Coumestrol induces oxidative stress and impairs migration and embryonic growth

in Reproduction
Authors:
Margeaux W Marbrey Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

Search for other papers by Margeaux W Marbrey in
Current site
Google Scholar
PubMed
Close
,
Elizabeth S Douglas Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

Search for other papers by Elizabeth S Douglas in
Current site
Google Scholar
PubMed
Close
,
Emma R Goodwin Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

Search for other papers by Emma R Goodwin in
Current site
Google Scholar
PubMed
Close
, and
Kathleen M Caron Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA

Search for other papers by Kathleen M Caron in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-7033-9232

Correspondence should be addressed to K M Caron; Email: kathleen_caron@med.unc.edu
Restricted access
Rent on DeepDyve

Sign up for journal news

In brief

Healthy development of the placenta is dependent on trophoblast cell migration and reduced oxidative stress presence. This article describes how a phytoestrogen found in spinach and soy causes impaired placental development during pregnancy.

Abstract

Although vegetarianism has grown in popularity, especially among pregnant women, the effects of phytoestrogens in placentation lack understanding. Factors such as cellular oxidative stress and hypoxia and external factors including cigarette smoke, phytoestrogens, and dietary supplements can regulate placental development. The isoflavone phytoestrogen coumestrol was identified in spinach and soy and was found to not cross the fetal–placental barrier. Since coumestrol could be a valuable supplement or potent toxin during pregnancy, we sought to examine its role in trophoblast cell function and placentation in murine pregnancy. After treating trophoblast cells (HTR8/SVneo) with coumestrol and performing an RNA microarray, we determined 3079 genes were significantly changed with the top differentially changed pathways related to the oxidative stress response, cell cycle regulation, cell migration, and angiogenesis. Upon treatment with coumestrol, trophoblast cells exhibited reduced migration and proliferation. Additionally, we observed increased reactive oxygen species accumulation with coumestrol administration. We then examined the role of coumestrol within an in vivo pregnancy by treating wildtype pregnant mice with coumestrol or vehicle from day 0 to 12.5 of gestation. Upon euthanasia, fetal and placental weights were significantly decreased in coumestrol-treated animals with the placenta exhibiting a proportional decrease with no obvious changes in morphology. Therefore, we conclude that coumestrol impairs trophoblast cell migration and proliferation, causes accumulation of reactive oxygen species, and reduces fetal and placental weights in murine pregnancy.

 

  • Collapse
  • Expand
  • Adams NR 1990 Permanent infertility in ewes exposed to plant oestrogens. Australian Veterinary Journal 67 197201. (https://doi.org/10.1111/j.1751-0813.1990.tb07758.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Allalou A & & Wahlby C 2009 BlobFinder, a tool for fluorescence microscopy image cytometry. Computer Methods and Programs in Biomedicine 94 5865. (https://doi.org/10.1016/j.cmpb.2008.08.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barzilai A, Rotman G & & Shiloh Y 2002 ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair (Amst) 1 325. (https://doi.org/10.1016/s1568-7864(0100007-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Berkane N, Liere P, Oudinet JP, Hertig A, Lefevre G, Pluchino N, Schumacher M & & Chabbert-Buffet N 2017 From pregnancy to preeclampsia: A key role for estrogens. Endocrine Reviews 38 123144. (https://doi.org/10.1210/er.2016-1065)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bonacasa B, Siow RC & & Mann GE 2011 Impact of dietary soy isoflavones in pregnancy on fetal programming of endothelial function in offspring. Microcirculation 18 270285. (https://doi.org/10.1111/j.1549-8719.2011.00088.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bukovsky A, Caudle MR, Cekanova M, Fernando RI, Wimalasena J, Foster JS, Henley DC & & Elder RF 2003 Placental expression of estrogen receptor beta and its hormone binding variant--comparison with estrogen receptor alpha and a role for estrogen receptors in asymmetric division and differentiation of estrogen-dependent cells. Reproductive Biology and Endocrinology: RB&E 1 36. (https://doi.org/10.1186/1477-7827-1-36)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chaiworapongsa T, Chaemsaithong P, Yeo L & & Romero R 2014 Pre-eclampsia part 1: current understanding of its pathophysiology. Nature Reviews. Nephrology 10 466480. (https://doi.org/10.1038/nrneph.2014.102)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chiarello DI, Abad C, Rojas D, Toledo F, Vazquez CM, Mate A, Sobrevia L & & Marin R 2020 Oxidative stress: normal pregnancy versus preeclampsia. Biochimica et Biophysica Acta. Molecular Basis of Disease 1866 165354. (https://doi.org/10.1016/j.bbadis.2018.12.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cindrova-Davies T, Fogarty NME, Jones CJP, Kingdom J & & Burton GJ 2018 Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas. Placenta 68 1522. (https://doi.org/10.1016/j.placenta.2018.06.307)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ebegboni VJ, Balahmar RM, Dickenson JM & & Sivasubramaniam SD 2019 The effects of flavonoids on human first trimester trophoblast spheroidal stem cell self-renewal, invasion and JNK/p38 MAPK activation: understanding the cytoprotective effects of these phytonutrients against oxidative stress. Biochemical Pharmacology 164 289298. (https://doi.org/10.1016/j.bcp.2019.04.023)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Elias EA & & Kincaid RL 1984 Fertility of female mice fed coumestrol and diethylstilbestrol. Journal of Environmental Science and Health. Part. B, Pesticides, Food Contaminants, and Agricultural Wastes 19 441451. (https://doi.org/10.1080/03601238409372442)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Elustondo PA, Hannigan GE, Caniggia I & & MacPhee DJ 2006 Integrin-linked kinase (ILK) is highly expressed in first trimester human chorionic villi and regulates migration of a human cytotrophoblast-derived cell line. Biology of Reproduction 74 959968. (https://doi.org/10.1095/biolreprod.105.050419)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Foster WG, Chan S, Platt L & & Hughes CL Jr 2002 Detection of phytoestrogens in samples of second trimester human amniotic fluid. Toxicology Letters 129 199205. (https://doi.org/10.1016/s0378-4274(0200018-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fujimoto J, Nakagawa Y, Toyoki H, Sakaguchi H, Sato E & & Tamaya T 2005 Estrogen-related receptor expression in placenta throughout gestation. Journal of Steroid Biochemistry and Molecular Biology 94 6769. (https://doi.org/10.1016/j.jsbmb.2004.12.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Geisert RD & & Spencer TE 2021 Mammalian placentation: A tribute to E.C. Amoroso's contributions to placenta development. Advances in Anatomy, Embryology, and Cell Biology 234 16. (https://doi.org/10.1007/978-3-030-77360-1_1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Giguere V 2002 To ERR in the estrogen pathway. Trends in Endocrinology and Metabolism 13 220225. (https://doi.org/10.1016/s1043-2760(0200592-1)

  • Gingrich J, Ticiani E & & Veiga-Lopez A 2020 Placenta disrupted: endocrine disrupting chemicals and pregnancy. Trends in Endocrinology and Metabolism 31 508524. (https://doi.org/10.1016/j.tem.2020.03.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hertig A, Liere P, Chabbert-Buffet N, Fort J, Pianos A, Eychenne B, Cambourg A, Schumacher M, Berkane N & Lefevre G et al.2010 Steroid profiling in preeclamptic women: evidence for aromatase deficiency. American Journal of Obstetrics and Gynecology 203 477.e1477.e9. (https://doi.org/10.1016/j.ajog.2010.06.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kirihata Y, Kawarabayashi T, Imanishi S, Sugimoto M & & Kume S 2008 Coumestrol decreases intestinal alkaline phosphatase activity in post-delivery mice but does not affect vitamin D receptor and calcium channels in post-delivery and neonatal mice. Journal of Reproduction and Development 54 3541. (https://doi.org/10.1262/jrd.19095)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kramer F, Jensen PS, Vinggaard AM, Larsen EH & & Breinholt VM 2003 Effect of in utero-administered coumestrol, equol, and organic selenium on biomarkers for phase 2 enzyme capacity and redox status. Nutrition and Cancer 46 7381. (https://doi.org/10.1207/S15327914NC4601_10)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lim W & & Song G 2016 Stimulatory effects of coumestrol on embryonic and fetal development through AKT and ERK1/2 MAPK signal transduction. Journal of Cellular Physiology 231 27332740. (https://doi.org/10.1002/jcp.25381)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lim W, Yang C, Jeong M, Bazer FW & & Song G 2017 Coumestrol induces mitochondrial dysfunction by stimulating ROS production and calcium ion influx into mitochondria in human placental choriocarcinoma cells. Molecular Human Reproduction 23 786802. (https://doi.org/10.1093/molehr/gax052)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu J, Mi S, Du L, Li X, Li P, Jia K, Zhao J, Zhang H, Zhao W & & Gao Y 2018 The associations between plasma phytoestrogens concentration and metabolic syndrome risks in Chinese population. PLoS One 13 e0194639. (https://doi.org/10.1371/journal.pone.0194639)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lowensohn RI, Stadler DD & & Naze C 2016 Current concepts of maternal nutrition. Obstetrical and Gynecological Survey 71 413426. (https://doi.org/10.1097/OGX.0000000000000329)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Luo J, Sladek R, Bader JA, Matthyssen A, Rossant J & & Giguere V 1997 Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. Nature 388 778782. (https://doi.org/10.1038/42022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mann GE, Bonacasa B, Ishii T & & Siow RC 2009 Targeting the redox sensitive Nrf2-Keap1 defense pathway in cardiovascular disease: protection afforded by dietary isoflavones. Current Opinion in Pharmacology 9 139145. (https://doi.org/10.1016/j.coph.2008.12.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McFarlane L, Truong V, Palmer JS & & Wilhelm D 2013 Novel PCR assay for determining the genetic sex of mice. Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation 7 207211. (https://doi.org/10.1159/000348677)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meakin AS, Cuffe JSM, Darby JRT, Morrison JL & & Clifton VL 2021 Let's talk about placental sex, baby: understanding mechanisms that drive female- and male-specific fetal growth and developmental outcomes. International Journal of Molecular Sciences 22. (https://doi.org/10.3390/ijms22126386)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Messina M 2010 A brief historical overview of the past two decades of soy and isoflavone research. Journal of Nutrition 140 1350S1354S. (https://doi.org/10.3945/jn.109.118315)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miyake Y, Tanaka K, Okubo H, Sasaki S, Tokinobu A & & Arakawa M 2021 Maternal consumption of soy and isoflavones during pregnancy and risk of childhood behavioural problems: the Kyushu Okinawa Maternal and Child Health Study. International Journal of Food Sciences and Nutrition 72 11181127. (https://doi.org/10.1080/09637486.2021.1904844)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pinheiro D & & Bellaiotache Y 2018 Mechanical force-driven adherens junction remodeling and epithelial dynamics. Developmental Cell 47 391. (https://doi.org/10.1016/j.devcel.2018.10.021)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pringle KG, Kind KL, Sferruzzi-Perri AN, Thompson JG & & Roberts CT 2010 Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy. Human Reproduction Update 16 415431. (https://doi.org/10.1093/humupd/dmp046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schoenaker DA, Soedamah-Muthu SS & & Mishra GD 2014 The association between dietary factors and gestational hypertension and pre-eclampsia: a systematic review and meta-analysis of observational studies. BMC Medicine 12 157. (https://doi.org/10.1186/s12916-014-0157-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stopper H, Schmitt E & & Kobras K 2005 Genotoxicity of phytoestrogens. Mutation Research 574 139155. (https://doi.org/10.1016/j.mrfmmm.2005.01.029)

  • Todaka E, Sakurai K, Fukata H, Miyagawa H, Uzuki M, Omori M, Osada H, Ikezuki Y, Tsutsumi O & Iguchi T et al.2005 Fetal exposure to phytoestrogens--the difference in phytoestrogen status between mother and fetus. Environmental Research 99 195203. (https://doi.org/10.1016/j.envres.2004.11.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu F, Tian FJ & & Lin Y 2015 Oxidative stress in placenta: health and diseases. BioMed Research International 2015 293271. (https://doi.org/10.1155/2015/293271)

  • Xiao K, Liu C, Tu Z, Xu Q, Chen S, Zhang Y, Wang X, Zhang J, Hu CA & & Liu Y 2020 Activation of the NF-kappaB and MAPK signaling pathways contributes to the inflammatory responses, but not cell injury, in IPEC-1 cells challenged with hydrogen peroxide. Oxidative Medicine and Cellular Longevity 2020 5803639. (https://doi.org/10.1155/2020/5803639)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zamora-Ros R, Knaze V, Lujan-Barroso L, Kuhnle GG, Mulligan AA, Touillaud M, Slimani N, Romieu I, Powell N & Tumino R et al.2012 Dietary intakes and food sources of phytoestrogens in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort. European Journal of Clinical Nutrition 66 932941. (https://doi.org/10.1038/ejcn.2012.36)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zierau O, Kolba S, Olff S, Vollmer G & & Diel P 2006 Analysis of the promoter-specific estrogenic potency of the phytoestrogens genistein, daidzein and coumestrol. Planta Medica 72 184186. (https://doi.org/10.1055/s-2005-873182)

    • PubMed
    • Search Google Scholar
    • Export Citation