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, floating 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 showed a significant reduction in the number of anchoring villi. Also, the number of Ki67-positive cytotrophoblasts was dramatically decreased, indicating that fewer cells were in S phase of the mitotic cycle. Together, these results suggested premature depletion of the cytotrophoblast stem cell population. To test this hypothesis, we exposed anchoring villi from nonsmokers to nicotine in vitro and analyzed the effects on cytotrophoblast passage through the cell cycle. Nicotine (0.23 to 6.0 microM) negatively affected the expression of a number of cell cycle regulators/markers and BrdU incorporation, without discernable effects on apoptosis. These results link abnormal placental development secondary to maternal cigarette smoking to a substantial decrease in the mitotic potential of cytotrophoblasts.