RESUMEN
OBJECTIVES: Mechanisms underlying the carcinogenicity of night shift work remain uncertain. One compelling yet understudied cancer mechanism may involve altered DNA methylation in circadian genes due to melatonin secretion patterns. The objective of this study was to explore the relationship between melatonin secretion patterns and circadian gene methylation among day and night shift workers. METHODS: Female healthcare employees (n=38 day workers, n=36 night shift workers) for whom we had urinary 6-sulfatoxymelatonin secretion data from a previous study were recontacted. New blood samples were collected and used to measure methylation levels at 1150 CpG loci across 22 circadian genes using the Illumina Infinium MethylationEPIC beadchip. Linear regression was used to examine the association between melatonin (acrophase and mesor) and M values for each CpG site (false discovery rate, q=0.2), while testing for effect modification by shift work status. RESULTS: Among night shift workers, a higher mesor (24 hours of mean production of melatonin) was associated with increased methylation in the body of RORA (q=0.02) and decreased methylation in the putative promoter region of MTNR1A (q=0.03). Later acrophase (ie, time of peak concentration) was associated with increased methylation in the putative promoter region of MTNR1A (q=0.20) and decreased methylation in the body of PER3 (q=0.20). No associations were identified among day workers. CONCLUSIONS: In conclusion, patterns in melatonin secretion were associated with differential circadian gene methylation among night shift workers. Melatonin and alteration of DNA methylation in circadian genes may be one pathway towards increased cancer risk, although larger-scale studies examining multiple time points are needed.
RESUMEN
Night shift work is associated with increased breast cancer risk, but the molecular mechanisms are not well-understood. The objective of this study was to explore the relationship between night shift work parameters (current status, duration/years, and intensity) and methylation in circadian genes as a potential mechanism underlying the carcinogenic effects of night shift work. A cross-sectional study was conducted among 74 female healthcare employees (n = 38 day workers, n = 36 night shift workers). The Illumina Infinium MethylationEPIC beadchip was applied to DNA extracted from blood samples to measure methylation using a candidate gene approach at 1150 CpG loci across 22 circadian genes. Linear regression models were used to examine the association between night shift work parameters and continuous methylation measurements (ß-values) for each CpG site. The false-discovery rate (q = 0.2) was used to account for multiple comparisons. Compared to day workers, current night shift workers demonstrated hypermethylation in the 5'UTR region of CSNK1E (q = 0.15). Individuals that worked night shifts for ≥10 years exhibited hypomethylation in the gene body of NR1D1 (q = 0.08) compared to those that worked <10 years. Hypermethylation in the gene body of ARNTL was also apparent in those who worked ≥3 consecutive night shifts a week (q = 0.18). These findings suggest that night shift work is associated with differential methylation in core circadian genes, including CSNK1E, NR1D1 and ARNTL. Future, larger-scale studies with long-term follow-up and detailed night shift work assessment are needed to confirm and expand on these findings.