Simvastatin has deleterious effects on human first trimester placental explants.
BACKGROUND
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMG-CoA reductase), the rate-limiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolaemia. Animal models have provided evidence for the teratogenic effects of statins on pregnancy outcome. Thus statins are contraindicated during pregnancy. However, conflicting data are available from inadvertent use of statins in human pregnancy. Therefore we decided to explore the effects of simvastatin on the placenta in an in vitro human placental model.


METHODS
Human first trimester placental explants that were grown on matrigel were exposed to medium supplemented with simvastatin. Migration of extravillous trophoblast cells was assessed by visual observation. Proliferative and apoptotic events of the trophoblast cells were assesed by immunohistochemical examination using anti-Ki67 and anti-activated caspase-3 antibodies respectively. Hormone levels were measured.


RESULTS
Simvastatin sharply inhibited migration of extravillous trophoblast cells from the villi to the matrigel (P < 0.05). Moreover, simvastatin inhibited half of the proliferative events in the villi (P < 0.05) and increased apoptosis of cytotrophoblast cells compared to control. Moreover, simvastatin significantly decreased secretion of progesterone from the placental explants (P < 0.01).


CONCLUSIONS
Simvastatin adversely affects human first trimester trophoblast.
Kenis
I
I
Oncogenetic Laboratory, Department of Internal Medicine A, Sapir Medical Center, Kfar-Saba, Israel.
Tartakover-Matalon
S
S
Cherepnin
N
N
Drucker
L
L
Fishman
A
A
Pomeranz
M
M
Lishner
M
M
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D006937:Hypercholesterolemia / Q000188:drug therapy; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007797:Laminin / Q000494:pharmacology; D010920:Placenta / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D011374:Progesterone / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D019821:Simvastatin / Q000633:toxicity*; D013723:Teratogens; D013997:Time Factors; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism
D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019394:Ki-67 Antigen; D007797:Laminin; D011509:Proteoglycans; D013723:Teratogens; C059485:matrigel; D011374:Progesterone; D003094:Collagen; D019821:Simvastatin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases