Arce Domingo-Relloso1, Anne Bozack2, Samara Kiihl3, Zulema Rodriguez-Hernandez4, Pilar Rentero-Garrido5, J Antonio Casasnovas6, Montserrat Leon-Latre6, Tamara Garcia-Barrera7, J Luis Gomez-Ariza7, Belen Moreno8, Ana Cenarro6, Griselda de Marco9, Faruque Parvez10, Abu B Siddique10, Hasan Shahriar10, Mohammad N Uddin10, Tariqul Islam10, Ana Navas-Acien11, Mary Gamble11, Maria Tellez-Plaza12. 1. Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA; Department of Statistics and Operations Research, University of Valencia, Spain. 2. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA; Department of Environmental Health Sciences, School of Public Health, University of California, Berkeley, USA. 3. Department of Statistics, State University of Campinas, Brazil. 4. Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain. 5. Precision Medicine Unit, Biomedical Research Institute Hospital Clinic de Valencia INCLIVA, Valencia, Spain. 6. CIBERCV, And Aragon Health Research Institute Foundation (IIS Aragon), University of Zaragoza, Zaragoza, Spain; Aragon Health Research Institute Foundation (IIS Aragon), University of Zaragoza, Zaragoza, Spain. 7. Research Center on Natural Resources, Health and the Environment, Department of Chemistry, University of Huelva, Huelva, Spain. 8. Aragon Health Research Institute Foundation (IIS Aragon), University of Zaragoza, Zaragoza, Spain; Department of Microbiology, Pediatrics, Radiology and Public Health, University of Zaragoza, Zaragoza, Spain. 9. Genomics Area, Foundation for the Promotion of Health and Biomedical Research of the Valencian Region (FISABIO), Valencia, Spain. 10. Columbia University Arsenic Project in Bangladesh, Dhaka, Bangladesh. 11. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA. 12. Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: m.tellez@isciii.es.
Abstract
BACKGROUND: Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported; however, As exposure-related differences of the separated 5-mC and 5-hmC markers have rarely been studied. METHODS: In this study, we evaluated the association of arsenic exposure biomarkers and 5-mC and 5-hmC in 30 healthy men (43-55 years) from the Aragon Workers Health Study (AWHS) (Spain) and 31 healthy men (31-50 years) from the Folic Acid and Creatinine Trial (FACT) (Bangladesh). We conducted 5-mC and 5-hmC profiling using Infinium MethylationEPIC arrays, on paired standard and modified (ox-BS in AWHS and TAB in FACT) bisulfite converted blood DNA samples. RESULTS: The median for the sum of urine inorganic and methylated As species (ΣAs) (μg/L) was 12.5 for AWHS and 89.6 for FACT. The median of blood As (μg/L) was 8.8 for AWHS and 10.2 for FACT. At a statistical significance p-value cut-off of 0.01, the differentially methylated (DMP) and hydroxymethylated (DHP) positions were mostly located in different genomic sites. Several DMPs and DHPs were consistently found in AWHS and FACT both for urine ΣAs and blood models, being of special interest those attributed to the DIP2C gene. Three DMPs (annotated to CLEC12A) for AWHS and one DHP (annotated to NPLOC4) for FACT remained statistically significant after false discovery rate (FDR) correction. Pathways related to chronic diseases including cardiovascular, cancer and neurological were enriched. CONCLUSIONS: While we identified common 5-hmC and 5-mC signatures in two populations exposed to varying levels of inorganic As, differences in As-related epigenetic sites across the study populations may additionally reflect low and high As-specific associations. This work contributes a deeper understanding of potential epigenetic dysregulations of As. However, further research is needed to confirm biological consequences associated with DIP2C epigenetic regulation and to investigate the role of 5-hmC and 5-mC separately in As-induced health disorders at different exposure levels.
BACKGROUND: Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported; however, As exposure-related differences of the separated 5-mC and 5-hmC markers have rarely been studied. METHODS: In this study, we evaluated the association of arsenic exposure biomarkers and 5-mC and 5-hmC in 30 healthy men (43-55 years) from the Aragon Workers Health Study (AWHS) (Spain) and 31 healthy men (31-50 years) from the Folic Acid and Creatinine Trial (FACT) (Bangladesh). We conducted 5-mC and 5-hmC profiling using Infinium MethylationEPIC arrays, on paired standard and modified (ox-BS in AWHS and TAB in FACT) bisulfite converted blood DNA samples. RESULTS: The median for the sum of urine inorganic and methylated As species (ΣAs) (μg/L) was 12.5 for AWHS and 89.6 for FACT. The median of blood As (μg/L) was 8.8 for AWHS and 10.2 for FACT. At a statistical significance p-value cut-off of 0.01, the differentially methylated (DMP) and hydroxymethylated (DHP) positions were mostly located in different genomic sites. Several DMPs and DHPs were consistently found in AWHS and FACT both for urine ΣAs and blood models, being of special interest those attributed to the DIP2C gene. Three DMPs (annotated to CLEC12A) for AWHS and one DHP (annotated to NPLOC4) for FACT remained statistically significant after false discovery rate (FDR) correction. Pathways related to chronic diseases including cardiovascular, cancer and neurological were enriched. CONCLUSIONS: While we identified common 5-hmC and 5-mC signatures in two populations exposed to varying levels of inorganic As, differences in As-related epigenetic sites across the study populations may additionally reflect low and high As-specific associations. This work contributes a deeper understanding of potential epigenetic dysregulations of As. However, further research is needed to confirm biological consequences associated with DIP2C epigenetic regulation and to investigate the role of 5-hmC and 5-mC separately in As-induced health disorders at different exposure levels.
Authors: Anne K Bozack; Arce Domingo-Relloso; Karin Haack; Mary V Gamble; Maria Tellez-Plaza; Jason G Umans; Lyle G Best; Joseph Yracheta; Matthew O Gribble; Andres Cardenas; Kevin A Francesconi; Walter Goessler; Wan-Yee Tang; M Daniele Fallin; Shelley A Cole; Ana Navas-Acien Journal: Environ Health Perspect Date: 2020-06-30 Impact factor: 9.031