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Biological Trace Element Research

, Volume 187, Issue 2, pp 442–451 | Cite as

Co-exposure to an Aryl Hydrocarbon Receptor Endogenous Ligand, 6-Formylindolo[3,2-b]carbazole (FICZ), and Cadmium Induces Cardiovascular Developmental Abnormalities in Mice

  • Mahmoud Omidi
  • Hossein Niknahad
  • Ali Noorafshan
  • Reza Fardid
  • Elham Nadimi
  • Samaneh Naderi
  • Azizollah Bakhtari
  • Afshin Mohammadi-BardboriEmail author
Article
  • 70 Downloads

Abstract

6-Formylindolo[3,2-b]carbazole (FICZ) is a signal substance and an endogenous activator of aryl hydrocarbon receptor (AHR). Cadmium (Cd) is an environmental pollutant that can activate both AHR and Wnt/β-catenin signaling pathways. We aimed to determine how dysregulated signaling through AHR-Wnt/β-catenin cross-talk can influence mice heart development. Mice fetuses were exposed to Cd alone or in combination with FICZ in gestation day (GD) 0. In GD18, fetuses were harvested and randomly divided into two parts for stereological and molecular studies. Stereological and tessellation results revealed that when fetuses were co-exposed with FICZ and Cd, abnormalities were synergistically raised. In the presence of FICZ, mRNA expression levels of Wnt/β-catenin target genes significantly enhanced, especially when animals co-treated with FICZ and Cd. Based on these findings, we propose that chemical pollutants can interfere with the normal function of AHR that has a physiological role in regulating Wnt/β-catenin during cardiogenesis.

Keywords

Aryl hydrocarbon receptor Wnt/β-catenin FICZ Cadmium Cardiogenesis 

Notes

Acknowledgments

The authors of this manuscript wish to express their appreciation to Shiraz University of Medical Sciences, Shiraz, Iran.

Funding

This work was supported by the Shiraz University of Medical Sciences grant for the accomplishment of the Ph.D. thesis of Mahmoud Omidi [grant number 94-7557].

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12011_2018_1391_MOESM1_ESM.jpg (2.1 mb)
Supplementary Fig. S1 Voronoi tessellation results. A micrograph of the cardiomyocytes and micro-vessels in fetal heart in the control (A) and (C), Cd (4.5 mg/kg) plus FICZ (100 μg/kg) (B) and (D) groups respectively (n = 5–6). After setting the scale, cardiomyocytes nuclei and capillaries center are marked and the polygons were superimposed on them using the ImageJ software. The threshold color changed to clear out the background with black area boundaries (E-H). The areas of the polygons are calculated using the ImageJ software. The microscopic slides have stained with H&E or Heidenhain’s Azan trichrome for cardiomyocytes and micro-vessels, respectively. Lower diagrams (I) and (J) shows the polygon distribution percentage classified into different categories according to their areas (μm2). Lower left and right diagrams present the cardiomyocytes (I) and micro-vessels (J) distribution, respectively. Upper left (E and F) and right (G and H) diagrams show the cardiomyocytes and capillary centers of the histologic sections in the control (A and C) and Cd (4.5 mg/kg) plus FICZ (100 μg/kg) groups (B and D), respectively. Each spot marked a cardiomyocyte or capillary and the geometric center of a polygon. Since the profile of the polygons was determined by the arrangement of the points, hence, the cardiomyocyte or capillary pattern is different between the groups. The altered pattern of cardiomyocyte or capillary led to change in intermyocytic or intercapillary distances followed by the variability of polygon areas in Cd (4.5 mg/kg) plus FICZ (100 μg/kg) group. (JPG 2099 kb)
12011_2018_1391_MOESM2_ESM.jpg (1.9 mb)
Supplementary Fig. S2 Delaunay tessellation results. A micrograph of the cardiomyocytes and micro-vessels in fetal heart in the control (A) and (C), Cd (4.5 mg/kg) plus FICZ (100 μg/kg) (B) and (D) groups respectively (n = 5–6). After setting the scale, cardiomyocytes nuclei and capillaries center are marked and the triangles were superimposed on them using the ImageJ software. Each triangle represents the distance between a point and nearest adjacent points were marked by the software. The distances between intermyocytic or intercapillary points are estimated. The microscopic slides have stained with H&E or Heidenhain’s Azan trichrome for cardiomyocytes and micro-vessels, respectively. Lower left (E) and right (F) diagrams show the mean distances (μm) between cardiomyocytes and micro-vessels centers from each other in the control (A and C) and Cd (4.5 mg/kg) plus FICZ (100 μg/kg) groups (B and D), respectively. Since the profile of the triangles was determined by the arrangement of the points, hence, the cardiomyocyte or capillary distances are different between the groups. The altered pattern of cardiomyocyte or capillary led to change in intermyocytic or intercapillary distances followed by the variability of triangles sides in Cd (4.5 mg/kg) plus FICZ (100 μg/kg) group. Values are expressed as means ±S.E; Asterisks denote significant differences (*P < 0.05 and ***P < 0.001) between control and Cd (4.5 mg/kg) plus FICZ. (JPG 1926 kb)
12011_2018_1391_MOESM3_ESM.jpg (112 kb)
Supplementary Fig. S3 Counting of cardiomyocytes nuclei profiles at light microscopic level. The optical disector method was used to count the cardiomyocytes nuclei. An unbiased counting frame was superimposed onto each sampled test field. Cardiomyocytes nuclei were visualized by H&E staining and counted if nuclei were in focus (A) and (B) and located inside the counting frame (arrows) or touching the inclusion line (dashed line). Cardiomyocytes nuclei profiles touching the exclusion line or its extensions were not counted. (JPG 111 kb)

References

  1. 1.
    Barker DJ (2007) The origins of the developmental origins theory. J Intern Med 261(5):412–417CrossRefGoogle Scholar
  2. 2.
    Wang Q, Kurita H, Carreira V, Ko C-I, Fan Y, Zhang X, Biesiada J, Medvedovic M, Puga A (2016) Ah receptor activation by dioxin disrupts activin, BMP, and WNT signals during the early differentiation of mouse embryonic stem cells and inhibits cardiomyocyte functions. Toxicol Sci 149(2):346–357CrossRefGoogle Scholar
  3. 3.
    Schneider AJ, Branam AM, Peterson RE (2014) Intersection of AHR and Wnt signaling in development, health, and disease. Int J Mol Sci 15(10):17852–17885CrossRefGoogle Scholar
  4. 4.
    Korashy HM, El-Kadi AO (2006) The role of aryl hydrocarbon receptor in the pathogenesis of cardiovascular diseases. Drug Metab Rev 38(3):411–450CrossRefGoogle Scholar
  5. 5.
    Mohammadi-Bardbori A, Akbarizadeh AR, Delju F, Rannug A (2016) Chromatin remodeling by curcumin alters endogenous aryl hydrocarbon receptor signaling. Chem Biol Interact 252:19–27CrossRefGoogle Scholar
  6. 6.
    Mohammadi-Bardbori A, Bengtsson J, Rannug U, Rannug A, Wincent E (2012) Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chem Res Toxicol 25(9):1878–1884CrossRefGoogle Scholar
  7. 7.
    Mohammadi-Bardbori A, Vikström Bergander L, Rannug U, Rannug A (2015) NADPH oxidase-dependent mechanism explains how arsenic and other oxidants can activate aryl hydrocarbon receptor signaling. Chem Res Toxicol 28(12):2278–2286CrossRefGoogle Scholar
  8. 8.
    Wincent E, Bengtsson J, Bardbori AM, Alsberg T, Luecke S, Rannug U, Rannug A (2012) Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 109(12):4479–4484CrossRefGoogle Scholar
  9. 9.
    Mukai M, Tischkau SA (2007) Effects of tryptophan photoproducts in the circadian timing system: searching for a physiological role for aryl hydrocarbon receptor. Toxicol Sci 95(1):172–181CrossRefGoogle Scholar
  10. 10.
    Mohammadi-Bardbori A, Bastan F, Akbarizadeh AR (2017) The highly bioactive molecule and signal substance 6-formylindolo[3,2-b]carbazole (FICZ) plays bi-functional roles in cell growth and apoptosis in vitro. Arch Toxicol 91(10):3365–3372Google Scholar
  11. 11.
    Esser C, Rannug A, Stockinger B (2009) The aryl hydrocarbon receptor in immunity. Trends Immunol 30(9):447–454CrossRefGoogle Scholar
  12. 12.
    Scott JA, Walker MK (2011) Involvement of the AHR in cardiac function and regulation of blood pressure. In: Pohjanvirta R (ed) The AH Receptor in Biology and Toxicology, 1st edn. John Wiley & Sons, Inc, Hoboken, pp 423–436Google Scholar
  13. 13.
    Wincent E, Stegeman JJ, Jönsson ME (2015) Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: implications for physiological and toxicological AHR functions. Toxicol Appl Pharmacol 284(2):163–179CrossRefGoogle Scholar
  14. 14.
    Zhang H, Yao Y, Chen Y, Yue C, Chen J, Tong J, Jiang Y, Chen T (2016) Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2. 5 in zebrafish embryos. Toxicology 355:31–38CrossRefGoogle Scholar
  15. 15.
    Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779CrossRefGoogle Scholar
  16. 16.
    Prozialeck WC, Grunwald GB, Dey PM, Reuhl KR, Parrish AR (2002) Cadherins and NCAM as potential targets in metal toxicity. Toxicol Appl Pharmacol 182(3):255–265CrossRefGoogle Scholar
  17. 17.
    Thévenod F (2009) Cadmium and cellular signaling cascades: to be or not to be? Toxicol Appl Pharmacol 238(3):221–239CrossRefGoogle Scholar
  18. 18.
    Anwar-Mohamed A, Elbekai RH, El-Kadi AO (2009) Regulation of CYP1A1 by heavy metals and consequences for drug metabolism. Expert Opin Drug Metab Toxicol 5(5):501–521CrossRefGoogle Scholar
  19. 19.
    Falkner KC, McCallum GP, Cherian MG, Bend JR (1993) Effects of acute sodium arsenite administration on the pulmonary chemical metabolizing enzymes, cytochrome P-450 monooxygenase, NAD(P)H:quinone acceptor oxidoreductase and glutathione S-transferase in guinea pig: comparison with effects in liver and kidney. Chem Biol Interact 86(1):51–68CrossRefGoogle Scholar
  20. 20.
    Kaminsky L (2006) The role of trace metals in cytochrome P4501 regulation. Drug Metab Rev 38(1–2):227–234CrossRefGoogle Scholar
  21. 21.
    Mohammadi-Bardbori A, Rannug A (2014) Arsenic, cadmium, mercury and nickel stimulate cell growth via NADPH oxidase activation. Chem Biol Interact 224:183–188CrossRefGoogle Scholar
  22. 22.
    Burroughs Pena MS, Rollins A (2017) Environmental exposures and cardiovascular disease: A Challenge for Health and Development in Low- and Middle-Income Countries. Cardiol Clin 35(1):71–86CrossRefGoogle Scholar
  23. 23.
    Cosselman KE, Navas-Acien A, Kaufman JD (2015) Environmental factors in cardiovascular disease. Nat Rev Cardiol 12(11):627–642CrossRefGoogle Scholar
  24. 24.
    Noorafshan A (2014) Stereology as a valuable tool in the toolbox of testicular research. Ann Anat 196(1):57–66CrossRefGoogle Scholar
  25. 25.
    Mühlfeld C, Nyengaard JR, Mayhew TM (2010) A review of state-of-the-art stereology for better quantitative 3D morphology in cardiac research. Cardiovasc Pathol 19(2):65–82CrossRefGoogle Scholar
  26. 26.
    Nyengaard JR (1999) Stereologic methods and their application in kidney research. J Am Soc Nephrol 10(5):1100–1123PubMedGoogle Scholar
  27. 27.
    Safaeian N, David T (2013) A computational model of oxygen transport in the cerebrocapillary levels for normal and pathologic brain function. J Cereb Blood Flow Metab 33(10):1633–1641CrossRefGoogle Scholar
  28. 28.
    van Horssen P, van den Wijngaard JP, Brandt M, Hoefer IE, Spaan JA, Siebes M (2014) Perfusion territories subtended by penetrating coronary arteries increase in size and decrease in number toward the subendocardium. Am J Phys 306(4):H496–H504Google Scholar
  29. 29.
    Jönsson ME, Mattsson A, Shaik S, Brunström B (2016) Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo [3, 2-b] carbazole (FICZ) in chicken and Japanese quail embryos. Comp Biochem Physiol 179:125–136Google Scholar
  30. 30.
    Wincent E, Kubota A, Timme-Laragy A, Jönsson ME, Hahn ME, Stegeman JJ (2016) Biological effects of 6-formylindolo [3, 2-b] carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner. Biochem Pharmacol 110:117–129CrossRefGoogle Scholar
  31. 31.
    Chakraborty PK, Lee W-K, Molitor M, Wolff NA, Thévenod F (2010) Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells. Mol Cancer 9(1):102CrossRefGoogle Scholar
  32. 32.
    Kundak AA, Pektas A, Zenciroglu A, Ozdemir S, Barutcu UB, Orun UA, Okumus N (2017) Do toxic metals and trace elements have a role in the pathogenesis of conotruncal heart malformations? Cardiol Young 27(2):312–317CrossRefGoogle Scholar
  33. 33.
    Parmalee NL, Kitajewski J (2008) Wnt signaling in angiogenesis. Curr Drug Targets 9(7):558–564CrossRefGoogle Scholar
  34. 34.
    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359(6398):843–845CrossRefGoogle Scholar
  35. 35.
    Jayasundara N, Van Tiem Garner L, Meyer JN, Erwin KN, Di Giulio RT (2014) AHR2-mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of PAHs. Toxicol Sci 143(2):469–481CrossRefGoogle Scholar
  36. 36.
    Lyons I, Parsons LM, Hartley L, Li R, Andrews JE, Robb L, Harvey RP (1995) Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev 9(13):1654–1666CrossRefGoogle Scholar
  37. 37.
    Schott J-J, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG (1998) Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281(5373):108–111CrossRefGoogle Scholar
  38. 38.
    Norden J, Greulich F, Rudat C, Taketo MM, Kispert A (2011) Wnt/β-catenin signaling maintains the mesenchymal precursor pool for murine sinus horn formation novelty and significance. Circ Res 109(6):e42–e50CrossRefGoogle Scholar
  39. 39.
    Zamora M, Männer J, Ruiz-Lozano P (2007) Epicardium-derived progenitor cells require β-catenin for coronary artery formation. Proc Natl Acad Sci U S A 104(46):18109–18114CrossRefGoogle Scholar
  40. 40.
    Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, Raval KK, Zhang J, Kamp TJ, Palecek SP (2012) Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci U S A 109(27):E1848–E1857CrossRefGoogle Scholar
  41. 41.
    Lee H-C, Tsai J-N, Liao P-Y, Tsai W-Y, Lin K-Y, Chuang C-C, Sun C-K, Chang W-C, Tsai H-J (2007) Glycogen synthase kinase 3α and 3β have distinct functions during cardiogenesis of zebrafish embryo. BMC Dev Biol 7(1):93CrossRefGoogle Scholar
  42. 42.
    Ozhan G, Weidinger G (2015) Wnt/β-catenin signaling in heart regeneration. Cell Regen 4(1):3CrossRefGoogle Scholar
  43. 43.
    Miller JR, Hocking AM, Brown JD, Moon RT (1999) Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 18(55):7860–7872CrossRefGoogle Scholar
  44. 44.
    Son Y-O, Wang L, Poyil P, Budhraja A, Hitron JA, Zhang Z, Lee J-C, Shi X (2012) Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling. Toxicol Appl Pharmacol 264(2):153–160CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Mahmoud Omidi
    • 1
  • Hossein Niknahad
    • 1
  • Ali Noorafshan
    • 2
    • 3
  • Reza Fardid
    • 4
  • Elham Nadimi
    • 2
    • 5
  • Samaneh Naderi
    • 6
  • Azizollah Bakhtari
    • 7
  • Afshin Mohammadi-Bardbori
    • 1
    Email author
  1. 1.Department of Pharmacology and Toxicology, School of PharmacyShiraz University of Medical SciencesShirazIran
  2. 2.Histomorphometry and Stereology Research CenterShiraz University of Medical SciencesShirazIran
  3. 3.Departments of Anatomy, School of MedicineShiraz University of Medical SciencesShirazIran
  4. 4.Department of Radiology, School of Paramedical SciencesShiraz University of Medical SciencesShirazIran
  5. 5.Department of Immunology, Medical SchoolShiraz University of Medical SciencesShirazIran
  6. 6.Diagnostic Laboratory Science and Technology Research Center, School of Paramedical SciencesShiraz University of Medical SciencesShirazIran
  7. 7.Department of Reproductive Biology, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran

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