Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy.
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.
Shaw
Julie L V
JL
Centre for Reproductive Biology, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, UK.
Oliver
Elizabeth
E
Lee
Kai-Fai
KF
Entrican
Gary
G
Jabbour
Henry N
HN
Critchley
Hilary O D
HO
Horne
Andrew W
AW
D000328:Adult; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002460:Cell Line; D003367:Cotinine / Q000097:blood / Q000494:pharmacology*; D005187:Fallopian Tubes / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D008875:Middle Aged; D011247:Pregnancy; D011271:Pregnancy, Ectopic / Q000209:etiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*; D046509:Tissue Culture Techniques; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579167:Chrna7 protein, human; D007202:Indicators and Reagents; C470837:PROKR1 protein, human; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D064569:alpha7 Nicotinic Acetylcholine Receptor; D003367:Cotinine