Homocysteine thiolactone induces apoptosis in cultured human trophoblasts: a mechanism for homocysteine-mediated placental dysfunction?

• Published in: American journal of obstetrics and gynecology Vol. 191; no. 2; pp. 563 - 571
• Main Authors: Kamudhamas, Atiwut, Pang, Liyi, Smith, Steven D., Sadovsky, Yoel, Nelson, D.Michael
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Mosby, Inc 01.08.2004; Elsevier
• Subjects: Antioxidants; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cells, Cultured; Female; Gynecology. Andrology. Obstetrics; Homocysteine - analogs & derivatives; Homocysteine - pharmacology; Homocysteine-thiolactone; Human trophoblasts; Humans; Medical sciences; Placenta; Placenta - cytology; Placenta Diseases - blood; Placenta Diseases - physiopathology; Pregnancy; Time Factors; Trophoblasts - physiology; Antioxidants; Human trophoblasts; Placenta; Homocysteine-thiolactone; Apoptosis; Human; Trophoblaste; Cell culture; Thiol; Fetal membrane; Gynecology; Obstetrics; Sulfur containing aminoacid; Pregnancy; Homocystein; Dysfunction; Homocysteine- thiolactone Apoptosis Human trophoblasts Antioxidants Placenta
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2004.01.037

Hyperhomocystinemia is a thrombophilic condition associated with placental dysfunction. We tested the hypothesis that homocysteine-thiolactone, a metabolite of homocysteine, induces apoptosis in cultured trophoblasts. Cytotrophoblasts from term human placentas were cultured for 72 hours or less in the presence or absence of 50 to 400 μmol/L homocysteine-thiolactone or 400 μmol/L cysteine (control), with or without vitamin C, vitamin E, folate, or N-acetylcysteine. Cell death was assessed by cellular adenosine triphosphate concentration, medium lactate dehydrogenase level, and immunocytochemical staining for the cleavage products of cytokeratin 18 and poly(adenosine diphosphate ribose) polymerase. Changes in expression of p53, Bcl-2, Bax, and Bak were quantified by Western immunoblotting. Homocysteine-thiolactone induced a concentration dependent increase in total cell death and death by apoptosis, compared with control. Vitamin C ameliorated apoptosis in cytotrophoblasts, whereas N-acetylcysteine mitigated cell death in syncytiotrophoblasts. Apoptosis in both phenotypes occurred with increased expression of p53 and Bak, but no change in Bcl-2 or Bax. Homocysteine-thiolactone enhances apoptosis in cultured human trophoblast, and the effect can be limited by antioxidants.