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Abstract 3495: Associations between circulating estrogens and estrogens metabolites and blood DNA methylation

Background. Endogenous estrogen and its metabolites have widespread physiological actions and have been associated with several conditions and diseases, including bone density, atherosclerosis, and different cancers. The two parent estrogens, estrone and estradiol, are irreversibly hydroxylated at the C-2, C-4, and C-16 positions of the steroid ring, leading to a cascade of metabolites with potentially different effects on disease risk. Little is known about the relation between estrogen metabolism and DNA methylation, although different estrogen metabolites may alter DNA methylation, which could ultimately result in expression changes in genes affecting hormonally related diseases. Here, we analyze the relationship between circulating parent estrogens and estrogen metabolites and blood DNA methylation. Methods. Estrone, estradiol (total and unconjugated) and 13 estrogen metabolites (five metabolites in the 2-hydroxylation pathway, three in the 4-pathway, and five in the 16-pathway) were measured using highly sensitive liquid chromatography-tandem mass spectrometry in serum from 260 postmenopausal women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who were not currently taking exogenous hormones at the time of blood collection. Using the same blood draw, DNA methylation was measured in 638,586 CpG sites using the Ilumina MethylationEPIC BeadChip array. Associations between estrogens and estrogen metabolites and methylation were estimated using linear regression, adjusting for age, BMI, smoking, and alcohol intake. The Bonferroni correction at the 5% level was used to account for multiple testing. The relationships between estrogens and estrogen metabolites and previously derived methylation measures of age acceleration were also investigated. Results. Median age at blood collection was 63 years. We identified 235 statistically significant associations between different parent estrogens and estrogen metabolites and CpG sites at the Bonferroni level. Approximately 60-70% of these sites, depending on the estrogen/estrogen metabolite, lie in the promoter or the body of a gene. Genes included GPR180 and SDK1, which are related to vascular function and fat metabolism. Approximately 40% of the CpG sites associated with the 2- and 4-hydroxylation pathways lie in enhancer regions. The Horvath measure of age acceleration was inversely associated with 4-hydroxyestrone (P=0.02) and the overall 4-hydroxylation pathway (P=0.04). Conclusions. Circulating estrogens and estrogen metabolites were statistically significantly associated with blood DNA methylation at several hormonally related genes, which could partially explain mechanisms underlying associations between estrogen and hormonally related cancers and other conditions. Work is ongoing to validate these findings. Citation Format: Clara Bodelon. Associations between circulating estrogens and estrogens metabolites and blood DNA methylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3495.