title: Epigenetic effects of prenatal estradiol-17β exposure on the reproductive system of pigs.
abstract: There is growing evidence that early life exposure to endocrine disrupting chemicals might increase the risk for certain adult onset diseases, in particular reproductive health problems and hormone dependent cancers. Studies in rodents suggest that perinatal exposure to even low doses of estrogenic substances can cause adverse effects, including epigenetic reprogramming of the prostate and increased formation of precancerous lesions. We analyzed the effects of an in utero exposure to the strongest natural estrogen, estradiol-17β, in a pig model. Two different low and one high dose of estradiol-17β (0.05, 10 and 1000 μg/kg body weight/day) were orally applied to gilts during pregnancy and potential effects on the reproductive system of the offspring were analyzed. No significant effects on sperm vitality parameters and testes size were observed in adult boars. However, prenatal exposure to the high dose decreased absolute, but not relative weight of the testes in prepubertal piglets. RNA sequencing revealed significantly regulated genes of the prepubertal prostate, while testes and uteri were not affected. Notably, we found an increased prostate expression of CCDC80 and a decreased ADH1C expression in the low dose treatment groups. BGN and SPARC, two genes associated with prostate tumor progression, were as well more abundant in exposed animals. Strikingly, the gene body DNA methylation level of BGN was accordingly increased in the high dose group. Thus, while only prenatal exposure to a high dose of estrogen altered testes development and local DNA methylation of the prostate, even low dose exposure had significant effects on gene expression in the prostate of prepubertal piglet offspring. The relevance of these distinct, but subtle transcriptional changes following low dose treatment lacking a clear phenotype calls for further long-term investigations. An epigenetic reprogramming of the pig prostate due to prenatal estrogen cannot be neglected.
authors.affiliation: ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, Zurich, Switzerland. Electronic address: david.kradolfer@usys.ethz.ch.
authors.forename: David
authors.initials: D
authors.lastname: Kradolfer
authors.affiliation: Technische Universität München, Physiology Weihenstephan, Freising, Germany.
authors.forename: Veronika L
authors.initials: VL
authors.lastname: Flöter
authors.affiliation: ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, Zurich, Switzerland.
authors.forename: Jochen T
authors.initials: JT
authors.lastname: Bick
authors.affiliation: Technische Universität München, Physiology Weihenstephan, Freising, Germany.
authors.forename: Rainer W
authors.initials: RW
authors.lastname: Fürst
authors.affiliation: University of Veterinary Medicine Hannover, Institute of Anatomy, Hannover, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Rode
authors.affiliation: University of Veterinary Medicine Hannover, Institute of Anatomy, Hannover, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Brehm
authors.affiliation: University of Veterinary Medicine Hannover, Unit for Reproductive Medicine, Hannover, Germany; Utrecht University, Dep. of Equine Sciences, Faculty of Vet. Med., Utrecht, The Netherlands.
authors.forename: Heiko
authors.initials: H
authors.lastname: Henning
authors.affiliation: University of Veterinary Medicine Hannover, Unit for Reproductive Medicine, Hannover, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Waberski
authors.affiliation: ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauersachs
authors.affiliation: ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, Zurich, Switzerland; Technische Universität München, Physiology Weihenstephan, Freising, Germany. Electronic address: susanne.ulbrich@usys.ethz.ch.
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Ulbrich
mesh_terms: D000818:Animals; D058578:Biglycan / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D011467:Prostate / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D012098:Reproduction / Q000187:drug effects / Q000235:genetics*; D013094:Spermatozoa / Q000187:drug effects; D034421:Sus scrofa / Q000235:genetics*; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D058578:Biglycan; D006023:Glycoproteins; D004958:Estradiol
keywords: DNA methylation; Developmental reprogramming; Endocrine disrupting chemicals; Estradiol-17β; Pig; Prostate