Aberrant effect of genistein on placenta development expressed through alteration in transforming growth factor-β1 and alkaline phosphatase across the maternal serum, the placenta and the amniotic fluid

Document Type: Original Article

Authors

1 Department of Physiology, Faculty of Basic Medical Sciences, University of Lagos, Nigeria

2 Department of Biochemistry, Faculty of Basic Medical Sciences, University of Lagos, Nigeria

10.22038/ijbms.2020.42493.10022

Abstract

Objective(s): The mechanism via which genistein, the major isoflavone content of soya, adversely influenced placenta and fetal development was evaluated in pregnant laboratory rats.
Materials and Methods: There were control, 2 mg/kg and 4 mg/kg genistein groups of rats with five sub-groups based on gestation termination day. At the end of the experiment, animals were sacrificed by CO2 and cervical dislocation, while plasma and serum were processed and stored. The abdomen was opened and the amniotic fluid was siphoned from the uterine sacs, processed and stored. The embryonic implants were excised, the placenta was separated from the fetus and weighed separately. Placenta homogenate was prepared from the harvested placenta, while the rest were processed for histological studies. Transforming growth factor (TGf-β1) and alkaline phosphatase (ALP) were assayed for in all samples. A significant decrease in the placenta and fetal weights, and a significant decrease in serum and placenta homogenate ALP levels were recorded in genistein groups.
Results: There was a reduction in the Trophoblast giant cells population (TGCs). TGCs zone depth, perimeter, and an increase in the placenta and amniotic fluid’s TGf-β1 in all genistein groups at GD-13 towards term, and GD-18 and GD-20, respectively. Maternal plasma TGf-β1 was increased in 2 mg group early in pregnancy while its level significantly decreased in both 2 mg and 4 mg genistein groups at mid-gestation towards GD-19.
Conclusion: Genistein aberrant effect on fetal development was via its adverse effect on TGCs proliferation and TGf-β1 activities in the placenta tissue.

Keywords


1. Hu D, Cross JC. Development and function of trophoblast giant cells in the rodent placenta. Int J Dev Biol 2010; 54:341-354.
2. Cline JM, Dixon D, Ernerudh J, Faas MM, Hner CG, Ger JH, et al. The placenta in toxicology. Part-III: Pathologic assessment of the placenta. Toxicol Pathol 2014; 42:339-344.
3. Simmons DG, Fortier AL, Cross JC. Diverse subtypes and developmental origins of trophoblast giant cells in the mouse placenta. Dev Biol 2007; 304:567-578.
4. Forbes K, Westwood M. Maternal growth factor regulation of human placental development and fetal growth. J Endocrinol 2010; 207:1-16.
5. DeFalco S. The discovery of placenta growth factor and its biological activity. Exp Mol Med 2012; 44:1-9.
6. Muy-Rivera M, Sanchez SE, Vadachkoria S, Qiu C, Bazul V, Williams MA. Transforming growth factor-1 (TGf-β1) in plasma is associated with preeclampsia risk in Peruvian women with systemic inflammation. Am J Hypert 2004; 17:334-338.
7. Li X, Shen L, Tan H. Polymorphisms and plasma level of transforming growth factor- β1 and risk for preeclampsia: a systematic review. PLoS ONE 2014; 9:97230.
8. Lala PK, Hamilton GS. Growth factors, proteases and protease inhibitors in the maternal fetal dialogue. Placenta 1996; 17:545-555.
9. Caniggia I, Grisaru-Gravnosky S, Kuliszewsky M, Post M, Lye SJ. Inhibition of TGf-β3 restores the invasive capability of extravillous trophoblasts in preeclamptic pregnancies. J Clin Invest 1999; 103:1641-1650.
10. Wojcicka-Bentyn J, Czajkowski K, Sienko J, Grymowicz M, Bros M. Extremely elevated activity of serum alkaline phosphatase in gestational diabetes: a case report. Am J Obstet Gynecol 2004; 190:566-567.
11. Saraç F, Saygılı F. Causes of high bone alkaline phosphatase. J Biotech Biotech Equip 2007; 21:194-197.
12. Ferianec V, Linhartova L. Extreme elevation of placental alkaline phosphatase as a marker of preterm delivery, placental insufficiency and low birth weight. Neuro Endocrinol Lett 2011; 32:154-157.
13. Chaparro A, Gaedechens D, Ramirez V, Zuniga E, Kusanovic JP, Inostroza C, et al. Placental biomarkers and angiogenic factors in oral fluids of patients with preeclampsia. Prenatal Diagnosis 2016; 36:476-482.
14. Kalaiselvan V, Kalaivani M, Vijayakumar A, Sureshkumar K, Venkateskumar K. Current knowledge and future direction of research on soy isoflavones as a therapeutic agents. Pharmacogn Rev 2010; 4:111-117.
15. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987; 262:5592-5595. 16. Markovits j, Linassier C, Fosse P, Couprie J, Pierre J, Jacquemin-Sablon A, et al. Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res 1989; 49:5111-5117.
17. Constantinou A, Kiguchi K, Huberman E. Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. Cancer Res 1990; 50:2618-2624.
18. Yanagihara K, Ito A, Toge T, Numoto M. Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res 1993; 53:5815-5821.
19. McCabe MJ, Orrenius S. Genistein induces apoptosis in immature human thymocytes by inhibiting topoisomerase-II. Biochem Biophys Res Commun 1993; 194:944-950.
20. Zhang Z, Wang CZ, Du G, Qi L, Calway T, He T, et al. Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int J Oncol 2013; 43:289-296.
21. Levy JR, Faber KA, Ayyash L, Hughes CLJ. The effect of prenatal exposure to the phytoestrogen genistein on sexual differentiation in rats. Proc Soc Exp Biol Med 1995; 208:60-66.
22. Awobajo FO, Nandedkar TD, Balasinor NH. Genistein alters oestrous cyclicity, oocyte fertilization and implantation process in rats. Niger Q J Hosp Med 2013; 23:188-193.
23. Awobajo FO, Onokpite BO, Ali YM, Babaleye TA, Uzor PO, Tijani KO. Genistein precipitated hypothyroidism, altered leptin and c-reactive protein synthesis in pregnant rats. Niger J Physiol Sci 2015; 30:79-85.
24. Awobajo FO, Morakinyo AO, Samuel TA, Oyelowo OT, Ogunsola BO, Onyekwele PU, et al. Dynamics of inflammatory reaction and oxidative stress across maternal serum, placenta and amniotic fluid in laboratory rats and the role played by genistein aglycone. J Basic Clin Physiol Pharmacol 2019; 30:37-45.
25. Murdoch RN, Kay DJ, Cross M. Activity and Subcellular Distribution of Mouse Uterine Alkaline Phosphatase During Pregnancy and Pseudopregnancy. J Reprod Fert 1978; 54:293-300.
26. National Research Council (NRC). Division of earth and Life Studies. Institute for Laboratory Animal Research, Committee: guide for the care and use of laboratory animals, 8th edition. Washington, D.C.: National Academy Press. 1996;11-124.
27. Su RW, Fazleabas AT. Implantation and establishment of pregnancy in human and nonhuman primates. Adv Anat Embryol Cell Biol 2015; 216:189-213.
28. John R, Hemberger M. A placenta for life. Reprod BioMed 2012; 25:5-11.
29. Brett KE, Ferraro ZM, Yockell-Lelievre J, Gruslin A, Adamo KB. Maternal–fetal nutrient transport in pregnancy pathologies: the role of the placenta. Int J Mol Sci 2014; 15:16153-16185.
30. Chan WH, Hsiang-yu LU, Nion-heng S. Effects of genistein on mouse blastocysts. Acta Pharmacol 2007; 27:238-245.
31. Okesina AB, Donaldson D, Lascelles PT, Morris P. Effect of gestational age on levels of serum alkaline phosphatase isoenzymes in healthy pregnant women. Int J Gynaecol Obstet 1995; 48:25-29.
32. Best RG, Meyer RE, Shipley CF. Maternal serum placental alkaline phosphatase as a marker for low birth weight: results of a pilot study. South Med J 1991; 84:740-742.
33. Vergote IB, Abeler VM, Bormer OP, Stigbrand T, Trope C, Nustad K. CA125 and placental alkaline phosphatase as serum tumor markers in epithelial ovarian carcinoma. Tumor Biol 1992; 13:168-174.
34. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch 2010; 77:4-12.
35. Nozawa S, Fishman WH. Heat-stable Alkaline Phosphatase: Chemistry And Biology. In: Grudzinskas JG, Teisner B, Seppala M, eds. Pregnancy proteins, biology, chemistry, clinical application. Australia: Academic. 1982; 99:121-153.
36. Cross JC, Hemberger M, Lu Y, Nozaki T, Whiteley K, Masutani M, et al. Trophoblast Functions, Angiogenesis and Remodelling of the Maternal Vasculature in the Placenta. Mol Cell Endocrinol 2002; 187:207-212.
37. Boronkai A, Than NG, Magenheim R, Bellyei S, Szigeti A, Deres P, et al. Extremely high maternal alkaline phosphatase serum concentration with syncytiotrophoblastic origin. J Clin Pathol 2005; 58:72-76.
38. Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy; the role of the immune system at the implantation site. Ann NY Acad Sc 2011; 1221:80-87.
39. Han G, Li F, Singh TP, Wolf P, Wang XJ. The pro-inflammatory role of TGFβ1: a paradox. Int J Biol Sci 2012; 8:228-235.
40. Wahl SM, Hunt DA, Wong HL, Dougherty S, McCartney-Francis N, Wahl LM, et al. Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation. J Immunol 1988; 140:3026-3032.
41. Huang SS, Huang JS. TGF-beta control of cell proliferation. J Cell Biochem 2005; 15:447-462.
42. Morito K, Hirose T, Kinjo J, Hirakawa T, Okawa M, Nohara T, et al. Interaction of phytoestrogens with estrogen receptors alpha and beta. Biol Pharm Bull 2001; 24:351-356.
43. Xu J, Sivasubramaniyam T, Yinon Y, Tagliaferro A, Ray J, Nevo O, et al. Aberrant TGF-β signaling contributes to altered trophoblast differentiation in preeclampsia. Endocrinology 2016; 157:883-899.