Involvement of mTOR, JNK and PI3K in the negative effect of ethanol and metformin on the human first-trimester extravillous trophoblast HTR-8/SVneo cell line

Our aim was to investigate the effect of two xenobiotics to which pregnant woman may be exposed, the drug of abuse ethanol (EtOH) (and its metabolite acetaldehyde (ACA)) and the therapeutic agent metformin (METF), on placentation-related processes in an extravillous trophoblastic (EVTs) cell line (HTR-8/SVneo cells). EtOH, ACA and METF (24 h) significantly reduced cell proliferation rates, culture growth, viability and migratory capacity of HTR-8/SVneo cells. Moreover, both EtOH (100 mu M) and METF (1 mM) increased the apoptosis index and inhibited H-3-deoxy-D-glucose (H-3-DG) and H-3-folic acid (H-3-FA) uptake. mTOR, JNK and PI3K intracellular signaling pathways were involved in the effect of EtOH upon H-3-FA uptake and in the effect of METF upon cell viability, and mTOR and JNK in the effect of EtOH upon cell viability and H-3-DG uptake. We show that EtOH and METF have a detrimental effect in placentation-related processes of HTR-8/SVneo cells. Moreover, mTOR, JNK and PI3K appear to mediate some of these negative effects.