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Research Article

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism

View ORCID ProfileDavid Møbjerg Kristensen, Christèle Desdoits-Lethimonier, Abigail L. Mackey, Marlene Danner Dalgaard, Federico De Masi, Cecilie Hurup Munkbøl, Bjarne Styrishave, Jean-Philippe Antignac, Bruno Le Bizec, Christian Platel, Anders Hay-Schmidt, Tina Kold Jensen, Laurianne Lesné, Séverine Mazaud-Guittot, View ORCID ProfileKarsten Kristiansen, Søren Brunak, Michael Kjaer, Anders Juul, and Bernard Jégou
PNAS January 23, 2018 115 (4) E715-E724; first published January 8, 2018; https://doi.org/10.1073/pnas.1715035115
David Møbjerg Kristensen
aDanish Headache Center, Department of Neurology, Rigshospitalet, University of Copenhagen, 1165 Copenhagen, Denmark;
bUniversité de Rennes I, Inserm, EHESP-School of Public Health, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000 Rennes, France;
cNovo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, 2200 Copenhagen, Denmark;
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  • ORCID record for David Møbjerg Kristensen
  • For correspondence: david.moebjerg.boslev.kristensen@regionh.dk bernard.jegou@inserm.fr
Christèle Desdoits-Lethimonier
bUniversité de Rennes I, Inserm, EHESP-School of Public Health, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000 Rennes, France;
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Abigail L. Mackey
dInstitute of Sports Medicine, Department of Orthopaedic Surgery M, Bispebjerg Hospital, 2400 Copenhagen NV, Denmark;
eCenter for Healthy Aging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark;
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Marlene Danner Dalgaard
fDTU Bio and Health Informatics, Technical University of Denmark, 2800 Kongens Lyngby, Denmark;
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Federico De Masi
fDTU Bio and Health Informatics, Technical University of Denmark, 2800 Kongens Lyngby, Denmark;
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Cecilie Hurup Munkbøl
gDepartment of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark;
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Bjarne Styrishave
gDepartment of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark;
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Jean-Philippe Antignac
hL'Université Nantes Angers Le Mans (LUNAM), Oniris, UMR 1329 INRA Laboratoire d'Etude des Résidus et Contaminants dans les Aliments (LABERCA), F-44307 Nantes, France;
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Bruno Le Bizec
hL'Université Nantes Angers Le Mans (LUNAM), Oniris, UMR 1329 INRA Laboratoire d'Etude des Résidus et Contaminants dans les Aliments (LABERCA), F-44307 Nantes, France;
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Christian Platel
iUnité de coordination hospitalière des prélèvements d’organes et de tissus, Centre Hospitalier Universitaire de Rennes, 35000 Rennes, France;
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Anders Hay-Schmidt
jDepartment of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark;
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Tina Kold Jensen
kDepartment of Environmental Medicine, University of Southern Denmark, 5000 Odense, Denmark;
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Laurianne Lesné
bUniversité de Rennes I, Inserm, EHESP-School of Public Health, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000 Rennes, France;
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Séverine Mazaud-Guittot
bUniversité de Rennes I, Inserm, EHESP-School of Public Health, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000 Rennes, France;
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Karsten Kristiansen
lDepartment of Biology, Faculty of Science, University of Copenhagen, 2100 Copenhagen, Denmark;
mInstitute of Metagenomics, BGI-Shenzhen, Shenzhen 518083, China;
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  • ORCID record for Karsten Kristiansen
Søren Brunak
aDanish Headache Center, Department of Neurology, Rigshospitalet, University of Copenhagen, 1165 Copenhagen, Denmark;
cNovo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, 2200 Copenhagen, Denmark;
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Michael Kjaer
dInstitute of Sports Medicine, Department of Orthopaedic Surgery M, Bispebjerg Hospital, 2400 Copenhagen NV, Denmark;
eCenter for Healthy Aging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark;
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Anders Juul
nDepartment of Growth and Reproduction, Rigshospitalet, University of Copenhagen, DK-2200 Copenhagen, Denmark;
oEDMaRC (International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health), Rigshospitalet, University of Copenhagen, DK-2200 Copenhagen, Denmark
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Bernard Jégou
bUniversité de Rennes I, Inserm, EHESP-School of Public Health, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, F-35000 Rennes, France;
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  • For correspondence: david.moebjerg.boslev.kristensen@regionh.dk bernard.jegou@inserm.fr
  1. Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 1, 2017 (received for review August 31, 2017)

This article has a Correction. Please see:

  • Correction for Kristensen et al., Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism - April 16, 2018
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    Fig. 1.

    Ibuprofen increases gonadotropins and decreases AMH in adult men. (A–D) Fold change in the Leydig cell–pituitary axis (A and C) and the Sertoli cell–pituitary axis (B and D) compared with baseline after 14 d (A and B) and at the end of the intervention after 44 d (C and D). Values are means ± SEM, and differences were analyzed with an unpaired Student’s t test. (E) Correlation between absolute ibuprofen levels in plasma (x axis) and fold change in LH levels compared with baseline levels (y axis) 14 d after intervention. The slope and P value were calculated with a Pearson product-moment coefficient correlation. AMH, anti-Müllerian hormone; Free T, free testosterone; Inh B, inhibin B; SHBG, sex hormone-binding protein; Total T, total testosterone. *P ≤ 0.05, **P ≤ 0.01.

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    Fig. 2.

    Ibuprofen inhibits Leydig cell hormone production in human testicular explants. (A) Dose effect of ibuprofen for 24 and 48 h on testosterone production by the adult human testis. Values are means ± SEM of five independent experiments from different donors. Dose responses were analyzed for significance with the Mann–Whitney U test. The slopes and P values of these results were calculated with Spearman correlation. (B) Effect of 10−5 and 10−4 M ibuprofen on the Δ4 and Δ5 steroidogenic pathways. Steroid precursors were measured by GC-MS/MS. Values are means ± SEM of three independent experiments from different donors. Dose effects were analyzed for significance with the Mann–Whitney U test. DHEA, dehydroepiandrosterone. (C) Effect of 10−5 and 10−4 M ibuprofen on the gene expression of steroidogenic enzymes after 48-h exposure. Values are means ± SEM of five independent experiments from different donors. Each bar represents the mean ± SEM of the fold change in target gene expression relative to the reference genes BZW1 and GUSB. Dose responses were analyzed for significance with the Mann–Whitney U test. (D) Dose effect of ibuprofen for 24 and 48 h on INSL3 production by the adult human testis. Values are means ± SEM of three independent experiments from different donors. Dose responses were analyzed for significance with the Mann–Whitney U test. (E) Specific Leydig cell hormone gene expression. Values are means ± SEM of five independent experiments from different donors. Each bar represents the mean ± SEM of the fold change in target gene expression relative to the reference genes BZW1 and GUSB. Dose responses were analyzed for significance with the Mann–Whitney U test. BZW1, basic leucine zipper and W2 domains 1; CYP11A1, cytochrome P450 family 11 subfamily A member 1; CYP17A1, cytochrome P450 family 17 subfamily A member 1; CYP19A1, cytochrome P450 family 19 subfamily A member 1; GUSB, β-glucuronidase; INSL3, insulin-like factor 3; HSD17B3, hydroxysteroid 17-β dehydrogenase 3; HSD3B2, hydroxy-δ-5-steroid dehydrogenase 3 β- and steroid δ-isomerase 2; LHCGR, luteinizing hormone/choriogonadotropin receptor; StAR, steroidogenic acute regulatory protein; TSPO: translocation protein. *P ≤ 0.05, **P ≤ 0.01.

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    Fig. 3.

    The steroid screen identifies ibuprofen as an inhibitor of steroidogenesis in the human NCI-H295R cell line. (A) Effects of ibuprofen (red trace; n = 9–18) and abiraterone (blue trace; n = 6–15) exposure on the relative steroidogenic hormone production in the dose ranges of 10−6–10−3 M and 3.15 × 10−11–3.15 × 10−6 M (x axis), respectively, in the human NCI-H295R cell line, according to OECD standards. The position of each graph corresponds to the position of that particular steroid hormone in steroidogenesis. Steroid concentrations (y axis; % of control) are depicted as mean ± SEM with key enzymes shown in blue boxes. For statistics see Table S1. (B–D) Quantitative RT-PCR screen of steroidogenic gene expression in NCI-H295R cells after 48 h of culture with 10−7–10−3 M ibuprofen. Values are means ± SEM of three independent experiments analyzed with one-way ANOVA followed by a post hoc Dunnett’s test. CYP11A1, cytochrome P450 family 11 subfamily A member 1; CYP17A1, cytochrome P450 family 17 subfamily A member 1; CYP19A1, cytochrome P450 family 19 subfamily A member 1; HSD17B3, hydroxysteroid 17-β dehydrogenase 3; HSD3B2, hydroxy-δ-5-steroid dehydrogenase 3 β- and steroid δ-isomerase 2; StAR, steroidogenic acute regulatory protein; TSPO, translocation protein. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.

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    Fig. 4.

    Ibuprofen affects Sertoli cell activity in human testicular explants. (A and B) Dose effect of ibuprofen on the production of inhibin B after 24 and 48 h (A) and anti-Müllerian hormone (AMH) after 48 h (B) by the adult human testis. Values are means ± SEM of three independent experiments from different donors. Slopes and P values of Spearman correlation are indicated. (C) Quantitative RT-PCR performed after 48 h of culture treated with 10−5 and 10−4 M ibuprofen for specific Sertoli cell gene expression. Values are means ± SEM of five independent experiments from different donors. Each bar represents the mean ± SEM of the fold change in target gene expression relative to the reference genes BZW1 and GUSB. Dose responses were analyzed for significance with the Mann–Whitney U test. AMH, anti-Müllerian hormone; BZW1, basic leucine zipper and W2 domains 1; FSHR, follicle-stimulating hormone receptor; GUSB, β-glucuronidase; INHBB, inhibin B subunit B; LAMA5, laminin subunit α5. *P ≤ 0.05, **P ≤ 0.01.

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    Fig. 5.

    Ibuprofen decreases gene expression in peritubular cells but does not affect germ cells or morphology in human testicular explants. (A and B) Quantitative RT-PCR performed after 48 h of culture treated with 10−5 and 10−4 M ibuprofen for gene expression in peritubular cells (A) and germ cells (B). Each bar represents the mean ± SEM of the fold change in target gene expression relative to the reference genes BZW1 and GUSB. Values are means ± SEM of five independent experiments from different donors. A Mann–Whitney U test was performed. (C) Number of apoptotic germ cells. Values are means ± SEM of caspase+ cells in three independent experiments from different donors. (D) Immunostaining of apoptotic germ cells in testis explants cultured for 48 h in the presence of DMSO (control) or 10−5 or 10−4 M ibuprofen. Each micrograph shows representative areas of ibuprofen-induced morphology compared with corresponding area. (Scale bars: 50 µm.) ACTA2, actin α2 smooth muscle aorta; ALPP, alkaline phosphatase, placental; BZW1, basic leucine zipper and W2 domains 1; GUSB, β-glucuronidase; KCNIP4, potassium voltage-gated channel interacting protein 4; MYH11, myosin heavy polypeptide 11, smooth muscle; PGK2, phosphoglycerate kinase 2; PRM2, protamine 2; THY1, Thy-1 cell-surface antigen. **P ≤ 0.01.

  • Fig. 6.
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    Fig. 6.

    Ibuprofen decreases PGE2 and PGD2 production and PTGS gene expression in human testicular explants. (A and B) Dose effect of ibuprofen exposure after 24 and 48 h on PGD2 (A) and PGE2 (B) production by adult human testicular explants. Values are means ± SEM of five independent experiments from different donors. Dose responses were analyzed for significance with the Mann–Whitney U test. Slopes and P values of Spearman correlation are indicated. (C) Quantitative RT-PCR was performed after 48 h of culture treated with 10−5 and 10−4 M ibuprofen. Each bar represents the mean ± SEM of the fold change in target gene expression relative to the reference genes BZW1 and GUSB. Values are means ± SEM of five independent experiments from different donors. Differences in gene expression were analyzed with a Mann–Whitney U test. BZW1, basic leucine zipper and W2 domains 1; GUSB, β-glucuronidase; PTGS, prostaglandin-endoperoxide synthase. *P ≤ 0.05, **P ≤ 0.01.

  • Fig. 7.
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    Fig. 7.

    Ibuprofen dose-dependently reduces prostaglandin levels and mRNA expression in human endocrine NCI-H295R cells. (A) Effects of ibuprofen on general prostaglandin production from NCI-H295R cells after 24 h. Values are means ± SEM of three independent experiments analyzed with one-way ANOVA followed by a post hoc Dunnett’s test. (B) Quantitative RT-PCR screen of steroidogenic and PTGS gene expression in NCI-H295R cells after 48 h of culture with 10−7–10−3 M ibuprofen. Values are means ± SEM of three independent experiments analyzed with one-way ANOVA followed by a post hoc Dunnett’s test. PTGS, prostaglandin-endoperoxide synthase. *P ≤ 0.05, **P ≤ 0.01.

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NSAID ibuprofen alters human testicular function
David Møbjerg Kristensen, Christèle Desdoits-Lethimonier, Abigail L. Mackey, Marlene Danner Dalgaard, Federico De Masi, Cecilie Hurup Munkbøl, Bjarne Styrishave, Jean-Philippe Antignac, Bruno Le Bizec, Christian Platel, Anders Hay-Schmidt, Tina Kold Jensen, Laurianne Lesné, Séverine Mazaud-Guittot, Karsten Kristiansen, Søren Brunak, Michael Kjaer, Anders Juul, Bernard Jégou
Proceedings of the National Academy of Sciences Jan 2018, 115 (4) E715-E724; DOI: 10.1073/pnas.1715035115

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NSAID ibuprofen alters human testicular function
David Møbjerg Kristensen, Christèle Desdoits-Lethimonier, Abigail L. Mackey, Marlene Danner Dalgaard, Federico De Masi, Cecilie Hurup Munkbøl, Bjarne Styrishave, Jean-Philippe Antignac, Bruno Le Bizec, Christian Platel, Anders Hay-Schmidt, Tina Kold Jensen, Laurianne Lesné, Séverine Mazaud-Guittot, Karsten Kristiansen, Søren Brunak, Michael Kjaer, Anders Juul, Bernard Jégou
Proceedings of the National Academy of Sciences Jan 2018, 115 (4) E715-E724; DOI: 10.1073/pnas.1715035115
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