Environmental Medicine Update

by Marianne Marchese, ND

Heart Disease and Hormone Disruptors

Introduction

Bisphenol A (BPA) and phthalates are common chemicals present in plastic beverage bottles, baby bottles, canned foods, dental sealants, plastic wrap, plastic food storage containers, cosmetics, and other common household products. These chemicals have hormone mimicking properties and are often called hormone disruptors. Both BPA and phthalates have been linked to reproductive health problems in both men and women, specifically; prostate cancer, breast cancer, thyroid disorders, infertility, endometriosis, fibroids and PCOS.¹ Recently, these chemicals have been discovered to disrupt more than hormones in the body and are now being linked to cardiovascular disease.

Hormone Disruptors

Most people in the US are exposed to BPA and phthalates daily, often without knowing it. These chemicals can be fund circulating in the body at any given time. We know this from studies done to determine the body burden of chemicals in the general population. In the Fourth National Report on Human Exposure to Environmental Chemicals, CDC scientists measured BPA in the urine of over 2400 participants aged 6 years and older who took part in CDC’s National Health and Nutrition Examination Survey (NHANES) during 2003–2004. CDC scientists found BPA in the urine of more than 90% of the people tested. CDC scientists also measured 13 phthalate metabolites in the urine of more than 2600 participants. Many of the phthalates were found in the urine, with estimates that over 80% had detectable phthalate metabolites present. The full report can be found online at www.cdc.gov/exposurereport. It is clear from these body burden studies that exposure to these chemicals is widespread. What isn’t clear is their role in the development of cardiovascular disease.

Heart Disease

Cardiovascular disease is often associated with atherosclerosis or hardening of the arteries. Many factors contribute to atherosclerosis, and recently researchers began looking at BPA and phthalates. In a study published in the Journal of Atherosclerosis in 2011, 1016 participants, all aged 70, underwent ultrasound testing for plaques in both carotid arteries and the thickness of the arteries was measured as well. Each participant was also measured for blood levels of BPA and 10 phthalates. The study determined that the phthalate metabolite MMP was related to atherosclerotic plaques independently of CV risk factors. Some phthalates and BPA were also related to the echogenicity of the plaques, which is an ability of the ultrasound to create an echo in the plaque, suggesting a role for plaque-associated chemicals in atherosclerosis.² Echogenic plaques have a higher content of calcifications. The phthalate MMP is found in insect repellant, plastics, and water pollution from cosmetic chemicals and cleaning supplies.³

David Melzer, an epidemiologist at the University of Exeter (UK), and colleagues were the first to show an association between higher levels of BPA metabolites in urine and heart disease. Melzer used data from the NHANES 2003–2004 and 2005–2006 to assess the health status of the general US population who had high levels of BPA. The study found that higher urinary BPA concentrations were associated with cardiovascular diagnoses (Table 1.)⁴ While this study is helpful for making associations and may help research in the future, cross-sectional studies such as these cannot say whether BPA contributes to heart disease or if heart disease changes the exposure to or metabolism of BPA in adults. The mechanism of BPA and phthalates in heart disease needs to be addressed

Table 1

Disease prevalence, and survey weighted, age, gender and ethnicity adjusted model estimates (odds ratios with 95% confidence intervals) of associations with per standard deviation increases of bisphenol A concentration with adjustment for urinary creatinine: adults aged 18 to 74.

	NHANES 2003–2004	NHANES 2005–2006	Pooled data
Condition	N (%)	OR (95% CI), p-value	N (%)	OR (95% CI), p-value	N (%)	OR (95% CI), p-value
Myocardial Infarction	42/1277 (2.8)	1.34 (1.11 to 1.61), p = 0.004	38/1329 (3.2)	1.31 (1.02 to 1.68), p = 0.036	80/2606 (3.0)	1.28 (1.13 to 1.46), p = 0.001
Angina	42/1274 (2.7)	1.26 (1.08 to 1.46), p = 0.006	31/1327 (2.4)	1.29 (0.98 to 1.70), p=0.064	73/2602 (2.5)	1.27 (1.10 to 1.47), p = 0.002
Coronary heart disease	46/1276 (2.8)	1.45 (1.16 to 1.80), p = 0.003	42/1328 (3.3)	1.29 (0.96 to 1.74), p=0.089	88/2605 (3.1)	1.37 (1.16 to 1.63), p = 0.001
CVD (any diagnoses of MI, angina or CHD)	83/1279 (5.0)	1.31 (1.10 to 1.56), p = 0.005	76/1331 (5.9)	1.21 (0.92 to 1.59), p=0.164	159/2610 (5.5)	1.26 (1.11 to 1.43), p = 0.001
Diabetes	136/1456 (7.9)	1. 41 (1.21 to 1.64), p = 0.0003	141/1491 (8.8)	1.07 (0.85 to 1.34), p=0.536	277/2947 (8.4)	1.27 (1.12 to 1.43), p = 0.0004

©Melzer et al. PLoS One. 2010;5(1):e8673. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided that the original author and source are credited.

The Mechanism

Scott Belcher, PhD, associate professor in the University of Cincinnati Department of Pharmacology and Cell Biophysics, discovered that BPA exposure increases risk of abnormal heart rhythms in female rodents. The study was funded by the National Institutes of Health and found that low-dose BPA and estrogen can act alone or in combination to increase harmful arrhythmias in female rats and mice. Mice and rats in the study had normal heart rhythms at baseline, before administration of BPA or estradiol. The investigators studied heart rhythms in both the working heart and in cultured heart muscle cells. In both models, exposure to BPA increased the frequency of arrhythmias compared with baseline in females but not in male animals. Administration of estrogen alone also increased the frequency of arrhythmias in females. Arrhythmias were most frequent in the female rats and mice when they received both BPA and estrogen, at levels normally found in female humans. The mechanism discovered was exposure to estradiol and/or BPA rapidly altered myocyte calcium handling. Estrogens markedly increased sarcoplasmic reticulum calcium leak, and increased sarcoplasmic reticulum load.⁵ Another study done on human coronary smooth muscle cells showed that BPA activates Maxi-K channels in the heart. ⁶

Phthalates role in the development of heart disease has also been explored. Di-(2-ethylhexyl)-phthalate (DEHP) is common phthalate monoester and is a widely used plasticizer found in polyvinyl chloride products. It has been shown that DEHP can affect electrical coupling between cardiac myocytes causing significant rhythm disturbances. ⁷

The mechanism was discovered by studying rat cardiomyocytes. Exposure of neonatal rat cardiomyocytes to clinically relevant DEHP concentrations leads to global changes in mRNA expression. These changes help to explain the arrhythmogenic effects of phthalates on these cells.⁷ It is important to note that, as with most chemical effects in the body, probably more than one mechanism of action of BPA and phthalates on the heart exists.

Genetics

It is clear that the general population is exposed to BPA and phthalates, not surprising given their widespread exposure. As their effects on the cardiovascular system come to light, the role of genetics and genetic polymorphisms helps explain why some of the population develops heart disease with chemical exposure and others do not. The cytochrome P450 system (CYP) is a multigene superfamily of enzymes, which are important in the metabolism of exogenous and endogenous compounds. Genetic variations can lead to reduced, absent, or increased enzymatic activity. These genetic variations are called single nucleotide polymorphisms (SNPs) and can affect the ability of the CYP system to function. In the past, the liver’s CYP system has been looked at in terms of its role in the effects of chemicals on the body. As new evidence suggests that exposure to chemicals affects the cardiovascular system, we need to look at the cardiac CYP system. Cardiac expression of CYP subfamilies indentified in mammalian species include CYP1A, CYP1B, CYP2A, CYP2B, CYP2D, CYP2E, CYP2J, CYP2R, CYP2S, CYP2U, CYP4A, CYP4B, CYP4F, and CYP11B.⁸ Individual variations (SNPs) in these cardiac enzymes may make someone more susceptible to the effects of BPA and phthalate exposure or simply more susceptible to heart disease. There are commercial labs that test for SNPs in genes related to cardiovascular disease. It is possible to test for SNPs that modulate blood pressure regulation, lipid balance, nutrient metabolism, inflammation, and oxidative stress.

Summary

Chemicals such as BPA and phthalates have long been known to cause hormonal disruption in men and women. New evidence suggests a link between these hormone-disrupting compounds and heart disease. Although genetics plays a role in determining who develops disease linked to chemical exposure, it is important that people are made aware of how to avoid exposure to these chemicals. Physicians can offer testing to determine someone’s body burden of BPA and phthalates and offer treatment not only for cardiovascular disease but for exposure to these compounds as well. Learn more in the book 8 weeks to Women’s Wellness.

Notes

1. Marchese M. 8 Weeks to Women’s Wellness. Petaluma, CA: Smart Publ.; 2011.

2. Lind PM, Lind L. Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis in the elderly. Atherosclerosis. 2011;218(1):207–213.

3. Environmental Working Group. Monomethyl phthalate [Web page]. http://www.ewg.org/chemindex/chemicals/23305. Accessed Jan 31, 2012.

4. Lang IA et al. Association of urinary bisphenol-A concentration with medical disorders and laboratory abnormalities in adults. JAMA. 2008;300(11):1303–1310.

5. Yan S et al. Bisphenol A and 17β-estradiol promote arrhythmia in the female heart via alteration of calcium handling. PLoS One. 2011;6(9):e25455.

6. Asano A, Tune JD, Dick GM. Bisphenol A activates Maxi-K (K_Ca1.1) channels in coronary smooth muscle. Br J Pharmacol. 2010;160(1):160–170.

7. Posnack NG et al. Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity. Toxicology. 2011 Jan 11;279(1–3):54–64.

8. Chaudhary KR, Batchu SN, Seubert JM. Cytochrome P450 enzymes and the heart. IUBMB Life. 2009 Oct;61(10):954–960.

Dr. Marchese is the author of 8 Weeks to Women’s Wellness: The Detoxification Plan for Breast Cancer, Endometriosis, Infertility, and other Women’s Health Conditions. Dr. Marchese graduated from the National College of Naturopathic Medicine. She maintains a private practice in Phoenix, Arizona, and teaches gynecology at Southwest College of Naturopathic Medicine. She was named in Phoenix Magazine‘s 2010 Top Doctor Issue as one of the top naturopathic physicians in Phoenix. Dr. Marchese is a contributing author for the Townsend Letter and lectures on topics related to women’s health and environmental medicine throughout the US and Canada. She is past vice president of the Arizona Naturopathic Medical Association and current member of the board of directors for the Council on Naturopathic Medical Education.