Paulina Jedynak1, Jörg Tost2, Antonia M Calafat3, Ekaterina Bourova-Flin4, Lucile Broséus5, Florence Busato2, Anne Forhan6, Barbara Heude6, Milan Jakobi5, Joel Schwartz7, Rémy Slama5, Daniel Vaiman8, Johanna Lepeule9, Claire Philippat5. 1. University Grenoble Alpes, Inserm, CNRS, Team of Environmental Epidemiology applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France. Electronic address: paulina.jedynak@univ-grenoble-alpes.fr. 2. Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, University Paris Saclay, Evry, France. 3. National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA. 4. University Grenoble Alpes, Inserm, CNRS, EpiMed Group, Institute for Advanced Biosciences, Grenoble, France. 5. University Grenoble Alpes, Inserm, CNRS, Team of Environmental Epidemiology applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France. 6. Université de Paris, Centre for Research in Epidemiology and Statistics (CRESS), INSERM, INRAE, F-75004 Paris, France. 7. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 8. Genomics, Epigenetics and Physiopathology of Reproduction, Institut Cochin, U1016 Inserm - UMR 8104 CNRS - Paris-Descartes University, Paris, France. 9. University Grenoble Alpes, Inserm, CNRS, Team of Environmental Epidemiology applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France. Electronic address: johanna.lepeule@univ-grenoble-alpes.fr.
Abstract
BACKGROUND: Exposure to phthalates during pregnancy may alter DNA methylation in the placenta, a crucial organ for the growth and development of the fetus. OBJECTIVES: We studied associations between urinary concentrations of phthalate biomarkers during pregnancy and placental DNA methylation. METHODS: We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22 and 29 gestational weeks in 202 pregnant women. We analyzed DNA methylation levels in placental tissue (fetal side) collected at delivery. We first investigated changes in global DNA methylation of repetitive elements Alu and LINE-1. We then performed an adjusted epigenome-wide association study using IlluminaHM450 BeadChips and identified differentially methylated regions (DMRs) associated with phthalate exposure. RESULTS: Monobenzyl phthalate concentration was inversely associated with placental methylation of Alu repeats. Moreover, all phthalate biomarkers except for monocarboxy-iso-octyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were associated with at least one DMR. All but three DMRs showed increased DNA methylation with increased phthalate exposure. The largest identified DMR (22 CpGs) was positively associated with monocarboxy-iso-nonyl phthalate and encompassed heat shock proteins (HSPA1A, HSPA1L). The remaining DMRs encompassed transcription factors and nucleotide exchange factors, among other genes. CONCLUSIONS: This is the first description of genome-wide modifications of placental DNA methylation in association with pregnancy exposure to phthalates. Our results suggest epigenetic mechanisms by which exposure to these compounds could affect fetal development. Of interest, four identified DMRs had been previously associated with maternal smoking, which may suggest particular sensitivity of these genomic regions to the effect of environmental contaminants.
BACKGROUND: Exposure to phthalates during pregnancy may alter DNA methylation in the placenta, a crucial organ for the growth and development of the fetus. OBJECTIVES: We studied associations between urinary concentrations of phthalate biomarkers during pregnancy and placental DNA methylation. METHODS: We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22 and 29 gestational weeks in 202 pregnant women. We analyzed DNA methylation levels in placental tissue (fetal side) collected at delivery. We first investigated changes in global DNA methylation of repetitive elements Alu and LINE-1. We then performed an adjusted epigenome-wide association study using IlluminaHM450 BeadChips and identified differentially methylated regions (DMRs) associated with phthalate exposure. RESULTS: Monobenzyl phthalate concentration was inversely associated with placental methylation of Alu repeats. Moreover, all phthalate biomarkers except for monocarboxy-iso-octyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were associated with at least one DMR. All but three DMRs showed increased DNA methylation with increased phthalate exposure. The largest identified DMR (22 CpGs) was positively associated with monocarboxy-iso-nonyl phthalate and encompassed heat shock proteins (HSPA1A, HSPA1L). The remaining DMRs encompassed transcription factors and nucleotide exchange factors, among other genes. CONCLUSIONS: This is the first description of genome-wide modifications of placental DNA methylation in association with pregnancy exposure to phthalates. Our results suggest epigenetic mechanisms by which exposure to these compounds could affect fetal development. Of interest, four identified DMRs had been previously associated with maternal smoking, which may suggest particular sensitivity of these genomic regions to the effect of environmental contaminants.
Authors: Ni Zhao; Douglas A Bell; Arnab Maity; Ana-Maria Staicu; Bonnie R Joubert; Stephanie J London; Michael C Wu Journal: Genet Epidemiol Date: 2014-12-23 Impact factor: 2.135
Authors: Olivia Solomon; Paul Yousefi; Karen Huen; Robert B Gunier; Maria Escudero-Fung; Lisa F Barcellos; Brenda Eskenazi; Nina Holland Journal: Environ Mol Mutagen Date: 2017-05-28 Impact factor: 3.216
Authors: Victor Yuan; Desmond Hui; Yifan Yin; Maria S Peñaherrera; Alexander G Beristain; Wendy P Robinson Journal: BMC Genomics Date: 2021-01-06 Impact factor: 3.969