Advertisement

Cardiovascular Toxicology

, Volume 19, Issue 6, pp 565–574 | Cite as

2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression

  • Mary T. Walsh-Wilcox
  • Joel Kaye
  • Efrat Rubinstein
  • Mary K. WalkerEmail author
Article
  • 113 Downloads

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction.

Graphical Abstract

TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.

Keywords

Angiotensinogen Cytochrome P4501A1 Perivascular adipose tissue (PVAT) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Vascular dysfunction Nitric oxide 

Notes

Acknowledgements

We thank Emily Wheeler and Meera Shah for their expert technical support. This work was support by Teva Pharmaceutical Industries Ltd., Netanya, Israel [DS-2018-003].

Supplementary material

12012_2019_9529_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 11 kb)

References

  1. 1.
    Agabiti-Rosei, C., Paini, A., De Ciuceis, C., Withers, S., Greenstein, A., Heagerty, A. M., et al. (2018). Modulation of vascular reactivity by perivascular adipose tissue (PVAT). Current Hypertension Reports, 20, 44.CrossRefGoogle Scholar
  2. 2.
    Agbor, L. N., Wiest, E. F., Rothe, M., Schunck, W. H., & Walker, M. K. (2014). Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids. Journal of Pharmacology and Experimental Therapeutics, 351, 688–698.CrossRefGoogle Scholar
  3. 3.
    Brown, N. K., Zhou, Z., Zhang, J., Zeng, R., Wu, J., Eitzman, D. T., et al. (2014). Perivascular adipose tissue in vascular function and disease: A review of current research and animal models. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 1621–1630.CrossRefGoogle Scholar
  4. 4.
    Bui, P., Solaimani, P., Wu, X., & Hankinson, O. (2012). 2,3,7,8-Tetrachlorodibenzo-p-dioxin treatment alters eicosanoid levels in several organs of the mouse in an aryl hydrocarbon receptor-dependent fashion. Toxicology and Applied Pharmacology, 259, 143–151.CrossRefGoogle Scholar
  5. 5.
    Cassis, L. A., Police, S. B., Yiannikouris, F., & Thatcher, S. E. (2008). Local adipose tissue renin-angiotensin system. Current Hypertension Reports, 10, 93–98.CrossRefGoogle Scholar
  6. 6.
    Cypel, Y. S., Kress, A. M., Eber, S. M., Schneiderman, A. I., & Davey, V. J. (2016). Herbicide exposure, vietnam service, and hypertension risk in Army Chemical Corps Veterans. Journal of Occupational and Environmental Medicine, 58, 1127–1136.CrossRefGoogle Scholar
  7. 7.
    Emond, C., Michalek, J. E., Birnbaum, L. S., & DeVito, M. J. (2005). Comparison of the use of a physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure assessments. Environmental Health Perspectives, 113, 1666–1668.CrossRefGoogle Scholar
  8. 8.
    Fernandez-Alfonso, M. S., Gil-Ortega, M., Garcia-Prieto, C. F., Aranguez, I., Ruiz-Gayo, M., & Somoza, B. (2013). Mechanisms of perivascular adipose tissue dysfunction in obesity. International journal of endocrinology, 2013, 402053.CrossRefGoogle Scholar
  9. 9.
    Gerassimou, C., Kotanidou, A., Zhou, Z., Simoes, D. C., Roussos, C., & Papapetropoulos, A. (2007). Regulation of the expression of soluble guanylyl cyclase by reactive oxygen species. British Journal of Pharmacology, 150, 1084–1091.CrossRefGoogle Scholar
  10. 10.
    Hankinson, O. (2016). The role of AHR-inducible cytochrome P450s in metabolism of polyunsaturated fatty acids. Drug Metabolism Reviews, 48(3), 342–350.CrossRefGoogle Scholar
  11. 11.
    Houlahan, K. E., Prokopec, S. D., Sun, R. X., Moffat, I. D., Linden, J., Lensu, S., et al. (2015). Transcriptional profiling of rat white adipose tissue response to 2,3,7,8-tetrachlorodibenzo-rho-dioxin. Toxicology and Applied Pharmacology, 288, 223–231.CrossRefGoogle Scholar
  12. 12.
    Jackson, E., Shoemaker, R., Larian, N., & Cassis, L. (2017). Adipose tissue as a site of toxin accumulation. Comprehensive Physiology, 7, 1085–1135.CrossRefGoogle Scholar
  13. 13.
    Kang, H. K., Dalager, N. A., Needham, L. L., Patterson, D. G., Jr., Lees, P. S., Yates, K., et al. (2006). Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. American Journal of Industrial Medicine, 49, 875–884.CrossRefGoogle Scholar
  14. 14.
    Kim, D., Aizawa, T., Wei, H., Pi, X., Rybalkin, S. D., Berk, B. C., et al. (2005). Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling. Journal of Molecular and Cellular Cardiology, 38, 175–184.CrossRefGoogle Scholar
  15. 15.
    Kim, M. J., Pelloux, V., Guyot, E., Tordjman, J., Bui, L. C., Chevallier, A., et al. (2012). Inflammatory pathway genes belong to major targets of persistent organic pollutants in adipose cells. Environmental Health Perspectives, 120, 508–514.CrossRefGoogle Scholar
  16. 16.
    Konkel, A., & Schunck, W. H. (2011). Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochimica et Biophysica Acta, 1814, 210–222.CrossRefGoogle Scholar
  17. 17.
    Kopf, P. G., Huwe, J. K., & Walker, M. K. (2008). Hypertension, cardiac hypertrophy, and impaired vascular relaxation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are associated with increased superoxide. Cardiovascular Toxicology, 8, 181–193.CrossRefGoogle Scholar
  18. 18.
    Kopf, P. G., Scott, J. A., Agbor, L. N., Boberg, J. R., Elased, K. M., Huwe, J. K., et al. (2010). Cytochrome P4501A1 is required for vascular dysfunction and hypertension induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicological Sciences, 117, 537–546.CrossRefGoogle Scholar
  19. 19.
    Kopf, P. G., & Walker, M. K. (2010). 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A1. Toxicology and Applied Pharmacology, 245, 91–99.CrossRefGoogle Scholar
  20. 20.
    Lund, A. K., Goens, M. B., Kanagy, N. L., & Walker, M. K. (2003). Cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice is correlated with elevated angiotensin II, endothelin-1 and mean arterial blood pressure. Toxicology and Applied Pharmacology, 193, 177–187.CrossRefGoogle Scholar
  21. 21.
    Mahiout, S., Linden, J., Esteban, J., Sanchez-Perez, I., Sankari, S., Pettersson, L., et al. (2017). Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats. Toxicology and Applied Pharmacology, 326, 54–65.CrossRefGoogle Scholar
  22. 22.
    Meyer, M. R., Fredette, N. C., Barton, M., & Prossnitz, E. R. (2013). Regulation of vascular smooth muscle tone by adipose-derived contracting factor. PLoS ONE, 8, e79245.CrossRefGoogle Scholar
  23. 23.
    Nishiumi, S., Yoshida, M., Azuma, T., Yoshida, K., & Ashida, H. (2010). 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes. Toxicological Sciences, 115, 482–491.CrossRefGoogle Scholar
  24. 24.
    Safonova, I., Aubert, J., Negrel, R., & Ailhaud, G. (1997). Regulation by fatty acids of angiotensinogen gene expression in preadipose cells. Biochemical Journal, 322(Pt 1), 235–239.CrossRefGoogle Scholar
  25. 25.
    Schlezinger, J. J., Struntz, W. D., Goldstone, J. V., & Stegeman, J. J. (2006). Uncoupling of cytochrome P450 1A and stimulation of reactive oxygen species production by co-planar polychlorinated biphenyl congeners. Aquatic Toxicology, 77, 422–432.CrossRefGoogle Scholar
  26. 26.
    Schwarz, D., Kisselev, P., Ericksen, S. S., Szklarz, G. D., Chernogolov, A., Honeck, H., et al. (2004). Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1: highly stereoselective formation of 17(R),18(S)-epoxyeicosatetraenoic acid. Biochemical Pharmacology, 67, 1445–1457.CrossRefGoogle Scholar
  27. 27.
    Shertzer, H. G., Clay, C. D., Genter, M. B., Chames, M. C., Schneider, S. N., Oakley, G. G., et al. (2004). Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes. Free Radical Biology and Medicine, 36, 618–631.CrossRefGoogle Scholar
  28. 28.
    Siriwardhana, N., Kalupahana, N. S., Fletcher, S., Xin, W., Claycombe, K. J., Quignard-Boulange, A., et al. (2012). n-3 and n-6 polyunsaturated fatty acids differentially regulate adipose angiotensinogen and other inflammatory adipokines in part via NF-kappaB-dependent mechanisms. Journal of Nutritional Biochemistry, 23, 1661–1667.CrossRefGoogle Scholar
  29. 29.
    Smyth, E. M. (2010). Thromboxane and the thromboxane receptor in cardiovascular disease. Clinical Lipidology, 5, 209–219.CrossRefGoogle Scholar
  30. 30.
    Walker, M. K., Boberg, J. R., Walsh, M. T., Wolf, V., Trujillo, A., Duke, M. S., et al. (2012). A less stressful alternative to oral gavage for pharmacological and toxicological studies in mice. Toxicology and Applied Pharmacology, 260, 65–69.CrossRefGoogle Scholar
  31. 31.
    Wiest, E. F., Walsh-Wilcox, M. T., Rothe, M., Schunck, W. H., & Walker, M. K. (2016). Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin. Toxicological Sciences, 154, 43–54.CrossRefGoogle Scholar
  32. 32.
    Yang, J., Solaimani, P., Dong, H., Hammock, B., & Hankinson, O. (2013). Treatment of mice with 2,3,7,8-Tetrachlorodibenzo-p-dioxin markedly increases the levels of a number of cytochrome P450 metabolites of omega-3 polyunsaturated fatty acids in the liver and lung. Journal of Toxicological Sciences, 38, 833–836.CrossRefGoogle Scholar
  33. 33.
    Yiannikouris, F., Gupte, M., Putnam, K., Thatcher, S., Charnigo, R., Rateri, D. L., et al. (2012). Adipocyte deficiency of angiotensinogen prevents obesity-induced hypertension in male mice. Hypertension, 60, 1524–1530.CrossRefGoogle Scholar
  34. 34.
    Zhao, W., Parrish, A. R., & Ramos, K. S. (1998). Constitutive and inducible expression of cytochrome P4501A1 and P4501B1 in human vascular endothelial and smooth muscle cells. In Vitro Cellular & Developmental Biology—Animal, 34, 671–673.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mary T. Walsh-Wilcox
    • 1
  • Joel Kaye
    • 2
    • 3
  • Efrat Rubinstein
    • 2
  • Mary K. Walker
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of New Mexico Health Sciences CenterAlbuquerqueUSA
  2. 2.Teva Pharmaceutical Industries LtdNetanyaIsrael
  3. 3.Ayala Targeted TherapiesRehovotIsrael

Personalised recommendations