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Nifedipine Prevents Apoptosis of Alcohol‐Exposed First‐Trimester Trophoblast Cells
Author(s) -
Bolnick Alan D.,
Bolnick Jay M.,
KohanGhadr HamidReza,
Kilburn Brian A.,
Hertz Michael,
Dai Jing,
Drewlo Sascha,
Armant D. Randall
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13534
Subject(s) - nifedipine , tunel assay , trophoblast , apoptosis , intracellular , terminal deoxynucleotidyl transferase , diazoxide , extracellular , andrology , pharmacology , biology , placenta , chemistry , endocrinology , medicine , microbiology and biotechnology , fetus , biochemistry , calcium , pregnancy , genetics , insulin
Background Maternal alcohol abuse leading to fetal alcohol spectrum disorder ( FASD ) includes fetal growth restriction ( FGR ). Ethanol (EtOH) induces apoptosis of human placental trophoblast cells, possibly disrupting placentation and contributing to FGR in FASD . EtOH facilitates apoptosis in several embryonic tissues, including human trophoblasts, by raising intracellular Ca 2+ . We previously found that acute EtOH exposure increases trophoblast apoptosis due to signaling from both intracellular and extracellular Ca 2+ . Therefore, nifedipine, a Ca 2+ channel blocker that is commonly administered to treat preeclampsia and preterm labor, was evaluated for cytoprotective properties in trophoblast cells exposed to alcohol. Methods Human first‐trimester chorionic villous explants and the human trophoblast cell line HTR ‐8/ SV neo (HTR) were pretreated with 12.5 to 50 nM of the Ca 2+ channel blocker nifedipine for 1 hour before exposure to 50 mM EtOH for an additional hour. Intracellular Ca 2+ concentrations were monitored in real time by epifluorescence microscopy, using fluo‐4‐ AM . Apoptosis was assessed by t erminal deoxynucleotidyl transferase d U TP n ick e nd l abeling ( TUNEL ), accumulation of cytoplasmic cytochrome c , and cleavage rates of caspase 3 and caspase 9. Results The increase in intracellular Ca 2+ upon exposure to EtOH in both villous explants and HTR cells was completely blocked ( p < 0.05) when pretreated with nifedipine, accompanied by inhibition of EtOH‐induced release of cytochrome c , caspase activities, and TUNEL . Conclusions This study indicates that nifedipine can interrupt the apoptotic pathway downstream of EtOH exposure and could provide a novel strategy for future interventions in women with fetuses at risk for FASD .