title: Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.
abstract: BACKGROUND
  Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol and/or to other mild analgesics is associated with an increased risk of cryptorchidism.
  
  
  OBJECTIVE
  We aimed to determine whether mild analgesics disrupted the morphology and endocrine function of the human testis.
  
  
  METHODS
  We used an in vitro system based on the culture of human fetal testes exposed or not to paracetamol, its metabolite N-(4-hydroxyphenyl)-arachidonoylethanolamide (AM404), aspirin, indomethacin, and ketoconazole at 10(-4) to 10(-7) M.
  
  
  METHODS
  The study was conducted at the University of Rennes I.
  
  
  METHODS
  Human fetal testes were from pregnant women after induced abortion, between 7 and 12 weeks of gestation (GW).
  
  
  METHODS
  Testosterone (RIA), anti-Müllerian hormone (ELISA), insulin-like factor 3 (RIA), and prostaglandin (PG) D2 and PGE2 (ELISA) were assayed in the medium. Testicular cells were counted using histology and image analysis. The possible nuclear receptor-mediated activities of the analgesics were investigated using reporter cell lines expressing estrogen, androgen, and peroxisome proliferator-activated γ receptors.
  
  
  RESULTS
  Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8-9 GW vs 10-12 GW). Paracetamol, AM404, and ketoconazole decreased insulin-like factor 3 levels. Aspirin stimulated whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol and aspirin in the 7 to 12 GW testes and by indomethacin but only in 7 to 9.86 GW testes. The inhibitory trends seen for PGD2 were not statistically significant.
  
  
  CONCLUSIONS
  Analgesics at concentrations relevant to human exposure cause endocrine disturbances in the fetal testis. We suggest that the fetal human testis displays slight critical age windows for sensitivity to direct exposure to aspirin, indomethacin, and paracetamol. The analgesic-induced inhibition of INSL3 may be the mechanism by which analgesics increase the risk of cryptorchidism. Greater caution is required concerning consumption of analgesics during pregnancy.
authors.affiliation: Institut de Recherche en Santé, Environnement et Travail-Institut National de la Santé et de la Recherche Médicale U1085, Campus de Beaulieu, F-35042 Rennes, France. bernard.jegou@inserm.fr.
authors.forename: Séverine
authors.initials: S
authors.lastname: Mazaud-Guittot
authors.forename: Christophe
authors.initials: C
authors.lastname: Nicolas Nicolaz
authors.forename: Christèle
authors.initials: C
authors.lastname: Desdoits-Lethimonier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coiffec
authors.forename: Millissia
authors.initials: M
authors.lastname: Ben Maamar
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: David M
authors.initials: DM
authors.lastname: Kristensen
authors.forename: Cécile
authors.initials: C
authors.lastname: Chevrier
authors.forename: Vincent
authors.initials: V
authors.lastname: Lavoué
authors.forename: Patrice
authors.initials: P
authors.lastname: Poulain
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dejucq-Rainsford
authors.forename: Bernard
authors.initials: B
authors.lastname: Jégou
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000028:Abortion, Induced; D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000728:Androgens / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D001241:Aspirin / Q000009:adverse effects*; D003456:Cryptorchidism / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects*; D008297:Male; D009924:Organ Culture Techniques; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D013737:Testis / Q000002:abnormalities / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D000728:Androgens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; D013739:Testosterone; D001241:Aspirin; D007213:Indomethacin