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Maternal smoking affects human fetal X-inactivation.

Sanam Zeib Khan1, Linn Salto Mamsen2, Erik Ernst3

  • 1Department of Cellular and Molecular Medicine, Faculty of Health Sciences, Panum Institute, University of Copenhagen, Blegdamsvej 3B, Copenhagen DK-2200, Denmark.

Reproductive Toxicology (Elmsford, N.Y.)
|July 24, 2025
PubMed
Summary

Maternal smoking during pregnancy may delay fetal X-chromosome inactivation. This process, essential for female development, appears to involve a larger pool of primordial cells in fetuses exposed to smoking.

Keywords:
Delayed human X-inactivation timingPrimordial cell pool, HUMARA assaySmoking during pregnancy

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Area of Science:

  • Genetics
  • Developmental Biology
  • Reproductive Health

Background:

  • X-chromosome inactivation (XI) is a crucial process in female mammals, typically occurring randomly before implantation.
  • Deviations from random XI, known as skewed inactivation, can arise from factors affecting the limited primordial cell pool size.
  • Maternal smoking is linked to growth inhibition and reduced fetal gonadal cell numbers, potentially influencing XI.

Purpose of the Study:

  • To investigate the impact of maternal smoking during pregnancy on fetal X-chromosome inactivation patterns.
  • To determine if smoking affects the primordial cell pool size, which influences the randomness of X-inactivation.
  • To analyze X-inactivation ratios (XI-ratios) in fetal tissues from smoking and non-smoking mothers.

Main Methods:

  • Analysis of X-inactivation ratios (XI-ratios) using androgen receptor gene (AR) CAG-repeats in fetal tissues.
  • Comparison of XI-ratios between fetuses exposed to maternal smoking (n=8) and non-smoking (n=10) pregnancies.
  • Calculation of primordial pool size from the variance of XI-ratios.

Main Results:

  • Tighter distribution of XI-ratios observed in fetuses from smoking mothers, indicating a potentially larger primordial cell pool.
  • More skewed X-inactivation (>=80%) and higher mean XI-ratio found in fetuses from non-smoking mothers.
  • Findings suggest that maternal smoking may lead to a delay in fetal X-inactivation.

Conclusions:

  • Maternal smoking during pregnancy appears to influence fetal X-chromosome inactivation.
  • A larger primordial cell pool in smoking-exposed fetuses may result in delayed X-inactivation.
  • This study provides evidence supporting the hypothesis that smoking affects early developmental processes influencing X-inactivation timing.