A Polyepigenetic Glucocorticoid Exposure Score and HPA Axis-related DNA Methylation Are Associated with Gestational Epigenetic Aging

Overview

Journal Epigenetics

Specialty Genetics

Date 2025 Feb 26

PMID 40007075

Authors

Allison A Appleton

Affiliations

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Abstract

Gestational epigenetic aging (GEA) is a novel approach for characterizing associations between prenatal exposures and postnatal risks. Psychosocial adversity in pregnancy may influence GEA, but the molecular mechanisms are not well understood. DNA methylation to glucocorticoid regulation and hypothalamic-pituitary-adrenal (HPA) axis genes are implicated but have not been fully examined in association with GEA. This study investigated whether a polyepigenetic glucocorticoid exposure score (PGES) and HPA axis gene () methylation were associated with GEA, and whether associations were sex-specific. Participants were from a prospective cohort of racial/ethnic diverse and socially disadvantaged pregnant women and infants ( = 200). DNA methylation variables were estimated using umbilical cord blood. PGES was derived with CpGs shown to be sensitive to synthetic dexamethasone exposure. , , and methylation was summarized via factor analysis. We found that PGES (β = -1.12, SE = 0.47, = 0.02) and several and factor scores were associated with decelerated GEA (all < 0.05). A significant sex interaction was observed for factor score 3 (β = -0.34, SE = 0.15, = 0.02) suggesting decelerated GEA for males but not females. This study showed that glucocorticoid regulation-related DNA methylation was associated with a decelerated aging phenotype at birth that might indicate a neonatal risk.

References

Paquette A, Lester B, Lesseur C, Armstrong D, Guerin D, Appleton A . Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics. 2015; 7(5):767-79. PMC: 4772971. DOI: 10.2217/epi.15.28. View

Michaud D, Skinner H, Wu K, Hu F, Giovannucci E, Willett W . Dietary patterns and pancreatic cancer risk in men and women. J Natl Cancer Inst. 2005; 97(7):518-24. DOI: 10.1093/jnci/dji094. View

McEwen L, Jones M, Lin D, Edgar R, Husquin L, MacIsaac J . Systematic evaluation of DNA methylation age estimation with common preprocessing methods and the Infinium MethylationEPIC BeadChip array. Clin Epigenetics. 2018; 10(1):123. PMC: 6192219. DOI: 10.1186/s13148-018-0556-2. View

Moran S, Arribas C, Esteller M . Validation of a DNA methylation microarray for 850,000 CpG sites of the human genome enriched in enhancer sequences. Epigenomics. 2015; 8(3):389-99. PMC: 4864062. DOI: 10.2217/epi.15.114. View

Chalfun G, Brasil A, Paravidino V, Soares-Lima S, Souza Almeida Lopes M, Salu M . gene methylation and cortisol levels in preterm and healthy full-term infants in the first 3 months of life. Epigenomics. 2023; 14(24):1545-1561. DOI: 10.2217/epi-2022-0444. View

Suarez A, Lahti J, Lahti-Pulkkinen M, Girchenko P, Czamara D, Arloth J . A polyepigenetic glucocorticoid exposure score at birth and childhood mental and behavioral disorders. Neurobiol Stress. 2020; 13:100275. PMC: 7739178. DOI: 10.1016/j.ynstr.2020.100275. View

McGill M, Pokhvisneva I, Clappison A, McEwen L, Beijers R, Tollenaar M . Maternal Prenatal Anxiety and the Fetal Origins of Epigenetic Aging. Biol Psychiatry. 2021; 91(3):303-312. DOI: 10.1016/j.biopsych.2021.07.025. View

Sundrani D, Roy S, Jadhav A, Joshi S . Sex-specific differences and developmental programming for diseases in later life. Reprod Fertil Dev. 2017; 29(11):2085-2099. DOI: 10.1071/RD16265. View

Lapehn S, Paquette A . The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis. Curr Environ Health Rep. 2022; 9(3):490-501. PMC: 9363315. DOI: 10.1007/s40572-022-00354-8. View

10.

Horn J . A RATIONALE AND TEST FOR THE NUMBER OF FACTORS IN FACTOR ANALYSIS. Psychometrika. 1965; 30:179-85. DOI: 10.1007/BF02289447. View

11.

Dye C, Alschuler D, Wu H, Duarte C, Monk C, Belsky D . Maternal Adverse Childhood Experiences and Biological Aging During Pregnancy and in Newborns. JAMA Netw Open. 2024; 7(8):e2427063. PMC: 11316241. DOI: 10.1001/jamanetworkopen.2024.27063. View

12.

Euclydes V, Gomes C, Gouveia G, Daguano Gastaldi V, Feltrin A, Camilo C . Gestational age acceleration is associated with epigenetic biomarkers of prenatal physiologic stress exposure. Clin Epigenetics. 2022; 14(1):152. PMC: 9703828. DOI: 10.1186/s13148-022-01374-9. View

13.

Girchenko P, Lahti J, Czamara D, Knight A, Jones M, Suarez A . Associations between maternal risk factors of adverse pregnancy and birth outcomes and the offspring epigenetic clock of gestational age at birth. Clin Epigenetics. 2017; 9:49. PMC: 5422977. DOI: 10.1186/s13148-017-0349-z. View

14.

Sosnowski D, Booth C, York T, Amstadter A, Kliewer W . Maternal prenatal stress and infant DNA methylation: A systematic review. Dev Psychobiol. 2018; 60(2):127-139. DOI: 10.1002/dev.21604. View

15.

Appleton A, Lin B, Holdsworth E, Feingold B, Schell L . Prenatal Exposure to Favorable Social and Environmental Neighborhood Conditions Is Associated with Healthy Pregnancy and Infant Outcomes. Int J Environ Res Public Health. 2021; 18(11). PMC: 8200992. DOI: 10.3390/ijerph18116161. View

16.

Oberlander T, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin A . Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008; 3(2):97-106. DOI: 10.4161/epi.3.2.6034. View

17.

Appleton A, Kiley K, Schell L, Holdsworth E, Akinsanya A, Beecher C . Prenatal Lead and Depression Exposures Jointly Influence Birth Outcomes and DNA Methylation. Int J Environ Res Public Health. 2021; 18(22). PMC: 8620070. DOI: 10.3390/ijerph182212169. View

18.

Liu H, Liu Y, Huang K, Yan S, Hao J, Zhu P . Gender-specific associations of pregnancy-related anxiety with placental epigenetic patterning of glucocorticoid response genes and preschooler's emotional symptoms and hyperactivity. BMC Pediatr. 2021; 21(1):479. PMC: 8555194. DOI: 10.1186/s12887-021-02938-z. View

19.

Haftorn K, Lee Y, Denault W, Page C, Nustad H, Lyle R . An EPIC predictor of gestational age and its application to newborns conceived by assisted reproductive technologies. Clin Epigenetics. 2021; 13(1):82. PMC: 8056641. DOI: 10.1186/s13148-021-01055-z. View

20.

Horvath S, Raj K . DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018; 19(6):371-384. DOI: 10.1038/s41576-018-0004-3. View