Excess placental secreted frizzled-related protein 1 in maternal smokers impairs fetal growth
Alice Wang, … , Saira Salahuddin, S. Ananth Karumanchi
Alice Wang, … , Saira Salahuddin, S. Ananth Karumanchi
Published September 28, 2015
Citation Information: J Clin Invest. 2015;125(11):4021-4025. https://doi.org/10.1172/JCI80457.
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Brief Report Reproductive biology

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

Alice Wang, Zsuzsanna K. Zsengellér, Jonathan L. Hecht, Roberto Buccafusca, Suzanne D. Burke, Augustine Rajakumar, Emily Weingart, Paul B. Yu, Saira Salahuddin, S. Ananth Karumanchi

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Figure 1

Elevated SFRP1 gene and protein expression in the placentas of smokers.

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Elevated SFRP1 gene and protein expression in the placentas of smokers. ...
(A) Relative quantification (RQ) of SFRP1 mRNA levels measured, as by qRT-PCR of placentas from smoking mothers (n = 7) and nonsmoking mothers (n = 14) (mean ± SEM, *P < 0.05 versus nonsmoking controls by t test). (B) Representative immunoblot of sFRP1 and β-actin protein expression in placental extracts obtained from nonsmoking and smoking mothers. (C) Quantification of immunoblots by densitometry of sFRP1 and β-actin protein expression in placental extracts obtained from nonsmoking (n = 8) and smoking (n = 9) mothers (mean ± SEM, *P < 0.001 versus nonsmoking controls by t test). (D–G) Representative images of human placental tissue sections with immunostaining for anti-sFRP1 from (D) a nonsmoker and (E) a smoker. Serial placental sections from a smoker with immunostaining (F) for anti-sFRP1 and (G) for anti-cytokeratin show localization of sFRP1 to the extravillous trophoblast. The boxed region in E is shown at high magnification in F and G. Five placentas from smokers and five placentas from nonsmokers were compared. Scale bar: 100 μm (D and E); 50 μm (F and G).