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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.<\/jats:p>","DOI":"10.1093\/toxsci\/kfad076","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T15:28:45Z","timestamp":1690558125000},"page":"169-183","source":"Crossref","is-referenced-by-count":11,"title":["Antiepileptic drugs are endocrine disruptors for the human fetal testis<i>ex vivo<\/i>"],"prefix":"10.1093","volume":"195","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3165-9986","authenticated-orcid":false,"given":"Laurianne","family":"Lesn\u00e9","sequence":"first","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christ\u00e8le","family":"Desdoits-Lethimonier","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Hug","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-4812","authenticated-orcid":false,"given":"Nathalie","family":"Costet","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9o","family":"Raffenne","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryne","family":"Toupin","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Evrard","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indusha","family":"Kugathas","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4682-2806","authenticated-orcid":false,"given":"Vincent","family":"Lavou\u00e9","sequence":"additional","affiliation":[{"name":"Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Chalmel","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"J\u00e9gou","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"},{"name":"EHESP\u2014School of Public Health , 35043 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9verine","family":"Mazaud-Guittot","sequence":"additional","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail)\u2014UMR_S 1085 , 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,28]]},"reference":[{"key":"2023092810512071700_kfad076-B1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13059-019-1671-x","article-title":"BRB-seq: Ultra-affordable high-throughput transcriptomics enabled by bulk RNA barcoding and sequencing","volume":"20","author":"Alpern","year":"2019","journal-title":"Genome Biol"},{"key":"2023092810512071700_kfad076-B2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.reprotox.2013.09.009","article-title":"Carbamazepine-exposure during gestation and lactation affects pubertal onset and spermatic parameters in male pubertal offspring","volume":"44","author":"Andretta","year":"2014","journal-title":"Reprod. 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