Maternal smoking affects human fetal X-inactivation

Females inactivate one of their two X-chromosomes in each cell before implantation, at a time where any factor that affect the number of these primordial cells may lead to deviation from the usual random choice. Thus, non-random (skewed) X-inactivation may occur due to early stochastic effects in the limited primordial pool size. The primodial pool size can be calculated from the variance of the ratio between the unmethylated and methylated CAG-repeats within exon 1 of the androgen receptor gene (AR) corresponding to the active and inactive X-chromosome (X-inactivation (XI)-ratio), respectively. Since maternal smoking during pregnancy is associated with a general growth inhibition and a reduced number of fetal gonadal cells, we have tested the XI-ratios in tissues obtained from fetuses of smoking (n = 8) and non-smoking (n = 10) mothers in connection with legal termination of the pregnancy. A tighter distribution of XI-ratios was seen in tissues from fetuses in the smoking group. Combined with more skewed X-inactivation (>=80 %) and a higher mean XI-ratio in the fetal samples from pregnancies of non-smoking mothers, this support a larger pool of primordial cells in fetuses exposed to smoking, suggesting that smoking during pregnancy delays fetal X inactivation.