Naslov
Valproate targets mammalian gastrulation impairing neural tissue differentiation and development of the placental source in vitro

Autori
Katušić-Bojanac, Ana ; Plazibat, Milvija ; Himelreich- Perić, Marta ; Eck-Raković, Katarina ; Krasić, Jure ; Sinčić, Nino ; Jurić-Lekić, Gordana ; Ježek, Davor ; Bulić-Jakuš, Floriana

Izvornik
International journal of molecular sciences (1422-0067) 23 (2022), 16; 8861, 19

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
valproate ; HDACi ; neural tissue ; ectoplacental cone ; embryo

Sažetak
The teratogenic activity of valproate (VPA), an antiepileptic and an inhibitor of histone deacetylase (HDACi), is dose-dependent in humans. Previous results showed that VPA impairs in vitro development and neural differentiation of the gastrulating embryo proper. We aimed to investigate the impact of a lower VPA dose in vitro and whether this effect is retained in transplants in vivo. Rat embryos proper (E9.5) and ectoplacental cones were separately cultivated at the air-liquid interface with or without 1 mM VPA. Embryos were additionally cultivated with HDACi Trichostatin A (TSA), while some cultures were syngeneically transplanted under the kidney capsule for 14 days. Embryos were subjected to routine histology, immunohistochemistry, Western blotting and pyrosequencing. The overall growth of VPA-treated embryos in vitro was significantly impaired. However, no differences in the apoptosis or proliferation index were found. Incidence of the neural tissue was lower in VPA-treated embryos than in controls. TSA also impaired growth and neural differentiation in vitro. VPA-treated embryos and their subsequent transplants expressed a marker of undifferentiated neural cells compared to controls where neural differentiation markers were expressed. VPA increased the acetylation of histones. Our results point to gastrulation as a sensitive period for neurodevelopmental impairment caused by VPA.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA