Endocrine and transcriptomic signatures of analgesics...

Endocrine and transcriptomic signatures of analgesics in the human fetal testis ex vivo

Lesné L. 1, Desdoits-Lethimonier C. 1, Toupin M. 1, Costet N. 1, Lavoué V. 2, Chalmel F. 1, Mazaud-Guittot S. 1*

1 Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France

2 Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France

Epidemiological studies and experimental evidence have suggested that commonly used analgesics, such as paracetamol and ibuprofen, may act as endocrine disruptors1, 2, 3, 4. However, women may also be exposed to other painkillers whose effects on the endocrine system remain unknown. Notably, the cytotoxicity of high doses of these compounds in multiple adult organs and cell types raises concerns regarding their potential reprotoxicity to the fetus and to developing reproductive organs during morphogenesis.

The aim of this study was to investigate and compare the endocrine-disrupting properties and cytotoxicity mechanisms of a subset of potential substitute painkillers that may be used by pregnant women, focusing on their effects on the human fetal testis.

Human fetal testes from first-trimester elective terminations were cultured and exposed to analgesics from the non-steroidal anti-inflammatory drugs (NSAID) family (fenoprofen, flurbiprofen, and naproxen) or to paracetamol. Hormone levels were quantified in the culture media, cell viability was assessed in situ, and transcriptomic signatures were determined by RNA sequencing.

Alterations in Leydigian and Sertolian hormone productions were observed at concentrations close to the maximum serum levels reported for these compounds in adults, pregnant women, and, when available, in the fetus. Comparative transcriptomic analyses did not reveal an endocrine disruption signature but identified comparable toxicity signatures among NSAIDs, which were distinct from that observed for paracetamol. In particular, we found that Leydig cells were highly sensitive to NSAIDs, whereas paracetamol deregulated genes involved in the cell cycle checkpoint and the stress response genes, especially in Sertoli cells.

The analgesics studied here did not show endocrine disrupting properties as reported for ibuprofen. However, drug-dependent mechanisms of toxicity were observed at concentrations close to the peak serum concentrations, suggesting that they should be used with caution during pregnancy, regardless of the stage.

Références :

1. Mazaud-Guittot S, Nicolas Nicolaz C, Desdoits-Lethimonier C, Coiffec I, Ben Maamar M, Balaguer P, Kristensen DM, et al. Paracetamol, Aspirin, and Indomethacin Induce Endocrine Disturbances in the Human Fetal Testis Capable of Interfering With Testicular Descent. The Journal of Clinical Endocrinology & Metabolism 98 (11): E1757‑67. 2013.

2. Van den Driesche S, Macdonald J, Anderson RA, Johnston ZC, Chetty T, Smith LB, McKinnell C, et al. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model. Science translational medicine 7 (288): 288ra80. 2015.

3. Ben Maamar M, Lesné L, Hennig K, Desdoits-Lethimonier C, Kilcoyne KR, Coiffec I, Rolland AD et al. Ibuprofen results in alterations of human fetal testis development. Scientific Reports 7 (mars). https://doi.org/10.1038/SREP44184. 2017.

4. Hurtado-Gonzalez P, Anderson RA, Macdonald J, van den Driesche S, Kilcoyne KR, Jørgensen A, McKinnell C, Macpherson S, Sharpe RM, et Mitchell RT. Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems. Environmental Health Perspectives 126 (4): 047006. https://doi.org/10.1289/EHP2307. 2018.

Mots Clés : analgesics, endocrine disruption, cytotoxicity, human fetal testis.