Dennis Khodasevich

All Publications

• 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