q., Rahman, M., Mostofa, G., Christiani, D. C., Kile, M. L. 2020; 183: 109134

  Abstract

  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.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, log2 (toenail As), birth weight, and gestational age.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).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.

  View details for DOI 10.1016/j.envres.2020.109134

  View details for Web of Science ID 000526177500124

  View details for PubMedID 32018205

  View details for PubMedCentralID PMC7167334

• Early-Life Arsenic Exposure, Nutritional Status, and Adult Diabetes Risk CURRENT DIABETES REPORTS Navas-Acien, A., Spratlen, M. J., Abuawad, A., LoIacono, N. J., Bozack, A. K., Gamble, M. V. 2019; 19 (12): 147

  Abstract

  In utero influences, including nutrition and environmental chemicals, may induce long-term metabolic changes and increase diabetes risk in adulthood. This review evaluates the experimental and epidemiological evidence on the association of early-life arsenic exposure on diabetes and diabetes-related outcomes, as well as the influence of maternal nutritional status on arsenic-related metabolic effects.Five studies in rodents have evaluated the role of in utero arsenic exposure with diabetes in the offspring. In four of the studies, elevated post-natal fasting glucose was observed when comparing in utero arsenic exposure with no exposure. Rodent offspring exposed to arsenic in utero also showed elevated insulin resistance in the 4 studies evaluating it as well as microRNA changes related to glycemic control in 2 studies. Birth cohorts of arsenic-exposed pregnant mothers in New Hampshire, Mexico, and Taiwan have shown that increased prenatal arsenic exposure is related to altered cord blood gene expression, microRNA, and DNA methylation profiles in diabetes-related pathways. Thus far, no epidemiologic studies have evaluated early-life arsenic exposure with diabetes risk. Supplementation trials have shown B vitamins can reduce blood arsenic levels in highly exposed, undernourished populations. Animal evidence supports that adequate B vitamin status can rescue early-life arsenic-induced diabetes risk, although human data is lacking. Experimental animal studies and human evidence on the association of in utero arsenic exposure with alterations in gene expression pathways related to diabetes in newborns, support the potential role of early-life arsenic exposure in diabetes development, possibly through increased insulin resistance. Given pervasive arsenic exposure and the challenges to eliminate arsenic from the environment, research is needed to evaluate prevention interventions, including the possibility of low-cost, low-risk nutritional interventions that can modify arsenic-related disease risk.

  View details for DOI 10.1007/s11892-019-1272-9

  View details for Web of Science ID 000498472800001

  View details for PubMedID 31758285

  View details for PubMedCentralID PMC7004311

• Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh AMERICAN JOURNAL OF CLINICAL NUTRITION Bozack, A. K., Hall, M. N., Liu, X., Ilievski, V., Lomax-Luu, A. M., Parvez, F., Siddique, A. B., Shahriar, H., Uddin, M. N., Islam, T., Graziano, J. H., Gamble, M. V. 2019; 109 (2): 380-391

  Abstract

  Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine.This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine.In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 μg per day), 3 g creatine per day, 400 μg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo.Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation.The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.

  View details for DOI 10.1093/ajcn/nqy148

  View details for Web of Science ID 000460615600017

  View details for PubMedID 30590411

  View details for PubMedCentralID PMC6367980

• DNA methylation in cord blood as mediator of the association between prenatal arsenic exposure and gestational age EPIGENETICS Bozack, A. K., Cardenas, A., Quamruzzaman, Q., Rahman, M., Mostofa, G., Christiani, D. C., Kile, M. L. 2018; 13 (9): 923-940

  Abstract

  Prenatal arsenic exposure is associated with adverse birth outcomes and disease risk later in life, which could be mediated through epigenetic dysregulation. We evaluated the association between arsenic and gestational age (GA) that was mediated through DNA methylation (DNAm) using data from a Bangladeshi birth cohort. Arsenic exposure was measured in maternal drinking water at ≤16 weeks GA and maternal toenails collected ≤1 month postpartum. Cord blood DNAm was measured using Infinium HumanMethylation450 arrays (n = 44, discovery phase). Top loci identified in the discovery phase were then pyrosequenced in a second group (n = 569, validation phase). Structural equation models (SEM) evaluated the direct and indirect effects of arsenic and DNAm on GA. In the discovery phase, arsenic was associated with differential DNAm of 139 loci that were associated with GA (P < 1.10X10-6; |β regression|>0.10). Each doubling in water arsenic concentration decreased GA by 2 days, which was fully mediated through the main principal component of the top-ten CpGs (P < 0.001). In the validation phase, there were direct and indirect effects of miR214-3 and MCC DNAm on GA. In an adjusted SEM model, mediation of the association between arsenic and GA by miR124-3 was borderline significant (P = 0.061). This study therefore identified DNAm at specific loci in cord blood that mediated the effect of arsenic exposure on GA. Specifically, prenatal arsenic exposure was associated with lower methylation of miR124-3 that mediated the exposure-response of arsenic on GA. Future research should evaluate if these epigenetic changes are persistent and associated with disease risk.

  View details for DOI 10.1080/15592294.2018.1516453

  View details for Web of Science ID 000450445600003

  View details for PubMedID 30175652

  View details for PubMedCentralID PMC6284783

• Nutritional Influences on One-Carbon Metabolism: Effects on Arsenic Methylation and Toxicity ANNUAL REVIEW OF NUTRITION, VOL 38 Bozack, A. K., Saxena, R., Gamble, M. V., Stover, P. J., Balling, R. 2018; 38: 401-429

  Abstract

  Exposure to inorganic arsenic (InAs) via drinking water and/or food is a considerable worldwide problem. Methylation of InAs generates monomethyl (MMAsIII+V)- and dimethyl (DMAsIII+V)-arsenical species in a process that facilitates urinary As elimination; however, MMAs is considerably more toxic than either InAs or DMAs. Emerging evidence suggests that incomplete methylation of As to DMAs, resulting in increased MMAs, is associated with increased risk for a host of As-related health outcomes. The biochemical pathway that provides methyl groups for As methylation, one-carbon metabolism (OCM), is influenced by folate and other micronutrients, including choline and betaine. Individuals and species differ widely in their ability to methylate As. A growing body of research, including cell-culture, animal-model, and epidemiological studies, has demonstrated the role of OCM-related micronutrients in As methylation. This review examines the evidence that nutritional status and nutritional interventions can influence the metabolism and toxicity of As, with a primary focus on folate.

  View details for DOI 10.1146/annurev-nutr-082117-051757

  View details for Web of Science ID 000443931300017

  View details for PubMedID 29799766

  View details for PubMedCentralID PMC6441546

• Housing Status, Medical Care, and Health Outcomes Among People Living With HIV/AIDS: A Systematic Review AMERICAN JOURNAL OF PUBLIC HEALTH Aidala, A. A., Wilson, M. G., Shubert, V., Gogolishvili, D., Globerman, J., Rueda, S., Bozack, A. K., Caban, M., Rourke, S. B. 2016; 106 (1): E1-E23

  Abstract

  Accumulating evidence suggests responses to HIV that combine individual-level interventions with those that address structural or contextual factors that influence risks and health outcomes of infection. Housing is such a factor. Housing occupies a strategic position as an intermediate structural factor, linking "upstream" economic, social, and cultural determinants to the more immediate physical and social environments in which everyday life is lived. The importance of housing status for HIV prevention and care has been recognized, but much of this attention has focused on homeless individuals as a special risk group. Analyses have less often addressed community housing availability and conditions as factors influencing population health or unstable, inadequate, or unaffordable housing as a situation or temporary state. A focus on individual-level characteristics associated with literal homelessness glosses over social, economic, and policy drivers operating largely outside any specific individual's control that affect housing and residential environments and the health resources or risk exposures such contexts provide.We examined the available empirical evidence on the association between housing status (broadly defined), medical care, and health outcomes among people with HIV and analyzed results to inform future research, program development, and policy implementation.We searched 8 electronic health and social science databases from January 1, 1996, through March 31, 2014, using search terms related to housing, dwelling, and living arrangements and HIV and AIDS. We contacted experts for additional literature.We selected articles if they were quantitative analyses published in English, French, or Spanish that included at least 1 measure of housing status as an independent variable and at least 1 health status, health care, treatment adherence, or risk behavior outcome among people with HIV in high-income countries. We defined housing status to include consideration of material or social dimensions of housing adequacy, stability, and security of tenure.Two independent reviewers performed data extraction and quality appraisal. We used the Cochrane Risk of Bias Tool for randomized controlled trials and a modified version of the Newcastle Ottawa Quality Appraisal Tool for nonintervention studies. In our quality appraisal, we focused on issues of quality for observational studies: appropriate methods for determining exposure and measuring outcomes and methods to control confounding.Searches yielded 5528 references from which we included 152 studies, representing 139,757 HIV-positive participants. Most studies were conducted in the United States and Canada. Studies examined access and utilization of HIV medical care, adherence to antiretroviral medications, HIV clinical outcomes, other health outcomes, emergency department and inpatient utilization, and sex and drug risk behaviors. With rare exceptions, across studies in all domains, worse housing status was independently associated with worse outcomes, controlling for a range of individual patient and care system characteristics.Lack of stable, secure, adequate housing is a significant barrier to consistent and appropriate HIV medical care, access and adherence to antiretroviral medications, sustained viral suppression, and risk of forward transmission. Studies that examined the history of homelessness or problematic housing years before outcome assessment were least likely to find negative outcomes, homelessness being a potentially modifiable contextual factor. Randomized controlled trials and observational studies indicate an independent effect of housing assistance on improved outcomes for formerly homeless or inadequately housed people with HIV. Housing challenges result from complex interactions between individual vulnerabilities and broader economic, political, and legal structural determinants of health. The broad structural processes sustaining social exclusion and inequality seem beyond the immediate reach of HIV interventions, but changing housing and residential environments is both possible and promising.

  View details for DOI 10.2105/AJPH.2015.302905

  View details for Web of Science ID 000373428000001

  View details for PubMedID 26562123

  View details for PubMedCentralID PMC4695926

• Reducing Childhood Asthma Triggers in Public Housing: Implementation and Outcomes from an East Harlem Community Health Worker Program ENVIRONMENTAL JUSTICE Lopez, R., Chantarat, T., Bozack, A., Lopez, A., Weiss, L. 2015; 8 (5): 185-191

  View details for DOI 10.1089/env.2015.0017

  View details for Web of Science ID 000363887700004

• Implementation and Outcomes of the New York State YMCA Diabetes Prevention Program: A Multisite Community-Based Translation, 2010-2012 PREVENTING CHRONIC DISEASE Bozack, A., Millstein, S., Garcel, J., Kelly, K., Ruberto, R., Weiss, L. 2014; 11: E115

  Abstract

  Weight loss and physical activity achieved through the Diabetes Prevention Program (DPP) have been shown to reduce type 2 diabetes risk among individuals with prediabetes. The New York State Young Men's Christian Association (YMCA) delivered the 16-week evidence-based model at 14 YMCAs. A mixed methods process and outcomes evaluation was conducted.Most participants were referred by clinicians and were encouraged to achieve 5% to 7% weight loss. Participants were weighed weekly; additional data were gathered from participant surveys and focus groups and staff surveys and interviews.Participants (N = 254) lost a mean of 9 pounds (P < .001), or 4.2% of body weight, by program completion; 40% achieved 5% or more weight loss and 25% achieved 7% or more weight loss. Ten months after baseline, 61% of participants reported 5% or more weight loss and 48% reported 7% or more weight loss. In multivariate models, weight loss was negatively associated with black race (16 weeks: adjusted odds ratio [AOR], 0.190, P = .002; 10 months: AOR, 0.244, P = .005) and positively associated with attendance (16 weeks: AOR, 18.699, P < .001; 10 months: AOR, 2.808, P = .024). Participants reported improvements in health and lifestyle changes after program completion. Factors contributing to program success included coaches who motivated participants, the group setting, curriculum, and program duration. However, sociodemographic diversity was limited.Outcomes demonstrate the potential for effectively implementing the DPP in community-based settings. Findings also suggest the need for replications among a broader population.

  View details for DOI 10.5888/pcd11.140006

  View details for Web of Science ID 000343522200004

  View details for PubMedID 25010997

  View details for PubMedCentralID PMC4094004

• Becoming a Patient-Centered Medical Home: A 9-Year Transition for a Network of Federally Qualified Health Centers ANNALS OF FAMILY MEDICINE Calman, N. S., Hauser, D., Weiss, L., Waltermaurer, E., Molina-Ortiz, E., Chantarat, T., Bozack, A. 2013; 11: S68-S73

  Abstract

  The patient-centered medical home (PCMH) model has great potential for optimizing the care of chronically ill patients, yet there is much to be learned about various implementations of this model and their impact on patient care processes and outcomes.We examined changes in patterns of health care use in a network of Federally Qualified Health Centers throughout a 9-year period of practice transformation that included recognition of all centers by the National Committee for Quality Assurance (NCQA) as Level 3 PCMH practices. We analyzed deidentified data from electronic health records for the period 2003 to 2011 to identify patterns of service use for all 4,595 patients with diabetes. We also examined a subsample of 545 patients who were in care throughout the study period to track improvement in glycated hemoglobin levels as a clinical measure over time.Through the transition to a PCMH, the mean number of encounters with outreach, diabetes educators, and psychosocial services increased for all diabetic patients; virtually all patients had visits with a primary care clinician, but the mean number of visits decreased slightly. Among patients in the subsample, mean annual levels of glycated hemoglobin decreased steadily during the 9-year study period, mainly driven by a reduction in patients having baseline levels exceeding 9%.This retrospective study conducted in a real-world setting using electronic health record data demonstrates a shift in resource use by diabetic patients from the primary care clinician to other members of the care team. The findings suggest that PCMH implementation has the potential to alter processes of care and improve outcomes of care, especially among those with higher disease burden.

  View details for DOI 10.1370/afm.1547

  View details for Web of Science ID 000336798200010

  View details for PubMedID 23690389

  View details for PubMedCentralID PMC3707249