Purpose of Review
Cardiovascular disease (CVD) is a non-subsiding disease that remains a leading cause of morbidity and mortality. CVD has been associated with endocrine disruptors, such as bisphenol A (BPA). This review critically summarizes existing findings on BPA and hypertension, with particular attention to genomic, non-genomic, molecular, and cellular mechanisms of action that render BPA as a cardiovascular estrogenic disruptor.
Owing to its similar estrogenic structure, BPA has been shown to affect various phenotypes that are regulated by the natural hormone, estrogen. Indeed, BPA has been shown to interact with estrogen receptors, located both in the cell membrane and in the cytoplasm/nucleus. Given that estrogen plays an important role in cardiovascular physiology, a contributing role for BPA in CVD would not be unexpected. Existing literature, though limited, established BPA as a source of disruption in cardiovascular health, particularly hypertension. However, effects of BPA are largely dependent on the dose, patient gender, tissue, and developmental stage of the exposed tissue/organ.
Accumulating evidence argues for an adverse effect of BPA on blood pressure, with this effect being gender, dose, and time specific. Thus, comprehensive studies which take these factors and other parameters, like epigenetic factors, into account are warranted before a thorough understanding is at hand.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
•• Iorga A, Cunningham CM, Moazeni S, Ruffenach G, Umar S, Eghbali M. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Differ. 2017;8(1):33 This review discusses the cardiovasculoprotective role of estrogen receptors and their dimorphic role in modulating the action of estrogen in cardiovascular disease.
Gray LE. Twenty-five years after “wingspread”- environmental endocrine disruptors (EDCs) and human health. Curr Opin Toxicol. 2017;3:40–7. https://doi.org/10.1016/j.cotox.2017.04.004.
Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM. Bisphenol A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev. 2009;30(1):75–95. https://doi.org/10.1210/er.2008-0021.
Fardoun M, Dehaini H, Shaito A, Mesmar J, El-Yazbi A, Badran A, et al. The hypertensive potential of estrogen: an untold story. Vasc Pharmacol. 2020;124:106600. https://doi.org/10.1016/j.vph.2019.106600.
Dehaini H, Fardoun M, Abou-Saleh H, El-Yazbi A, Eid AA, Eid AH. Estrogen in vascular smooth muscle cells: a friend or a foe? Vasc Pharmacol. 2018;111:15–21. https://doi.org/10.1016/j.vph.2018.09.001.
Eid AH, Maiti K, Mitra S, Chotani MA, Flavahan S, Bailey SR, et al. Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol. 2007;293(3):H1955–61. https://doi.org/10.1152/ajpheart.00306.2007.
Fardoun MM, Nassif J, Issa K, Baydoun E, Eid AH. Raynaud’s phenomenon: a brief review of the underlying mechanisms. Front Pharmacol. 2016;7:438. https://doi.org/10.3389/fphar.2016.00438.
Knight DC, Eden JA. Phytoestrogens--a short review. Maturitas. 1995;22(3):167–75.
Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1–24. https://doi.org/10.1016/j.pharmthera.2017.12.012.
Lecomte S, Demay F, Ferriere F, Pakdel F. Phytochemicals targeting estrogen receptors: beneficial rather than adverse effects? Int J Mol Sci. 2017;18(7):Artn 1381. https://doi.org/10.3390/Ijms18071381.
Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest. 1999;103(3):401–6. https://doi.org/10.1172/jci5347.
Herrington DM, Braden GA, Williams JK, Morgan TM. Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy. Am J Cardiol. 1994;73(13):951–2.
Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Up-regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett. 1995;360(3):291–3.
MacRitchie AN, Jun SS, Chen Z, German Z, Yuhanna IS, Sherman TS, et al. Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res. 1997;81(3):355–62.
Grande M, Carlström K, Stege R, Pousette A, Faxén M. Estrogens increase the endothelial nitric oxide synthase (ecNOS) mRNA level in LNCaP human prostate carcinoma cells. Prostate. 2000;45(3):232–7.
Shaul PW. Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol. 2002;64:749–74. https://doi.org/10.1146/annurev.physiol.64.081501.155952.
Zinkevich NS, Fancher IS, Gutterman DD, Phillips SA. Roles of NADPH oxidase and mitochondria in flow-induced vasodilation of human adipose arterioles: ROS-induced ROS release in coronary artery disease. Microcirculation. 2017;24(6). https://doi.org/10.1111/micc.12380.
Ansari MA, Roberts KN, Scheff SW. A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma. Free Radic Biol Med. 2014;77:21–9. https://doi.org/10.1016/j.freeradbiomed.2014.08.025.
Liu J, Conklin BR, Blin N, Yun J, Wess J. Identification of a receptor/G-protein contact site critical for signaling specificity and G-protein activation. Proc Natl Acad Sci U S A. 1995;92(25):11642–6.
Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev. 2002;23(5):665–86. https://doi.org/10.1210/er.2001-0045.
Prossnitz ER, Arterburn JB, Sklar LA. GPR30: a G protein-coupled receptor for estrogen. Mol Cell Endocrinol. 2007;265–266:138–42. https://doi.org/10.1016/j.mce.2006.12.010.
Meyer MR, Haas E, Prossnitz ER, Barton M. Non-genomic regulation of vascular cell function and growth by estrogen. Mol Cell Endocrinol. 2009;308(1–2):9–16. https://doi.org/10.1016/j.mce.2009.03.009.
Anwar MA, Samaha AA, Baydoun S, Iratni R, Eid AH. Rhus coriaria L. (Sumac) evokes endothelium-dependent vasorelaxation of rat aorta: involvement of the cAMP and cGMP pathways. Frontiers in pharmacology. 2018;9:688. https://doi.org/10.3389/fphar.2018.00688.
Eid AH. cAMP induces adhesion of microvascular smooth muscle cells to fibronectin via an Epac-mediated but PKA-independent mechanism. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2012;30(1):247–58. https://doi.org/10.1159/000339061.
Chotani MA, Mitra S, Eid AH, Han SA, Flavahan NA. Distinct cAMP signaling pathways differentially regulate alpha2C-adrenoceptor expression: role in serum induction in human arteriolar smooth muscle cells. Am J Physiol Heart Circ Physiol. 2005;288(1):H69–76. https://doi.org/10.1152/ajpheart.01223.2003.
Motawea HK, Jeyaraj SC, Eid AH, Mitra S, Unger NT, Ahmed AA, et al. Cyclic AMP-Rap1A signaling mediates cell surface translocation of microvascular smooth muscle alpha2C-adrenoceptors through the actin-binding protein filamin-2. American journal of physiology Cell physiology. 2013;305(8):C829–45. https://doi.org/10.1152/ajpcell.00221.2012.
Jeyaraj SC, Unger NT, Eid AH, Mitra S, Paul El-Dahdah N, Quilliam LA, et al. Cyclic AMP-Rap1A signaling activates RhoA to induce alpha(2c)-adrenoceptor translocation to the cell surface of microvascular smooth muscle cells. American journal of physiology Cell physiology. 2012;303(5):C499–511. https://doi.org/10.1152/ajpcell.00461.2011.
Eid AH, Chotani MA, Mitra S, Miller TJ, Flavahan NA. Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle alpha2C-adrenoceptors. Am J Physiol Heart Circ Physiol. 2008;295(1):H266–72. https://doi.org/10.1152/ajpheart.00084.2008.
Jankowski M, Rachelska G, Donghao W, McCann SM, Gutkowska J. Estrogen receptors activate atrial natriuretic peptide in the rat heart. Proc Natl Acad Sci U S A. 2001;98(20):11765–70. https://doi.org/10.1073/pnas.201394198.
Chen H, Levine YC, Golan DE, Michel T, Lin AJ. Atrial natriuretic peptide-initiated cGMP pathways regulate vasodilator-stimulated phosphoprotein phosphorylation and angiogenesis in vascular endothelium. J Biol Chem. 2008;283(7):4439–47. https://doi.org/10.1074/jbc.M709439200.
Gao X, Wang HS. Impact of bisphenol A on the cardiovascular system - epidemiological and experimental evidence and molecular mechanisms. Int J Environ Res Public Health. 2014;11(8):8399–413. https://doi.org/10.3390/ijerph110808399.
Shankar A, Teppala S. Urinary bisphenol A and hypertension in a multiethnic sample of US adults. J Environ Public Health. 2012;2012:481641. https://doi.org/10.1155/2012/481641.
Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS. Association of urinary bisphenol A concentration with heart disease: evidence from NHANES 2003/06. PLoS One. 2010;5(1):e8673. https://doi.org/10.1371/journal.pone.0008673.
Aungst J. 2014 Updated safety assessment of bisphenol A (BPA) for use in food contact applications. In: SERVICES DOHH, editor.: Public Health Service Food and Drug Administration; 2014.
vom Saal FS, Akingbemi BT, Belcher SM, Birnbaum LS, Crain DA, Eriksen M, et al. 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. Reprod Toxicol. 2007;24(2):131–8. https://doi.org/10.1016/j.reprotox.2007.07.005.
Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006;147(6 Suppl):S56–S69. https://doi.org/10.1210/en.2005-1159.
Morrissey RE, George JD, Price CJ, Tyl RW, Marr MC, Kimmel CA. The developmental toxicity of bisphenol A in rats and mice. Fundam Appl Toxicol. 1987;8(4):571–82.
Somm E, Schwitzgebel VM, Toulotte A, Cederroth CR, Combescure C, Nef S, et al. Perinatal exposure to bisphenol A alters early adipogenesis in the rat. Environ Health Perspect. 2009;117(10):1549–55. https://doi.org/10.1289/ehp.11342.
vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, et al. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997;94(5):2056–61.
Das UN. Free radicals, cytokines and nitric oxide in cardiac failure and myocardial infarction. Mol Cell Biochem. 2000;215(1–2):145–52. https://doi.org/10.1023/A:1026579422132.
Moustafa GG, Ahmed AAM. Impact of prenatal and postnatal exposure to bisphenol A on female rats in a two generational study: Genotoxic and immunohistochemical implications. Toxicol Rep. 2016;3:685–95. https://doi.org/10.1016/j.toxrep.2016.08.008.
Genuis SJ, Beesoon S, Birkholz D, Lobo RA. Human excretion of bisphenol A: blood, urine, and sweat (BUS) study. J Environ Public Health. 2012;2012:185731. https://doi.org/10.1155/2012/185731.
Yan SJ, Song WZ, Chen YM, Hong K, Rubinstein J, Wang HS. Low-dose bisphenol A and estrogen increase ventricular arrhythmias following ischemia-reperfusion in female rat hearts. Food Chem Toxicol. 2013;56:75–80. https://doi.org/10.1016/j.fct.2013.02.011.
Yan S, Chen Y, Dong M, Song W, Belcher SM, Wang HS. Bisphenol A and 17beta-estradiol promote arrhythmia in the female heart via alteration of calcium handling. PLoS One. 2011;6(9):e25455. https://doi.org/10.1371/journal.pone.0025455.
•• Posnack NG, Brooks D, Chandra A, Jaimes R, Sarvazyan N, Kay M. Physiological response of cardiac tissue to bisphenol A: alterations in ventricular pressure and contractility. Am J Physiol-Heart C. 2015;309(2):H267–H75. https://doi.org/10.1152/ajpheart.00272.2015This original mansucript shows how BPA negatively impact electrical conduction and venticular contractility in excised rat hearts.
Patel BB, Raad M, Sebag IA, Chalifour LE. Lifelong exposure to bisphenol A alters cardiac structure/function, protein expression, and DNA methylation in adult mice. Toxicol Sci. 2013;133(1):174–85. https://doi.org/10.1093/toxsci/kft026.
Bae S, Kim JH, Lim YH, Park HY, Hong YC. Associations of bisphenol A exposure with heart rate variability and blood pressure. Hypertension. 2012;60(3):786−+. https://doi.org/10.1161/Hypertensionaha.112.197715.
Khalil N, Ebert JR, Wang L, Belcher S, Lee M, Czerwinski SA, et al. Bisphenol A and cardiometabolic risk factors in obese children. Sci Total Environ. 2014;470:726–32. https://doi.org/10.1016/j.scitotenv.2013.09.088.
Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol. 2007;24(2):139–77. https://doi.org/10.1016/j.reprotox.2007.07.010.
Gould JC, Leonard LS, Maness SC, Wagner BL, Conner K, Zacharewski T, et al. Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. Mol Cell Endocrinol. 1998;142(1–2):203–14.
Noguchi S, Nakatsuka M, Asagiri K, Habara T, Takata M, Konishi H, et al. Bisphenol A stimulates NO synthesis through a non-genomic estrogen receptor-mediated mechanism in mouse endothelial cells. Toxicol Lett. 2002;135(1–2):95–3. Pii S0378–4274(02)00252–7. https://doi.org/10.1016/S0378-4274(02)00252-7.
Belcher SM, Chen YM, Yan SJ, Wang HS. Rapid estrogen receptor-mediated mechanisms determine the sexually dimorphic sensitivity of ventricular myocytes to 17 beta-estradiol and the environmental endocrine disruptor bisphenol A. Endocrinology. 2012;153(2):712–20. https://doi.org/10.1210/en.2011-1772.
Pant J, Ranjan P, Deshpande SB. Bisphenol A decreases atrial contractility involving NO-dependent G-cyclase signaling pathway. J Appl Toxicol. 2011;31(7):698–702. https://doi.org/10.1002/jat.1647.
Marinko M, Novakovic A, Nenezic D, Stojanovic I, Milojevic P, Jovic M, et al. Nicorandil directly and cyclic GMP-dependently opens K+ channels in human bypass grafts. J Pharmacol Sci. 2015;128(2):59–64. https://doi.org/10.1016/j.jphs.2015.03.003.
• Anwar MA, Saleh AI, Al Olabi R, Al Shehabi TS, Eid AH. Glucocorticoid-induced fetal origins of adult hypertension: association with epigenetic events. Vascular Pharmacol. 2016;82:41–50. https://doi.org/10.1016/j.vph.2016.02.002An important review discussing how adult-onset hypertension may be intimately associated with epigenetic alteration resulting from fetal exposure to molecules like glucocorticoids.
Alexander BT, Dasinger JH, Intapad S. Fetal programming and cardiovascular pathology. Compr Physiol. 2015;5(2):997–1025. https://doi.org/10.1002/cphy.c140036.
Schonfelder G, Wittfoht W, Hopp H, Talsness CE, Paul M, Chahoud I. Parent bisphenol A accumulation in the human maternal-fetal-placental unit. Environmental health perspectives. 2002;110(11):A703-A7. https://doi.org/10.1289/ehp.021100703.
Iwamuro S, Sakakibara M, Terao M, Ozawa A, Kurobe C, Shigeura T, et al. Teratogenic and anti-metamorphic effects of bisphenol A on embryonic and larval Xenopus laevis. Gen Comp Endocr. 2003;133(2):189–98. https://doi.org/10.1016/S0016-6480(03)00188-6.
Watson CS, Bulayeva NN, Wozniak AL, Alyea RA. Xenoestrogens are potent activators of nongenomic estrogenic responses. Steroids. 2007;72(2):124–34. https://doi.org/10.1016/j.steroids.2006.11.002.
•• Chapalamadugu KC, Vandevoort CA, Settles ML, Robison BD, Murdoch GK. Maternal bisphenol A exposure impacts the fetal heart transcriptome. PLoS One. 2014;9(2):e89096. https://doi.org/10.1371/journal.pone.0089096A very interesting paper that elegantly shows how fetal exposure to BPA alters the heart transcriptome in rhesus monkeys (Macaca multatta).
• MohanKumar SM, Rajendran TD, Vyas AK, Hoang V, Asirvatham-Jeyaraj N, Veiga-Lopez A, et al. Effects of prenatal bisphenol A exposure and postnatal overfeeding on cardiovascular function in female sheep. J Dev Orig Health Dis. 2017;8(1):65–74. https://doi.org/10.1017/S204017441600057XAn important paper that sheds light on how prenatal exposure to BPA may have deleterious effects on cardiac functions, especially when animals becomes obese as they age.
vom Saal FS, Hughes C. An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment. Environ Health Perspect. 2005;113(8):926–33. https://doi.org/10.1289/ehp.7713.
This publication was made possible by an MPP Fund (#320133) from the American University of Beirut-Faculty of Medicine to and a Farouk Jabre Research Award to Dr. Ali Eid.
Conflict of Interest
The authors declare no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Hypertension and the Heart
Rights and permissions
About this article
Cite this article
Wehbe, Z., Nasser, S.A., El-Yazbi, A. et al. Estrogen and Bisphenol A in Hypertension. Curr Hypertens Rep 22, 23 (2020). https://doi.org/10.1007/s11906-020-1022-z
- Bisphenol A
- Cardiovascular disease
- Environmental pollution