Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo - EHESP - École des hautes études en santé publique Access content directly
Journal Articles Toxicological Sciences Year : 2023

Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo

Laurianne Lesné
Elisa Hug
  • Function : Author
Nathalie Costet
Léo Raffenne
  • Function : Author
Maryne Toupin
  • Function : Author
Bertrand Evrard
  • Function : Author
Indusha Kugathas
  • Function : Author
Vincent Lavoué
Frédéric Chalmel
Séverine Mazaud-Guittot

Abstract

Valproic acid (VPA) has long been the most widely used antiepileptic drug (AED) for the treatment of epilepsy, bipolar psychiatric disorders, and migraine. However, long-term VPA treatment has several adverse effects on the male reproductive system notably on endocrine functions and/or spermatic parameters. In utero exposure of the fetus to VPA is well known to be associated with a higher risk of several congenital malformations including those of male reproductive organs. Subsequent generations of AEDs, such as carbamazepine (CARB) and lamotrigine (LAM), are considered safer and are currently recommended for women of child-bearing age with epilepsy. Because anomalies of the male genital tract mostly result from endocrine imbalance during fetal life, we hypothesized that AEDs could directly impair testis differentiation. We thus aimed at identifying and characterizing the effects of VPA, CARB, and LAM on the differentiation and function of the different testicular cell types, and at understanding the mechanisms underlying these effects. By using ex vivo culture of first-trimester human fetal testes, we show that VPA induces multiple endocrine disruptive effects, compared with the milder ones caused by CARB and LAM. AED also subtly altered the germ cell lineage in distinct manners. Transcriptomic analysis of VPA-induced alterations highlighted a very broad range of effects on the fetal testis. Overall, our results show that AEDs can behave as endocrine disruptors for the human fetal testis ex vivo. This is consistent with, and likely underlies, the VPA-induced male genital tract masculinization abnormalities observed in patients.
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Dates and versions

hal-04190597 , version 1 (29-08-2023)

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Laurianne Lesné, Christèle Desdoits-Lethimonier, Elisa Hug, Nathalie Costet, Léo Raffenne, et al.. Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicological Sciences, 2023, ⟨10.1093/toxsci/kfad076⟩. ⟨hal-04190597⟩
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