Skip to main content
Log in

Chronic Exposure to Bisphenol A can Accelerate Atherosclerosis in High-Fat-Fed Apolipoprotein E Knockout Mice

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

In epidemiological studies, there is growing concern regarding the association between human exposure to bisphenol A (BPA) and an increased risk for cardiovascular disease. Therefore, we investigated whether BPA accelerates atherosclerosis in mouse model. Apolipoprotein E knockout (ApoE−/−) mice were fed a high-fat and high-cholesterol diet with or without 50 μg/kg body weight/day BPA for 12 weeks. Atherosclerotic lesions of the aorta and aortic sinus were evaluated by Oil red O staining. After the 12-week BPA treatment, BPA significantly increased atherosclerotic lesions in the aortas of ApoE−/− mice by 1.7-fold (p = 0.03). Non-high-density lipoprotein (HDL) cholesterol levels in the BPA group were significantly higher compared to those in the control group (1,035 ± 70 vs. 484 ± 48 mg/dL, p = 0.02) although body weight and blood glucose levels were not different between groups. Human umbilical vein endothelial cells (HUVECs) were treated with 0.1–10 nM BPA but BPA did not affect HUVEC proliferation or migration. BPA could accelerate atherosclerosis in ApoE−/− mice, which may have resulted from an increase in non-HDL cholesterol levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Brotons, J. A., Olea-Serrano, M. F., Villalobos, M., Pedraza, V., & Olea, N. (1995). Xenoestrogens released from lacquer coatings in food cans. Environmental Health Perspectives, 103, 608–612.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Calafat, A. M., Ye, X., Wong, L. Y., Reidy, J. A., & Needham, L. L. (2008). Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environmental Health Perspectives, 116, 39–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Takeuchi, T., Tsutsumi, O., Ikezuki, Y., Takai, Y., & Taketani, Y. (2004). Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocrine Journal, 51, 165–169.

    Article  CAS  PubMed  Google Scholar 

  4. Lang, I. A., Galloway, T. S., Scarlett, A., Henley, W. E., Depledge, M., Wallace, R. B., et al. (2008). Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA, 300, 1303–1310.

    Article  CAS  PubMed  Google Scholar 

  5. Melzer, D., Rice, N. E., Lewis, C., Henley, W. E., & Galloway, T. S. (2010). Association of urinary bisphenol a concentration with heart disease: Evidence from NHANES 2003/06. PLoS One, 5, e8673.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Melzer, D., Osborne, N. J., Henley, W. E., Cipelli, R., Young, A., Money, C., et al. (2012). Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women. Circulation, 125, 1482–1490.

    Article  CAS  PubMed  Google Scholar 

  7. Melzer, D., Gates, P., Osborn, N. J., Henley, W. E., Cipelli, R., Young, A., et al. (2012). Urinary bisphenol a concentration and angiography-defined coronary artery stenosis. PLoS One, 7, e43378.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Lind, P. M., & Lind, L. (2011). Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis in the elderly. Atherosclerosis, 218, 207–213.

    Article  CAS  PubMed  Google Scholar 

  9. Shankar, A., & Teppala, S. (2012). Urinary bisphenol A and hypertension in a multiethnic sample of US adults. Journal of Environmental and Public Health, 2012, 481641.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Bae, S., Kim, J. H., Lim, Y. H., Park, H. Y., & Hong, Y. C. (2012). Associations of bisphenol A exposure with heart rate variability and blood pressure. Hypertension, 60, 786–793.

    Article  CAS  PubMed  Google Scholar 

  11. Weber, C., & Noels, H. (2011). Atherosclerosis: Current pathogenesis and therapeutic options. Nature Medicine, 17, 1410–1422.

    Article  CAS  PubMed  Google Scholar 

  12. Madamanchi, N. R., Vendrov, A., & Runge, M. S. (2005). Oxidative stress and vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 29–38.

    Article  CAS  PubMed  Google Scholar 

  13. Wang, T., Li, M., Chen, B., Xu, M., Xu, Y., Huang, Y., et al. (2012). Urinary bisphenol A (BPA) concentration associates with obesity and insulin resistance. Journal of Clinical Endocrinology and Metabolism, 97, E223–E227.

    Article  CAS  PubMed  Google Scholar 

  14. Trasande, L., Attina, T. M., & Blustein, J. (2012). Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA, 308, 1113–1121.

    Article  CAS  PubMed  Google Scholar 

  15. Carwile, J. L., & Michels, K. B. (2011). Urinary bisphenol A and obesity: NHANES 2003–2006. Environmental Research, 111, 825–830.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Alonso-Magdalena, P., Vieira, E., Soriano, S., Menes, L., Burks, D., Quesada, I., et al. (2010). Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environmental Health Perspectives, 118, 1243–1250.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Rubin, B. S., Murray, M. K., Damassa, D. A., King, J. C., & Soto, A. M. (2001). Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environmental Health Perspectives, 109, 675–680.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Miyawaki, J., Sakayama, K., Kato, H., Yamamoto, H., & Masuno, H. (2007). Perinatal and postnatal exposure to bisphenol A increases adipose tissue mass and serum cholesterol level in mice. Journal of Atherosclerosis and Thrombosis, 14, 245–252.

    Article  CAS  PubMed  Google Scholar 

  19. Alonso-Magdalena, P., Morimoto, S., Ripoll, C., Fuentes, E., & Nadal, A. (2006). The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environmental Health Perspectives, 114, 106–112.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Batista, T. M., Alonso-Magdalena, P., Vieira, E., Amaral, M. E., Cederroth, C. R., Nef, S., et al. (2012). Short-term treatment with bisphenol-A leads to metabolic abnormalities in adult male mice. PLoS One, 7, e33814.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. US FDA (2008) Draft assessment of bisphenol A for use in food contact applications. Available at http://www.fda.gov/ForConsumers/ConsumerUpdates/UCM169136. Accessed 1 Mar 2012.

  22. Rodriguez, L. G., Wu, X., & Guan, J. (2005). Wound-healing assay. Cell Migration, 294, 23–29.

    Article  Google Scholar 

  23. Jackson, C. L., Bennett, M. R., Biessen, E. A., Johnson, J. L., & Krams, R. (2007). Assessment of unstable atherosclerosis in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 714–720.

    Article  CAS  PubMed  Google Scholar 

  24. vom Saal, F. S., Nagel, S. C., Timms, B. G., & Welshons, W. V. (2005). Implications for human health of the extensive bisphenol A literature showing adverse effects at low doses: A response to attempts to mislead the public. Toxicology, 212, 244–252.

  25. vom Saal, F. S., Akingbemi, B. T., Belcher, S. M., Birnbaum, L. S., Crain, D. A., Eriksen, M., Farabollini, F., Guillette, L. J., Jr., Hauser, R., Heindel, J. J., Ho, S. M., Hunt, P. A., Iguchi, T., Jobling, S., Kanno, J., Keri, R. A., Knudsen, K. E., Laufer, H., LeBlanc, G. A., Marcus, M., McLachlan, J. A., Myers, J. P., Nadal, A., Newbold, R. R., Olea, N., Prins, G. S., Richter, C. A., Rubin, B. S., Sonnenschein, C., Soto, A. M., Talsness, C. E., Vandenbergh, J. G., Vandenberg, L. N., Walser-Kuntz, D. R., Watson, C. S., Welshons, W. V., Wetherill, Y., & Zoeller, R. T. (2007). Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reproductive Toxicology, 24, 131–138.

    Google Scholar 

  26. Masuno, H., Iwanami, J., Kidani, T., Sakayama, K., & Honda, K. (2005). Bisphenol A accelerates terminal differentiation of 3T3-L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway. Toxicological Sciences, 84, 319–327.

    Article  CAS  PubMed  Google Scholar 

  27. Hugo, E. R., Brandebourg, T. D., Woo, J. G., Loftus, J., Alexander, J. W., & Ben-Jonathan, N. (2008). Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environmental Health Perspectives, 116, 1642–1647.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Marmugi, A., Ducheix, S., Lasserre, F., Polizzi, A., Paris, A., Priymenko, N., et al. (2012). Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver. Hepatology, 55, 395–407.

    Article  CAS  PubMed  Google Scholar 

  29. Barrett-Connor, E., Slone, S., Greendale, G., Kritz-Silverstein, D., Espeland, M., Johnson, S. R., et al. (1997). The Postmenopausal Estrogen/Progestin Interventions Study: Primary outcomes in adherent women. Maturitas, 27, 261–274.

    Article  CAS  PubMed  Google Scholar 

  30. Navab, M., Reddy, S. T., Van Lenten, B. J., & Fogelman, A. M. (2011). HDL and cardiovascular disease: Atherogenic and atheroprotective mechanisms. Nature Reviews Cardiology, 8, 222–232.

    Article  CAS  PubMed  Google Scholar 

  31. Libby, P., Ridker, P. M., & Maseri, A. (2002). Inflammation and atherosclerosis. Circulation, 105, 1135–1143.

    Article  CAS  PubMed  Google Scholar 

  32. Moon, M. K., Kim, M. J., Jung, I. K., Koo, Y. D., Ann, H. Y., Lee, K. J., et al. (2012). Bisphenol A impairs mitochondrial function in the liver at doses below the no observed adverse effect level. Journal of Korean Medical Science, 27, 644–652.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Ben-Jonathan, N., Hugo, E. R., & Brandebourg, T. D. (2009). Effects of bisphenol A on adipokine release from human adipose tissue: Implications for the metabolic syndrome. Molecular and Cellular Endocrinology, 304, 49–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Sieli, P. T., Jasarevic, E., Warzak, D. A., Mao, J., Ellersieck, M. R., Liao, C., et al. (2011). Comparison of serum bisphenol A concentrations in mice exposed to bisphenol A through the diet versus oral bolus exposure. Environmental Health Perspectives, 119, 1260–1265.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. vom Saal, F. S., & Hughes, C. (2005). An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment. Environmental Health Perspectives, 113, 926–933.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Kuiper, G. G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson, S., et al. (1997). Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology, 138, 863–870.

    CAS  PubMed  Google Scholar 

  37. Elhage, R., Arnal, J. F., Pieraggi, M. T., Duverger, N., Fievet, C., Faye, J. C., et al. (1997). 17 beta-estradiol prevents fatty streak formation in apolipoprotein E-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 17, 2679–2684.

    Article  CAS  PubMed  Google Scholar 

  38. Cann, J. A., Register, T. C., Adams, M. R., St Clair, R. W., Espeland, M. A., & Williams, J. K. (2008). Timing of estrogen replacement influences atherosclerosis progression and plaque leukocyte populations in ApoE−/− mice. Atherosclerosis, 201, 43–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Freudenberger, T., Oppermann, M., Heim, H. K., Mayer, P., Kojda, G., Schror, K., et al. (2010). Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice. Basic Research in Cardiology, 105, 479–486.

    Article  CAS  PubMed  Google Scholar 

  40. Bindhumol, V., Chitra, K. C., & Mathur, P. P. (2003). Bisphenol A induces reactive oxygen species generation in the liver of male rats. Toxicology, 188, 117–124.

    Article  CAS  PubMed  Google Scholar 

  41. Hassan, Z. K., Elobeid, M. A., Virk, P., Omer, S. A., Elamin, M., Daghestani, M. H., et al. (2012). Bisphenol A induces hepatotoxicity through oxidative stress in rat model. Oxidative Medicine and Cellular Longevity, 2012, 194829.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Research Foundation of Korea (NRF) Grant funded by the Korean Government (2010-0023068).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Young Joo Park.

Additional information

Min Joo Kim and Min Kyong Moon have equally contributed to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, M.J., Moon, M.K., Kang, G.H. et al. Chronic Exposure to Bisphenol A can Accelerate Atherosclerosis in High-Fat-Fed Apolipoprotein E Knockout Mice. Cardiovasc Toxicol 14, 120–128 (2014). https://doi.org/10.1007/s12012-013-9235-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-013-9235-x

Keywords

Navigation