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Sci Transl Med. 2015 May 20;7(288):288ra80. doi: 10.1126/scitranslmed.aaa4097.

Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model.

Author information

1
MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.
2
Edinburgh Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh, EH9 1LF, Scotland, UK.
3
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.
4
University Department of Growth and Reproduction, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
#
Contributed equally

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.

PMID:
25995226
PMCID:
PMC5044981
DOI:
10.1126/scitranslmed.aaa4097
[Indexed for MEDLINE]
Free PMC Article

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