title: Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility.
abstract: Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life.
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark; david@moebjerg.com.
authors.forename: Jacob Bak
authors.initials: JB
authors.lastname: Holm
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Rennes, France;
authors.forename: Severine
authors.initials: S
authors.lastname: Mazaud-Guittot
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark;
authors.forename: Niels Banhos
authors.initials: NB
authors.lastname: Danneskiold-Samsøe
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Rennes, France;
authors.forename: Clementine
authors.initials: C
authors.lastname: Chalmey
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Jensen
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark;
authors.forename: Mette Marie
authors.initials: MM
authors.lastname: Nørregård
authors.affiliation: Toxicology Laboratory, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark;
authors.forename: Cecilie Hurup
authors.initials: CH
authors.lastname: Hansen
authors.affiliation: Toxicology Laboratory, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark;
authors.forename: Bjarne
authors.initials: B
authors.lastname: Styrishave
authors.affiliation: Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, 2860 Søborg, Denmark;
authors.forename: Terje
authors.initials: T
authors.lastname: Svingen
authors.affiliation: Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, 2860 Søborg, Denmark;
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Vinggaard
authors.affiliation: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance Institute of the Ruhr-Universität Bochum (IPA), 44789 Bochum, Germany;
authors.forename: Holger Martin
authors.initials: HM
authors.lastname: Koch
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; and.
authors.forename: Josephine
authors.initials: J
authors.lastname: Bowles
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Rennes, France; EHESP-School of Public Health, Rennes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jégou
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark;
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark; Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Rennes, France; david@moebjerg.com.
authors.forename: David Møbjerg
authors.initials: DM
authors.lastname: Kristensen
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005836:Genitalia, Female / Q000002:abnormalities* / Q000196:embryology; D005865:Gestational Age; D008297:Male; D008810:Mice, Inbred C57BL; D006080:Ovarian Follicle / Q000187:drug effects* / Q000196:embryology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000814:Aniline Compounds; D000082:Acetaminophen; C023650:aniline
keywords: aniline; development; follicle reserves; intrauterine exposure; paracetamol/acetaminophen; reproduction