title: Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.
abstract: Industrial use of aniline is increasing worldwide with production estimated to surpass 5.6 million metric tons in 2016. Exposure to aniline occurs via air, diet, and water augmenting the risk of exposing a large number of individuals. Early observations suggest that aniline is metabolized to paracetamol/acetaminophen, likely explaining the omnipresence of low concentrations of paracetamol in European populations. This is of concern as recent studies implicate paracetamol as a disrupter of reproduction. Here, we show through steroidogenic profiling that exposure to aniline led to increased levels of the Δ4 steroids, suggesting that the activity of CYP21 was decreased. By contrast, paracetamol decreased levels of androgens likely through inhibition of CYP17A1 activity. We confirm that aniline in vivo is rapidly converted to paracetamol by the liver. Intrauterine exposure to aniline and paracetamol in environmental and pharmaceutical relevant doses resulted in shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels that in humans is associated with reproductive malformations and later life reproductive disorders. In conclusion, our results provide evidence for a scenario where aniline, through its conversion into antiandrogenic paracetamol, impairs male reproductive development.
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark;
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, Campus de Beaulieu, F-35042 Rennes, France;
authors.forename: Clementine
authors.initials: C
authors.lastname: Chalmey
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: Hendrik
authors.initials: H
authors.lastname: Modick
authors.affiliation: Toxicology Laboratory, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; and.
authors.forename: Lars Skovgaard
authors.initials: LS
authors.lastname: Jensen
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: Georg
authors.initials: G
authors.lastname: Dierkes
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: Tobias
authors.initials: T
authors.lastname: Weiss
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark;
authors.forename: Benjamin Anderschou Holbech
authors.initials: BA
authors.lastname: Jensen
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark;
authors.forename: Mette Marie
authors.initials: MM
authors.lastname: Nørregård
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark;
authors.forename: Kamil
authors.initials: K
authors.lastname: Borkowski
authors.affiliation: Toxicology Laboratory, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; and.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Styrishave
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
authors.initials: H
authors.lastname: Martin Koch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, F-35042 Rennes, France;
authors.forename: Severine
authors.initials: S
authors.lastname: Mazaud-Guittot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, F-35042 Rennes, France; EHESP - School of Public Health, Avenue du Professeur Léon Bernard, F-35043 Rennes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jegou
authors.affiliation: *Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, DK-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, DK-2100 Copenhagen, Denmark; Institut National de la Santé et de la Recherche Médicale (Inserm) U1085-IRSET, Université de Rennes 1, Structure Fédérative Recherche Biosit, Campus de Beaulieu, F-35042 Rennes, France; david@moebjerg.com.
authors.forename: David Møbjerg
authors.initials: DM
authors.lastname: Kristensen
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000814:Aniline Compounds / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007248:Infertility, Male / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011374:Progesterone / Q000819:agonists / Q000378:metabolism; D046468:Sexual Development / Q000187:drug effects; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D066007:Toxicokinetics
chemical_list: D000814:Aniline Compounds; D002274:Carcinogens, Environmental; D052244:Endocrine Disruptors; D000082:Acetaminophen; D013739:Testosterone; D011374:Progesterone; C023650:aniline
keywords: acetaminophen; aniline; endocrine disruptors; paracetamol; reproduction; testosterone