title: Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro.
abstract: OBJECTIVE
  Do mild analgesics affect the endocrine system of the human adult testis?
  
  
  CONCLUSIONS
  Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro.
  
  
  BACKGROUND
  Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line.
  
  
  METHODS
  Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed.
  
  
  METHODS
  Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods.
  
  
  RESULTS
  The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play.
  
  
  CONCLUSIONS
  Our studies were performed in vitro.
  
  
  CONCLUSIONS
  We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.
authors.affiliation: Inserm (Institut national de la santé et de la recherche médicale), IRSET, U1085, Campus de Beaulieu, Rennes CEDEX F-35042, France.
authors.forename: O
authors.initials: O
authors.lastname: Albert
authors.forename: C
authors.initials: C
authors.lastname: Desdoits-Lethimonier
authors.forename: L
authors.initials: L
authors.lastname: Lesné
authors.forename: A
authors.initials: A
authors.lastname: Legrand
authors.forename: F
authors.initials: F
authors.lastname: Guillé
authors.forename: K
authors.initials: K
authors.lastname: Bensalah
authors.forename: N
authors.initials: N
authors.lastname: Dejucq-Rainsford
authors.forename: B
authors.initials: B
authors.lastname: Jégou
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000328:Adult; D001241:Aspirin / Q000494:pharmacology*; D002460:Cell Line; D052244:Endocrine Disruptors / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D007265:Inhibins / Q000378:metabolism; D008297:Male; D011453:Prostaglandins / Q000378:metabolism; D013737:Testis / Q000187:drug effects*; D013739:Testosterone / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D052244:Endocrine Disruptors; D011453:Prostaglandins; C422364:inhibin B; D000082:Acetaminophen; D013739:Testosterone; D007265:Inhibins; D001241:Aspirin; D007213:Indomethacin
keywords: aspirin; endocrine disruption; human testis; indomethacin; paracetamol