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 2

Exogenous sFRP1 leads to FGR, trophoblast karyorrhexis, and decreased proliferation.

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Exogenous sFRP1 leads to FGR, trophoblast karyorrhexis, and decreased pr...
(A) Fetal weights in CD1 pregnant mice injected on E15 with an adenovirus expressing sFRP1 (n = 9 litters, 120 fetuses) as compared with those injected with control virus (n = 7 litters, 77 fetuses). Data are presented as a box plot (25th–75th percentile), with horizontal bars representing median values and whiskers representing minimum and maximum values (*P < 0.001 versus control virus treated animals by t test). (B) Placental weights of CD1 pregnant mice shown in A. Data are presented as a box plot (25th–75th percentile), with horizontal bars representing median values and whiskers representing minimum and maximum values. (C) Representative images illustrating increased spongiotrophoblast karyorrhexis in the placentas of the sFRP1 virus–treated mice (n = 3) compared with control mice (n = 3). The arrow indicates karyorrhexis in the junctional zone. D, decidua; JZ, junctional zone; SPT, spongiotrophoblast; L, labyrinth. Scale bar: 100 μm (left column); 20 μm (right column). (D) Representative histology sections of the murine placentas demonstrate reduced Ki67 immunostaining, a marker of proliferation, in the sFRP1 virus–treated animals (n = 3) compared with the control virus–treated animals (n = 3) at E19. Scale bar: 50 μm. (E) Quantification of Ki67 staining by ImageJ for the data in D is presented as mean ± SEM (*P < 0.05 versus control virus treated animals by t test).