Toxicological effects of the different substances in tobacco smoke on human embryonic development by a systems chemo-biology approach

PLoS One. 2013 Apr 29;8(4):e61743. doi: 10.1371/journal.pone.0061743. Print 2013.


The physiological and molecular effects of tobacco smoke in adult humans and the development of cancer have been well described. In contrast, how tobacco smoke affects embryonic development remains poorly understood. Morphological studies of the fetuses of smoking pregnant women have shown various physical deformities induced by constant fetal exposure to tobacco components, especially nicotine. In addition, nicotine exposure decreases fetal body weight and bone/cartilage growth in addition to decreasing cranial diameter and tibia length. Unfortunately, the molecular pathways leading to these morphological anomalies are not completely understood. In this study, we applied interactome data mining tools and small compound interaction networks to elucidate possible molecular pathways associated with the effects of tobacco smoke components during embryonic development in pregnant female smokers. Our analysis showed a relationship between nicotine and 50 additional harmful substances involved in a variety of biological process that can cause abnormal proliferation, impaired cell differentiation, and increased oxidative stress. We also describe how nicotine can negatively affect retinoic acid signaling and cell differentiation through inhibition of retinoic acid receptors. In addition, nicotine causes a stress reaction and/or a pro-inflammatory response that inhibits the agonistic action of retinoic acid. Moreover, we show that the effect of cigarette smoke on the developing fetus could represent systemic and aggressive impacts in the short term, causing malformations during certain stages of development. Our work provides the first approach describing how different tobacco constituents affect a broad range of biological process in human embryonic development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone and Bones / cytology
  • Cell Communication / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cluster Analysis
  • Embryonic Development / drug effects*
  • Female
  • Fetus / cytology
  • Fetus / drug effects
  • Fetus / embryology
  • Fetus / metabolism
  • Humans
  • Nicotine / toxicity
  • Oxidation-Reduction / drug effects
  • Pregnancy
  • Prostaglandins / metabolism
  • Protein Interaction Maps / drug effects
  • Signal Transduction / drug effects
  • Smoke / adverse effects*
  • Smoke / analysis*
  • Systems Biology / methods*
  • Tobacco / chemistry*
  • Toxicology / methods*
  • Tretinoin / metabolism


  • Prostaglandins
  • Smoke
  • Tretinoin
  • Nicotine

Grant support

This work was supported by research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Grant Number 474117/2010-3), the Programa Institutos Nacionais de Ciência e Tecnologia (INCT de Processos Redox em Biomedicina-REDOXOMA; Grant Number 573530/2008-4;, Fundação de Amparo a Pesquisa do Rio Grande do Sul FAPERGS (PRONEM Grant Number 11/2072-2; and CAPES (Cordenação de Aperfeiçoamento de Pessoal do Ensino Superior; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.