Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy

Am J Pathol. 2010 Nov;177(5):2509-15. doi: 10.2353/ajpath.2010.100243. Epub 2010 Sep 23.


Tubal ectopic pregnancy (EP) is the most common cause of maternal mortality in the first trimester of pregnancy; however, its etiology is uncertain. In EP, embryo retention within the Fallopian tube (FT) is thought to be due to impaired smooth muscle contractility (SMC) and alterations in the tubal microenvironment. Smoking is a major risk factor for EP. FTs from women with EP exhibit altered prokineticin receptor-1 (PROKR1) expression, the receptor for prokineticins (PROK). PROK1 is angiogenic, regulates SMC, and is involved in intrauterine implantation. We hypothesized that smoking predisposes women to EP by altering tubal PROKR1 expression. Sera/FT were collected at hysterectomy (n=21). Serum levels of the smoking metabolite, cotinine, were measured by enzyme-linked immunosorbent assay. FTs were analyzed by q-RT-PCR, immunohistochemistry, and Western blotting for expression of PROKR1 and the predicted cotinine receptor, nicotinic acetylcholine receptor α-7 (AChRα-7). FT explants (n=4) and oviductal epithelial cells (cell line OE-E6/E7) were treated with cotinine and an nAChRα-7 antagonist. PROKR1 transcription was higher in FTs from smokers (P<0.01). nAChRα-7 expression was demonstrated in FT epithelium. Cotinine treatment of FT explants and OE-E6/E7 cells increased PROKR1 expression (P<0.05), which was negated by cotreatment with nAChRα-7 antagonist. Smoking targets human FTs via nAChRα-7 to increase tubal PROKR1, leading to alterations in the tubal microenvironment that could predispose to EP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Bungarotoxins / pharmacology
  • Cell Line
  • Cotinine / blood
  • Cotinine / pharmacology*
  • Fallopian Tubes / anatomy & histology
  • Fallopian Tubes / drug effects*
  • Fallopian Tubes / metabolism*
  • Female
  • Humans
  • Indicators and Reagents
  • Middle Aged
  • Pregnancy
  • Pregnancy, Ectopic / etiology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Nicotinic / metabolism*
  • Smoking / adverse effects*
  • Tissue Culture Techniques
  • Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor


  • Bungarotoxins
  • Chrna7 protein, human
  • Indicators and Reagents
  • PROKR1 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
  • alpha7 Nicotinic Acetylcholine Receptor
  • Cotinine