Nadia Vilahur1, Mariona Bustamante2, Hyang-Min Byun3, Mariana F Fernandez4, Loreto Santa Marina5, Mikel Basterrechea5, Ferran Ballester6, Mario Murcia6, Adonina Tardón7, Ana Fernández-Somoano7, Xavier Estivill8, Nicolas Olea4, Jordi Sunyer9, Andrea A Baccarelli3. 1. Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain; Genomics and Disease Group, Bioinformatics and Genomics Program, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain. Electronic address: nvilahur@creal.cat. 2. Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain; Genomics and Disease Group, Bioinformatics and Genomics Program, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain. 3. Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA. 4. Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain; Department of Radiology, Centro de Investigación Biomédica, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria de Granada, Hospital Universitario San Cecilio, Granada, Spain. 5. Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain; Subdirección de Salud Pública de Gipuzkoa, Department of Health of the Basque, Spain; Health Research Institute, BIODONOSTIA, Basque Country, Spain. 6. Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain; Centre for Public Health Research (CSISP-FISABIO), Valencia, Spain; University of Valencia, Valencia, Spain. 7. Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain; University of Oviedo, Oviedo, Asturias, Spain. 8. Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain; Genomics and Disease Group, Bioinformatics and Genomics Program, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain; Department of Health and Life Sciences, University Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. 9. Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catalonia, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain; Department of Health and Life Sciences, University Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
Abstract
BACKGROUND: Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks. OBJECTIVES: In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation. METHODS: The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated. RESULTS: A significant sex interaction was observed for AluYb8 (p-value for interaction <0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value<0.001), while no significant effects were found in girls (p-value=0.134). CONCLUSIONS: Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.
BACKGROUND: Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks. OBJECTIVES: In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation. METHODS: The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated. RESULTS: A significant sex interaction was observed for AluYb8 (p-value for interaction <0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value<0.001), while no significant effects were found in girls (p-value=0.134). CONCLUSIONS: Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.
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