Concordant in situ and in vitro data show that maternal cigarette smoking negatively regulates placental cytotrophoblast passage through the cell cycle

Maternal cigarette smoking is associated with fetal growth restriction and other pregnancy complications. To investigate possible mechanisms involving the placenta, we studied the morphology of first trimester chorionic villi from mothers who smoked. In mothers who smoked > 20 cigarettes/day, floati ng villi showed focal defects including an absence of cytotrophoblast stem cells and an abnormal thinning of the syncytium. Anchoring villi displayed a striking increase in the number of cytotrophoblast columns that failed to reach the uterus or degenerated in the intervillous space. Many samples sh owed a significant reduction in the number of anchoring villi. Also, the nu mber of Ki67-positive cytotrophoblasts was dramatically decreased, indicati ng that fewer cells were in S phase of the mitotic cycle. Together, these r esults suggested premature depletion of the cytotrophoblast stem cell popul ation. To test this hypothesis, we exposed anchoring villi from nonsmokers to nicotine in vitro and analyzed the effects on cytotrophoblast passage th rough the cell cycle. Nicotine (0.23 to 6.0 muM) negatively affected the ex pression of a number of cell cycle regulators/markers and BrdU incorporatio n, without discernable effects on apoptosis. These results link abnormal pl acental development secondary to maternal cigarette smoking to a substantia l decrease in the mitotic potential of cytotrophoblasts. (C) 2000 Elsevier Science Inc. All rights reserved.