Dennis Khodasevich

All Publications

• An assessment of organophosphate ester mixtures and the placental transcriptome. Environment international Lapehn, S., Parenti, M., Firsick, E. J., Khodasevich, D., Baker, B. H., Day, D. B., MacDonald, J. W., Bammler, T. K., Kannan, K., Choi, H. Y., Barrett, E. S., Howe, C. G., Carroll, K. N., LeWinn, K. Z., Zhao, Q., Cardenas, A., Szpiro, A. A., Sathyanarayana, S., Paquette, A. G. 2025; 198: 109402

  Abstract

  Prenatal exposure to organophosphate ester (OPE) chemicals, commonly used as flame retardants and plasticizers, has been associated with adverse birth outcomes. The placenta is a critical fetal organ and therefore may be involved in pathogenesis of birth outcomes. The goal of this study was to evaluate associations of 10 maternal urinary OPE metabolites, individually and as a mixture, with the placental transcriptome at birth in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Individual OPE metabolites were evaluated for associations with individual genes as well as co-expressed gene modules. Mixtures analysis was conducted using quantile g-computation. The analyses were performed with the entire data set (N=737) as well as the sex-stratified subsets. Two genes (HAP1 and RAP1GAP) were associated with bis(1,3-dichloro-2-propyl) phosphate (BDCPP), and six genes were associated the mixture in the full data set. 3 genes were associated with diphenyl phosphate (DPHP) and 36 genes were associated with the mixture in a male stratified analysis. 2 genes were associated with DPHP, and 1 gene was associated with diethyl phosphate (DEP) in a female stratified analysis. Three gene modules were associated with BDCPP or diphenyl phosphate (DPHP) and one module was associated with the OPE mixture. 12 WGCNA modules were associated with individual OPE metabolites or the mixture in males, and 1 WGCNA module was associated with DEP in females. Five of the OPE-associated gene modules were enriched for a total of 17 KEGG pathways, and 11 modules were enriched with targets of 12 nuclear hormone receptor transcription factors. Overall, novel associations were identified between the placental transcriptome and OPE metabolites, individually and in mixture, including differences based on fetal sex. These findings highlight the need for additional research on mechanisms of OPE-associated gene expression changes in the placenta and associated health outcomes.

  View details for DOI 10.1016/j.envint.2025.109402

  View details for PubMedID 40132437

• Comparing Veteran and Nonveteran Epigenetic Aging in a Representative Sample of United States Adults. Military medicine Nwanaji-Enwerem, J. C., Khodasevich, D., Gladish, N., Shen, H., Daredia, S., Needham, B. L., Rehkopf, D. H., Cardenas, A. 2025

  Abstract

  INTRODUCTION: Military service can significantly impact human health, with research showing that veterans experience higher mortality rates than the general population. However, limited data exist on the relationships of veteran status with biomarkers of aging that may precede clinical illness and mortality.METHODS: Using survey-design weighted generalized linear regression models, we examined the cross-sectional relationship of self-reported veteran status with DNA methylation (DNAm)-based biomarkers of aging (epigenetic age) in a representative sample of 2344 U.S. adults participating in the 1999-2000 and 2001-2002 cycles of the National Health and Nutrition Examination Survey. We tested 7 epigenetic aging markers: HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge2, DNAm Telomere Length (TL), and DunedinPoAm.RESULTS: After adjusting for basic demographics, veterans had marginally greater SkinBloodAge (beta=0.86years, 95% CI: -0.10, 1.81, P=.08) and GrimAge2 (beta=0.71years, 95% CI: -0.07, 1.49, P=.07) measures when compared to nonveterans. Similar SkinBloodAge (beta=1.00years, 95% CI: -0.01, 2.00, P=.05) and GrimAge2 (beta=0.69years, 95% CI: -0.14, 1.52, P=.09) relationships were observed in fully-adjusted models where missing health and lifestyle covariates were imputed. Compared to nonveterans, veterans also had higher DNAm-estimated blood levels of GrimAge2-components hemoglobin A1c (beta=0.006, 95% CI: 0.0005, 0.01, P=.03) and protein TIMP1 (beta=71.14, 95% CI: 8.28, 134.01, P=.03) in basic demographic-adjusted models. In fully-adjusted imputed models (beta=96.40, 95% CI: -15.05, 207.85, P=.08) and complete case models (beta=98.66, 95% CI: -25.24, 222.55, P=.099), the TIMP1 relationships remained marginally significant.CONCLUSIONS: Our marginal results support existing veteran morbidity and mortality literature while suggesting a modest utility of epigenetic aging biomarkers for further understanding veteran health. As veterans represent an important subset of the population and are a priority in federal government budgets, future research in this area holds the potential for significant public health and policy impact.

  View details for DOI 10.1093/milmed/usaf071

  View details for PubMedID 40080460

• Immigrant status and citizenship relationships with epigenetic aging in a representative sample of United States adults. Epigenomics Nwanaji-Enwerem, J. C., Rodriguez Espinosa, P., Khodasevich, D., Gladish, N., Shen, H., Bozack, A. K., Daredia, S., Needham, B. L., Rehkopf, D. H., Cardenas, A. 2025: 1-8

  Abstract

  Immigrant status and citizenship influence health and well-being, yet their associations with DNA methylation (DNAm)-based biomarkers of aging - key predictors of healthspan and lifespan, also known as epigenetic aging - remain underexplored.Using a representative sample of 2,336 United States (U.S.) adults from the 1999-2000 and 2001-2002 cycles of the National Health and Nutrition Examination Survey (NHANES), we analyzed cross-sectional associations of immigrant status and U.S. citizenship with seven epigenetic aging biomarkers: HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge2, DNAm Telomere Length, and DunedinPoAm.After adjusting for demographic factors, immigrants had 2.53-year lower GrimAge2 measures (95%CI: -3.44, -1.63, p < 0.001) compared to non-immigrants. U.S. citizens had 1.98-year higher GrimAge2 measures (95%CI: 0.66, 3.30, p = 0.005) compared to non-citizens. The GrimAge2 associations with immigrant status (β = -1.04-years, 95%CI: -1.87, -0.21, p = 0.02) and citizenship (β = 1.35-years, 95%CI: 0.38, 2.32, p = 0.02) were attenuated after adjusting for other lifestyle/health variables. Immigrant status and citizenship were associated with estimated levels of several GrimAge2 DNAm component proteins, including adrenomedullin and C-reactive protein.Our results support the paradigm of the immigrant mortality advantage and highlight the potential value of epigenetic age measures in studying socioeconomic and broader factors influencing citizen and immigrant health.

  View details for DOI 10.1080/17501911.2025.2476378

  View details for PubMedID 40067775

• Timing of menarche and menopause and epigenetic aging among U.S. adults: results from the National Health and Nutrition Examination Survey 1999-2002. Clinical epigenetics Daredia, S., Khodasevich, D., Gladish, N., Shen, H., Nwanaji-Enwerem, J. C., Bozack, A. K., Needham, B. L., Rehkopf, D. H., Deardorff, J., Cardenas, A. 2025; 17 (1): 31

  Abstract

  Reproductive aging, including timing of menarche and menopause, influences long-term morbidity and mortality in women, yet underlying biological mechanisms remain poorly understood. Using DNA methylation-based biomarkers, we assessed associations of age at menarche (N = 1,033) and menopause (N = 658) with epigenetic aging in a nationally representative sample of women ≥ 50 years. Later age at menopause was associated with lower GrimAge epigenetic age deviation ( B = - 0.10 years, 95% CI: - 0.19, - 0.02). No associations were observed for menarche timing. This suggests a connection between earlier menopause and biological aging, with potential clinical implications for identifying those at high risk for age-related disease.

  View details for DOI 10.1186/s13148-025-01827-x

  View details for PubMedID 39984995

  View details for PubMedCentralID 3488186

• Exposome-wide association study of environmental chemical exposures and epigenetic aging in the national health and nutrition examination survey. Aging Khodasevich, D., Gladish, N., Daredia, S., Bozack, A. K., Shen, H., Nwanaji-Enwerem, J. C., Needham, B. L., Rehkopf, D. H., Cardenas, A. 2025; 17

  Abstract

  Epigenetic clocks can serve as pivotal biomarkers linking environmental exposures with biological aging. However, research on the influence of environmental exposures on epigenetic aging has largely been limited to a small number of chemicals and specific populations. We harnessed data from the National Health and Nutrition Examination Survey 1999-2000 and 2001-2002 cycles to examine exposome-wide associations between environmental exposures and epigenetic aging. A total of 8 epigenetic aging biomarkers were obtained from whole blood in 2,346 participants ranging from 50-84 years of age. A total of 64 environmental exposures including phthalates, metals, pesticides, dioxins, and polychlorinated biphenyls (PCBs) were measured in blood and urine. Associations between log2-transformed/standardized exposure measures and epigenetic age acceleration (EAA) were assessed using survey-weighted generalized linear regression. A 1 standard deviation (SD) increase in log2 serum cadmium levels was associated with higher GrimAge acceleration (beta = 1.23 years, p = 3.63e-06), higher GrimAge2 acceleration (beta = 1.27 years, p = 1.62e-05), and higher DunedinPoAm (beta = 0.02, p = 2.34e-05). A 1 SD increase in log2 serum cotinine levels was associated with higher GrimAge2 acceleration (beta = 1.40 years, p = 6.53e-04) and higher DunedinPoAm (beta = 0.03, p = 6.31e-04). Associations between cadmium and EAA across several clocks persisted in sensitivity models adjusted for serum cotinine levels, and other associations involving lead, dioxins, and PCBs were identified. Several environmental exposures are associated with epigenetic aging in a nationally representative US adult population, with particularly strong associations related to cadmium and cotinine across several epigenetic clocks.

  View details for DOI 10.18632/aging.206201

  View details for PubMedID 39938123

• A SuperLearner-based pipeline for the development of DNA methylation-derived predictors of phenotypic traits. PLoS computational biology Khodasevich, D., Holland, N., van der Laan, L., Cardenas, A. 2025; 21 (2): e1012768

  Abstract

  DNA methylation (DNAm) provides a window to characterize the impacts of environmental exposures and the biological aging process. Epigenetic clocks are often trained on DNAm using penalized regression of CpG sites, but recent evidence suggests potential benefits of training epigenetic predictors on principal components.We developed a pipeline to simultaneously train three epigenetic predictors; a traditional CpG Clock, a PCA Clock, and a SuperLearner PCA Clock (SL PCA). We gathered publicly available DNAm datasets to generate i) a novel childhood epigenetic clock, ii) a reconstructed Hannum adult blood clock, and iii) as a proof of concept, a predictor of polybrominated biphenyl exposure using the three developmental methodologies. We used correlation coefficients and median absolute error to assess fit between predicted and observed measures, as well as agreement between duplicates. The SL PCA clocks improved fit with observed phenotypes relative to the PCA clocks or CpG clocks across several datasets. We found evidence for higher agreement between duplicate samples run on alternate DNAm arrays when using SL PCA clocks relative to traditional methods. Analyses examining associations between relevant exposures and epigenetic age acceleration (EAA) produced more precise effect estimates when using predictions derived from SL PCA clocks.We introduce a novel method for the development of DNAm-based predictors that combines the improved reliability conferred by training on principal components with advanced ensemble-based machine learning. Coupling SuperLearner with PCA in the predictor development process may be especially relevant for studies with longitudinal designs utilizing multiple array types, as well as for the development of predictors of more complex phenotypic traits.

  View details for DOI 10.1371/journal.pcbi.1012768

  View details for PubMedID 39913632

  View details for PubMedCentralID PMC11801726

• Timing of Menarche and Menopause and Epigenetic Aging among U.S. Adults: Results from the National Health and Nutrition Examination Survey 1999-2002. medRxiv : the preprint server for health sciences Daredia, S., Khodasevich, D., Gladish, N., Shen, H., Nwanaji-Enwerem, J. C., Bozack, A. K., Needham, B. L., Rehkopf, D. H., Deardorff, J., Cardenas, A. 2024

  Abstract

  Reproductive aging, including timing of menarche and menopause, influences long-term morbidity and mortality in women, yet underlying biological mechanisms remain poorly understood. Using DNA methylation-based biomarkers, we assessed associations of age at menarche (N=1,033) and menopause (N=658) with epigenetic aging in a nationally representative sample of women ≥50 years. Later age at menopause was associated with lower GrimAge epigenetic age deviation (B = -0.10 years, 95% CI: -0.19, -0.02). No associations were observed for menarche timing. This suggests a connection between earlier menopause and biological aging, with potential clinical implications for identifying those at high risk for age-related disease.

  View details for DOI 10.1101/2024.12.19.24319271

  View details for PubMedID 39763532

• Prenatal Phenol and Phthalate Exposure is Associated with Persistent Changes in DNA Methylation in Childhood Khodasevich, D., Harley, K. G., Eskenazi, B., Barcellos, L. F., Cardenas, A., Holland, N. WILEY. 2024: 45

  View details for Web of Science ID 001364266600076

• Prenatal exposure to environmental phenols and phthalates and altered patterns of DNA methylation in childhood. Environment international Khodasevich, D., Holland, N., Harley, K. G., Eskenazi, B., Barcellos, L. F., Cardenas, A. 2024; 190: 108862

  Abstract

  Epigenetic marks are key biomarkers linking the prenatal environment to health and development. However, DNA methylation associations and persistence of marks for prenatal exposure to multiple Endocrine Disrupting Chemicals (EDCs) in human populations have not been examined in great detail.We measured Bisphenol-A (BPA), triclosan, benzophenone-3 (BP3), methyl-paraben, propyl-paraben, and butyl-paraben, as well as 11 phthalate metabolites, in two pregnancy urine samples, at approximately 13 and 26 weeks of gestation in participants of the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study (N = 309). DNA methylation of cord blood at birth and child peripheral blood at ages 9 and 14 years was measured with 450K and EPIC arrays. Robust linear regression was used to identify differentially methylated probes (DMPs), and comb-p was used to identify differentially methylated regions (DMRs) in association with pregnancy-averaged EDC concentrations. Quantile g-computation was used to assess associations of the whole phenol/phthalate mixture with DMPs and DMRs.Prenatal BPA exposure was associated with 1 CpG among males and Parabens were associated with 10 CpGs among females at Bonferroni-level significance in cord blood. Other suggestive DMPs (unadjusted p-value < 1 × 10-6) and several DMRs associated with the individual phenols and whole mixture were also identified. A total of 10 CpG sites at least suggestively associated with BPA, Triclosan, BP3, Parabens, and the whole mixture in cord blood were found to persist into adolescence in peripheral blood.We found sex-specific associations between prenatal phenol exposure and DNA methylation, particularly with BPA in males and Parabens in females. Additionally, we found several DMPs that maintained significant associations with prenatal EDC exposures at age 9 and age 14 years.

  View details for DOI 10.1016/j.envint.2024.108862

  View details for PubMedID 38972116

• Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium. Aging cell Yeung, E., Biedrzycki, R. J., Gómez Herrera, L. C., Issarapu, P., Dou, J., Marques, I. F., Mansuri, S. R., Page, C. M., Harbs, J., Khodasevich, D., Poisel, E., Niu, Z., Allard, C., Casey, E., Berstein, F. M., Mancano, G., Elliott, H. R., Richmond, R., He, Y., Ronkainen, J., Sebert, S., Bell, E. M., Sharp, G., Mumford, S. L., Schisterman, E. F., Chandak, G. R., Fall, C. H., Sahariah, S. A., Silver, M. J., Prentice, A. M., Bouchard, L., Domellof, M., West, C., Holland, N., Cardenas, A., Eskenazi, B., Zillich, L., Witt, S. H., Send, T., Breton, C., Bakulski, K. M., Fallin, M. D., Schmidt, R. J., Stein, D. J., Zar, H. J., Jaddoe, V. W., Wright, J., Grazuleviciene, R., Gutzkow, K. B., Sunyer, J., Huels, A., Vrijheid, M., Harlid, S., London, S., Hivert, M. F., Felix, J., Bustamante, M., Guan, W. 2024: e14194

  Abstract

  Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

  View details for DOI 10.1111/acel.14194

  View details for PubMedID 38808605

• Associations between prenatal phthalate exposure and childhood epigenetic age acceleration. Environmental research Khodasevich, D., Holland, N., Hubbard, A., Harley, K., Deardorff, J., Eskenazi, B., Cardenas, A. 2023: 116067

  Abstract

  BACKGROUND: Phthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement.METHODS: Among 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood.RESULTS: We found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.58 years; 95% CI: 1.02 to -0.13), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: 2.79 to -0.28), while most other associations were nonsignificant.CONCLUSIONS: Our results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships.

  View details for DOI 10.1016/j.envres.2023.116067

  View details for PubMedID 37149020