Co-exposure to an Aryl Hydrocarbon Receptor Endogenous Ligand, 6-Formylindolo[3,2-b]carbazole (FICZ), and Cadmium Induces Cardiovascular Developmental Abnormalities in Mice
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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.
KeywordsAryl hydrocarbon receptor Wnt/β-catenin FICZ Cadmium Cardiogenesis
The authors of this manuscript wish to express their appreciation to Shiraz University of Medical Sciences, Shiraz, Iran.
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].
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Conflict of Interest
The authors declare that they have no conflict of interest.
- 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
- 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
- 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
- 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
- 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.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