title: Prenatal Exposure to DEHP Affects Spermatogenesis and Sperm DNA Methylation in a Strain-Dependent Manner.
abstract: Di-(2-ethylhexyl)phtalate (DEHP) is a plasticizer with endocrine disrupting properties found ubiquitously in the environment and altering reproduction in rodents. Here we investigated the impact of prenatal exposure to DEHP on spermatogenesis and DNA sperm methylation in two distinct, selected, and sequenced mice strains. FVB/N and C57BL/6J mice were orally exposed to 300 mg/kg/day of DEHP from gestation day 9 to 19. Prenatal DEHP exposure significantly decreased spermatogenesis in C57BL/6J (fold-change = 0.6, p-value = 8.7*10-4), but not in FVB/N (fold-change = 1, p-value = 0.9). The number of differentially methylated regions (DMRs) by DEHP-exposure across the entire genome showed increased hyper- and decreased hypo-methylation in C57BL/6J compared to FVB/N. At the promoter level, three important subsets of genes were massively affected. Promoters of vomeronasal and olfactory receptors coding genes globally followed the same trend, more pronounced in the C57BL/6J strain, of being hyper-methylated in DEHP related conditions. In contrast, a large set of micro-RNAs were hypo-methylated, with a trend more pronounced in the FVB/N strain. We additionally analyze both the presence of functional genetic variations within genes that were associated with the detected DMRs and that could be involved in spermatogenesis, and DMRs related with the DEHP exposure that affected both strains in an opposite manner. The major finding in this study indicates that prenatal exposure to DEHP can decrease spermatogenesis in a strain-dependent manner and affects sperm DNA methylation in promoters of large sets of genes putatively involved in both sperm chemotaxis and post-transcriptional regulatory mechanisms.
authors.affiliation: Department of Mental Health and Psychiatry, Division of Psychiatric Specialties, University Hospitals of Geneva, Geneva, Switzerland; Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Prados
authors.affiliation: Department of Genetic Medicine and Development, Geneva University and University Hospital, Geneva, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Stenz
authors.affiliation: Endocrinology, Diabetes & Metabolism Service of the Centre Hospitalier Universitaire Vaudois and Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Somm
authors.affiliation: Department of Genetic Medicine and Development, Geneva University and University Hospital, Geneva, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Stouder
authors.affiliation: Department of Mental Health and Psychiatry, Division of Psychiatric Specialties, University Hospitals of Geneva, Geneva, Switzerland; Department of Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dayer
authors.affiliation: Department of Genetic Medicine and Development, Geneva University and University Hospital, Geneva, Switzerland; Swiss Center for Applied Human Toxicology, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Ariane
authors.initials: A
authors.lastname: Paoloni-Giacobino
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000187:drug effects*; D004051:Diethylhexyl Phthalate / Q000009:adverse effects*; D052244:Endocrine Disruptors / Q000009:adverse effects*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010968:Plasticizers / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D013045:Species Specificity; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects*
chemical_list: D052244:Endocrine Disruptors; D010968:Plasticizers; D004051:Diethylhexyl Phthalate