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

This article focuses on the direct effects of antiepileptic drugs (AEDs)—valproic acid (VPA), carbamazepine (CARB), and lamotrigine (LAM)—on the differentiation and endocrine function of human fetal testes using ex vivo culture of first-trimester human fetal testicular explants. The study demonstrates that VPA induces significant endocrine disruption, notably reducing testosterone and insulin-like 3 (INSL3) production by Leydig cells, along with alterations in gene expression related to steroidogenesis and germ cell markers, whereas CARB and LAM exhibit milder but still detectable effects. Sertoli cell function and germ cell gene expression were also subtly affected, with complex and age-dependent responses observed. Transcriptomic analysis revealed broad molecular changes induced by VPA, including disruption of peroxisome proliferator-activated receptor gamma (PPARG) signaling pathways, suggesting multiple mechanisms underlying its endocrine-disrupting effects. These findings support the classification of AEDs, particularly VPA, as endocrine disruptors in the human fetal testis and provide insight into potential mechanisms contributing to male reproductive tract malformations associated with in utero exposure.