title: Excess placental secreted frizzled-related protein 1 in maternal smokers impairs fetal growth.
abstract: Maternal cigarette smoking during pregnancy remains one of the most common and preventable causes of fetal growth restriction (FGR), a condition in which a fetus is unable to achieve its genetically determined potential size. Even though epidemiologic evidence clearly links maternal cigarette smoking with FGR, insight into the molecular mechanisms of cigarette smoke-induced FGR is lacking. Here, we performed transcriptional profiling of placentas obtained from smoking mothers who delivered growth-restricted infants and identified secreted frizzled-related protein 1 (sFRP1), an extracellular antagonist of endogenous WNT signaling, as a candidate molecule. sFRP1 mRNA and protein levels were markedly upregulated (~10-fold) in placentas from smoking mothers compared with those from nonsmokers. In pregnant mice, adenovirus-mediated overexpression of sFRP1 led to FGR, increased karyorrhexis in the junctional zone, and decreased proliferation of labyrinthine trophoblasts. Consistent with our hypothesis that placental WNT signaling is suppressed in maternal smokers, we found that exposure to carbon monoxide analogs led to reduced WNT signaling, increased SFRP1 mRNA expression, and decreased cellular proliferation in a trophoblast cell line. Moreover, administration of carbon monoxide analogs to pregnant mice in late gestation led to FGR. In summary, our results indicate that the increased placental expression of sFRP1 seen in smokers impairs fetal growth by inhibiting WNT signaling and trophoblast proliferation.
authors.forename: Alice
authors.initials: A
authors.lastname: Wang
authors.forename: Zsuzsanna K
authors.initials: ZK
authors.lastname: Zsengellér
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Hecht
authors.forename: Roberto
authors.initials: R
authors.lastname: Buccafusca
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Burke
authors.forename: Augustine
authors.initials: A
authors.lastname: Rajakumar
authors.forename: Emily
authors.initials: E
authors.lastname: Weingart
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.forename: Saira
authors.initials: S
authors.lastname: Salahuddin
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002248:Carbon Monoxide / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors / Q000235:genetics; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008431:Maternal-Fetal Exchange; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects* / Q000097:blood / Q000503:physiopathology; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000166:cytology; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D002248:Carbon Monoxide; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins