Exploring the mechanisms of ED and cytotoxicity of paracetamol...

Exploring the mechanisms of endocrine disruption and cytotoxicity of paracetamol in the human fetal ovary ex vivo using transcriptomics

Lecante L.L.a, b, Toupin M.b, Desdoits-Lethimonier C. b, Lesné L. b, Lavoué V. c, Fowler P.A. a,, Chalmel F. b, Mazaud-Guittot S. b *

a Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Aberdeen, United Kingdom

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

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

Experimental and animal studies suggest that paracetamol, a painkiller commonly used by pregnant women (1), may have harmful effects on ovarian germ cells forming during fetal development (2, 3). We have previously shown that paracetamol can alter human fetal ovarian hormone production, although the mechanisms of endocrine disruption remain unclear. While high concentrations of paracetamol are cytotoxic to many adult organs, the mechanisms and threshold concentrations for cytotoxicity in the human fetal ovary are unknown.

The aim of this study was to identify the mechanisms of endocrine disruption and cytotoxicity of paracetamol in human fetal ovaries. To identify short-term effects of paracetamol, we used our validated human fetal ovary culture model3 to establish the metabolic and transcriptomic signatures of exposure to both therapeutic and toxic concentrations of paracetamol for 7 days.

Differential gene expression analysis revealed that one cluster was particularly enriched in markers of proliferating germ cells that were down-regulated, which is consistent with the previously identified mild depletion of oogonia following paracetamol exposure. Endocrine disruption, in the form of decreased steroid production, was associated with decreased expression of genes encoding enzymes of the cholesterol de novo synthesis pathway, and of the final enzyme in estradiol synthesis (CYP19A1), even at low paracetamol concentrations. Dysregulated genes included those involved in DNA damage detection and repair, and cell cycle regulation. This was consistent with a dramatic increase in DNA breakdown at toxic concentrations. Most of these genes are dysregulated at toxic concentrations, but a subset is also deregulated at sub-toxic concentrations. The overall analysis suggests that resistance to stress indirectly affect endocrine function. Since dysregulation of genes linked with DNA repair occurs at sub-toxic concentrations close to the maximum plasma concentration after 7 days of exposure to paracetamol, the precautionary medical usage recommendations must remain in force for pregnant women.

Références :

1 Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesné L, Serrano T, Main K, and Jégou B. Use of Paracetamol and NSAIDs: prevalence, biomonitoring, endocrine and reproductive effects. Nat Rev Endoc. Jul;12(7):381-93. 2016.

2 Arendrup FS, Mazaud-Guittot S, Jégou B, Kristensen DM. EDC IMPACT: Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development? Endocr Connect. 7(1):149-158. 2018.

3 Lecante LL, Leverrier-Penna S, Gicquel T, Giton F, Costet N, Desdoits-Lethimonier C, Lesné L, Fromenty B, Lavoué V, Rolland AD, Mazaud-Guittot S. Acetaminophen (APAP, Paracetamol) interferes with the first trimester human fetal ovary development in an ex vivo Model. J Clin Endocrinol Metab. ;107(6):1647-1661. 2022.

Mots Clés : human fetal ovary, paracetamol / acetaminophen, endocrine disruption, cytotoxicity, cell cycle.