title: Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model.
abstract: Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons, but effects on fetal testosterone production have not been demonstrated. We used a validated xenograft model to expose human fetal testes to clinically relevant doses and regimens of acetaminophen. Exposure to a therapeutic dose of acetaminophen for 7 days significantly reduced plasma testosterone (45% reduction; P = 0.025) and seminal vesicle weight (a biomarker of androgen exposure; 18% reduction; P = 0.005) in castrate host mice bearing human fetal testis xenografts, whereas acetaminophen exposure for just 1 day did not alter either parameter. Plasma acetaminophen concentrations (at 1 hour after the final dose) in exposed host mice were substantially below those reported in humans after a therapeutic oral dose. Subsequent in utero exposure studies in rats indicated that the acetaminophen-induced reduction in testosterone likely results from reduced expression of key steroidogenic enzymes (Cyp11a1, Cyp17a1). Our results suggest that protracted use of acetaminophen (1 week) may suppress fetal testosterone production, which could have adverse consequences. Further studies are required to establish the dose-response and treatment-duration relationships to delineate the maximum dose and treatment period without this adverse effect.
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Sander
authors.initials: S
authors.lastname: van den Driesche
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Joni
authors.initials: J
authors.lastname: Macdonald
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Zoe C
authors.initials: ZC
authors.lastname: Johnston
authors.affiliation: Edinburgh Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh, EH9 1LF, Scotland, UK.
authors.forename: Tarini
authors.initials: T
authors.lastname: Chetty
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Mckinnell
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Afshan
authors.initials: A
authors.lastname: Dean
authors.affiliation: Edinburgh CRF Mass Spectrometry Core, Centre for Cardiovascular Science, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Natalie Z
authors.initials: NZ
authors.lastname: Homer
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.|University Department of Growth and Reproduction, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Jorgensen
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Maria-Elena
authors.initials: ME
authors.lastname: Camacho-Moll
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
authors.affiliation: MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.|Edinburgh Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh, EH9 1LF, Scotland, UK.
authors.forename: Rod T
authors.initials: RT
authors.lastname: Mitchell
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009919:Orchiectomy; D009929:Organ Size; D011247:Pregnancy; D051381:Rats; D018570:Risk Assessment; D012669:Seminal Vesicles / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood; D013997:Time Factors
chemical_list: D000082:Acetaminophen; D013739:Testosterone; C582555:CYP17A1 protein, rat; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme