Endocrine Disruptors and the Heart: Unraveling the Cardiovascular Impact

INTRODUCTION

“Endocrine disruptors” are exogenous compounds that negatively impact endocrine functions and demonstrate a definite cause-and-effect relationship in individuals, offspring, or subpopulations exposed to them.^[1,2] Endocrine society defines EDC as “An Exogenous chemical, or mixture of chemicals, that interfere with hormone action.” They can originate from natural sources such as plants (phytoestrogens), animals, or humans. More commonly, endocrine disruptors are of environmental origin , and are otherwise known as endocrine-disrupting chemicals (EDCs). Exposure to EDCs can occur through inhalation (e.g., plasticizers), oral (e.g., food), dermal (e.g., cosmetics), embryonic transfer (e.g., from mother), and transfer to offspring through breast milk.

The publication of Rachel Carson’s Silent Spring in 1962 was a pivotal turning point that brought attention to the environmental and health impacts of synthetic pesticides, particularly dichlorodiphenyltrichloroethane (DDT). It highlighted the harmful effects on wildlife, particularly bird populations, and raised concerns about human cancer risks. This led to the nationwide ban on DDT in the United States and the creation of the Environmental Protection Agency.^[3] The year 1971 was pivotal for the discovery of transplacental carcinogenic effect of diethylstilbestrol (DES), a synthetic estrogen given to pregnant women to prevent miscarriages at the time, leading to cancer and reproductive issues in the daughters of women who had taken the drug during pregnancy. This catastrophe emphasized the dangers of endocrine disruptors, especially during pregnancy.^[4] In 1991, the term “Endocrine Disruptor” was coined during the Wingspread Conference, recognizing chemicals that interfere with the hormonal system.^[5]

EDCs have been increasingly recognized in our ecosystem since the discovery of their harmful effects. Their widespread presence in the environment raises major concerns about the impact of EDCs on human health, especially their role in the development of chronic conditions such as diabetes, obesity, and cardiovascular disease (CVD).^[6-9] The health implications of EDCs also span across generations. There is mounting evidence linking preterm delivery and intrauterine growth restriction to in utero exposure to EDCs.^[10-13]

Given the high prevalence of type 2 diabetes mellitus (T2DM) and macrovascular disease in contemporary society, it is imperative to understand the associations between environmental contaminants and these disease states to develop successful preventative measures and explore novel therapeutic strategies.

COMMON EDCs AND WHERE THEY ARE FOUND

EDCs are pervasive in nature and include phenols, phthalates, parabens, flame retardants, heavy metals, pesticides, perfluorinated chemicals, ultraviolet filter components, triclosan, and organochlorines. Among these, of particular concern are polychlorinated biphenyls (PCBs), polybrominated biphenyls, dioxins, bisphenols, DDT, vinclozolin, DES, and heavy metals, such as cadmium, mercury, arsenic, lead, manganese, and zinc. These chemicals are found in industrial products, agricultural pesticides, plastics, packaged foods, cosmetics, and pharmaceuticals.^[14-16] EDCs are thought to number more than 4000 currently and their presence in the environment is being increasingly recognized. Pertinent EDCs present in the environment and their health implications are been listed in Table 1.^[17]

CLASSIFICATION OF EDCs

EDCs can be classified as persistent EDCs and non-persistent EDCs. DDT, dichlorodiphenyl dichloroethylene (DDE), PCBs, polybrominated diphenyl ether, and per- and polyfluoroalkyl substances (PFAS) are persistent EDCs, they can persist in the environment for decades.^[18] This can occur secondary to bioamplification or biomagnification, which refers to an increase in the concentration of a substance as it moves up the food chain. This occurs when a pollutant is persistent; it cannot be, or is very slowly, broken down by natural processes. Hence, these persistent pollutants are transferred up the food chain faster than they are broken down. The extended latency interval between illness and exposure makes it challenging to establish a definitive cause-and-effect relationship.^[19]

Phenols, phthalates, parabens, acrylamide, and solvents are non-persistent EDCs. However, they can bioaccumulate in adipose tissue and lead to adverse health outcomes.^[20] Bioaccumulation refers to the process where a concentration of a substance, typically lipophilic rather than hydrophilic, builds up in the tissues because it is absorbed more quickly than eliminated (eg: DDT in adipose tissues). EDCs can also be classified as per their health impact such as those causing cardiometabolic effects, effects on reproductive axis, etc., which are discussed in detail in the subsequent sections.

MECHANISM OF ACTION OF EDCs

EDCs can interfere with hormonal signaling in the body through various mechanisms, primarily by functioning as receptor agonists or antagonists. As receptor agonists, EDCs mimic the structure of natural hormones, binding to hormone receptors and enhancing or initiating hormonal responses. Conversely, as receptor antagonists, EDCs bind to the same receptors but block their activity, preventing the natural hormone from exerting its effects.^[20] For nuclear hormone receptors, this interference extends to disrupting the receptor-hormone complex’s ability to bind to DNA, thereby altering the transcription of gene cascades and affecting downstream biological processes. These actions underline the significant impact of EDCs on endocrine system regulation and gene expression. The ways in which EDCs interact with cell surface and nuclear receptors to cause downstream effects are demonstrated in Figure 1.

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Figure 1:

Mechanisms of action of endocrine disrupting chemicals.

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PATHOPHYSIOLOGICAL MECHANISMS OF EDCs AFFECTING CARDIOVASCULAR SYSTEM

EDCs can impact cardiovascular function through several molecular and cellular mechanisms which primarily involve the disruption of hormonal signaling pathways. The major mechanisms by which EDCs influence cardiovascular health have been summarized in Figure 2, and discussed in detail as follows:

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Figure 2:

Mechanisms of impact of endocrine disrupting chemicals on cardiovascular health.

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• Hormone Receptor Binding and Activation: Many EDCs either mimic or block the actions of natural hormones by interacting with hormone receptors, which play a key role in cardiovascular functions. Estrogens support cardiovascular health by regulating vascular tone, cholesterol metabolism, and endothelial function. Bisphenol A (BPA) can bind to estrogen receptors, leading to abnormal signaling, which can result in arterial stiffness, endothelial dysfunction, and altered lipid metabolism.^[21] EDCs, such as certain pesticides, can disrupt androgen signaling, which may impair vascular function and elevate the risk of hypertension (HTN) and CVD in males. PCBs can interfere with thyroid hormone signaling, leading to changes in heart rate, cholesterol metabolism, and an increased risk of atherosclerosis and arrhythmias.^[15]

• Oxidative Stress and Inflammation: Many EDCs elevate oxidative stress levels in cardiovascular tissues. Excessive production of reactive oxygen species damages proteins, lipids, and endothelial cells, contributing to HTN and atherosclerosis.^[9] Chronic vascular inflammation may also arise from EDC-induced activation of pro-inflammatory signaling pathways, such as the nuclear factor kappa-light-chain-enhancer of activated B-cells pathway. This persistent inflammation plays a crucial role in the progression of atherosclerosis, cardiac remodeling, and endothelial dysfunction.^[22]

• Endothelial Dysfunction: EDCs like BPA reduce nitric oxide (NO) bioavailability by inducing oxidative stress or disrupting the NO synthase (NOS) pathway, which impairs vasodilation and elevates blood pressure.^[23] Prolonged exposure to EDCs can compromise the integrity of endothelial cells, increasing vascular permeability and facilitating the development of atherosclerosis.^[24]

• Altered Lipid Metabolism: EDCs, including phthalates and BPA, can interfere with peroxisome proliferator-activated receptors (PPARs) which leads to triglyceride accumulation, decreased high-density lipoprotein (HDL), and increased low-density lipoprotein (LDL) cholesterol, all of which contribute to the development of atherosclerosis.^[25]

• Insulin Resistance (IR): EDCs such as phthalates and BPA can disrupt insulin signaling, leading to IR.^[7,26] Furthermore, EDCs may impair cellular glucose uptake, increasing the risk of hyperglycemia and diabetes.^[27]

• Obesogens: Some EDCs, known as “obesogens,” promote adipogenesis, resulting in obesity, which is a major risk factor for CVD, HTN and heart failure.^[28] Exposure to obesogens during sensitive periods of early development predisposes individuals to weight gain due to changes in metabolic set-points.^[29,30]

• Mitochondrial Dysfunction: EDC-induced mitochondrial dysfunction can lead to the apoptosis of cardiomyocytes and endothelial cells, which contributes to cardiac remodeling and loss of vascular integrity.^[31]

• Epigenetic Modifications: EDCs can alter DNA methylation patterns and histones, affecting the expression of genes involved in regulating blood pressure, cholesterol metabolism, and vascular function.^[32] These epigenetic modifications may be passed down to future generations, potentially increasing the risk of CVD in children who have not been directly exposed to the chemicals.^[33]

• Miscellaneous actions: EDCs, such as BPA and certain heavy metals, can elevate angiotensin II levels, contributing to HTN and cardiac hypertrophy.^[34] In addition, some EDCs can elevate aldosterone secretion, leading to HTN and a higher risk of heart failure by promoting sodium and water retention.^[35] EDCs, such as lead and cadmium, can disrupt calcium homeostasis and cause arrhythmias, poor cardiac muscle contractility, and impaired vascular function by interfering with calcium signaling.^[36]

SPECIFIC EDCs AND CARDIOVASCULAR EFFECTS

DIABETOGENIC AND OBESOGENIC EFFECTS OF EDCS

The Parma Consensus 2015 introduced the “Metabolic Disruptor Hypothesis,” which explains how EDCs interfere with human metabolism, contributing to disorders such as obesity, type 2 diabetes, and MS. EDCs disrupt the hypothalamus, altering gene expression and leptin signaling, leading to metabolic dysregulation. In adipose tissue, they promote fat accumulation and IR. In the liver, EDCs cause epigenetic changes, promoting steatosis and lipogenesis. EDCs also impair insulin production in the pancreas, causing oxidative stress and β-cell exhaustion. In skeletal muscle, EDCs disrupt insulin signaling, impair glucose uptake, and reduce antioxidant defenses. In addition, EDCs affect the gut microbiota, altering its composition and contributing to metabolic disorders. Together, these disruptions lead to conditions such as obesity, MS, non-alcoholic fatty liver disease, and T2D, illustrating the broad impact of EDCs on human health.^[67]

Evidence summarizing the metabolic implications of EDCs have been discussed below:

TRANSGENERATIONAL IMPLICATIONS OF EDCs

The Developmental Origins of Health and Disease hypothesis posits that exposure to environmental factors, including EDCs, during critical periods of prenatal and early life development can result in permanent changes in the body’s structure, physiology, and metabolism, which can predispose individuals to chronic conditions such as CVDs, diabetes, and obesity later in life. Important transgenerational implications of EDCs have been summarized below:

EFFECTS OF EDCS ON REPRODUCTIVE HEALTH

EDCs significantly impact female reproductive health, causing infertility, hormonal imbalances, polycystic ovarian syndrome, endometriosis, and uterine fibroids. These effects, coupled with rising EDC exposure, contribute to declining global fertility rate.^[85] EDCs adversely affect male reproductive health, causing precocious puberty, delayed puberty, and infertility. These effects are linked to exposure to phthalates, PCBs, pesticides, pharmaceuticals, and other toxic substances.^[86]

HOW TO AVOID EXPOSURE TO EDCs?

EDCs have well-documented negative health consequences, especially on the cardiovascular, metabolic, and reproductive systems; thus, there is an urgent need to minimize exposure. Protecting vulnerable groups, such as children and pregnant women, is all the more critical to minimize their effects on current and future generations. The pervasive nature of EDCs makes this task very challenging, and hence, proactive measures must be implemented both at individual level, through lifestyle changes to reduce exposure and at the regulatory level, with strict policies and enforcement by concerned authorities to mitigate these risks.

Strategies to mitigate EDC exposure at individual level:

• Avoiding smoking and second hand smoke:^[14]

• Food handling:

  • Prefer organic and pesticide-free produce^[87]

  • Avoiding fast foods and processed foods^[88]

  • Limiting foods high in animal fat^[89]

  • Avoiding plastic food containers/bottles

  • Avoiding microwaving in plastic containers^[90]

  • Replacing non-stick cookware when damaged^[91]

• Checking ingredient list in cosmetics and skin care products. Choosing products that are labeled as “paraben-free” or “phthalate-free”^[92]

• Avoiding pesticide use around home^[93]

• Using volatile organic compound-free and water-based paints^[94]

• Implementing the tenets of 4 R’s: Reduce, reuse, recycle and recover.

Simple swaps to minimize EDC exposure in daily life are shown in Figure 3.

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Figure 3:

Easy endocrine disruptor swaps in daily life.

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Strategies for reducing EDC exposure at regulatory level:

• Strengthening premarketing studies and regulations

• Promoting research for safer alternatives

• Measures to decrease production of EDCs and entry into ecosystem

• Initiatives for raising public awareness

• Strong legislative interventions for mitigating exposure of general public.

The unfortunate fact remains that EDCs are pervasive and cannot be completely removed or avoided. However, individuals and societies can play a crucial role in minimizing EDC exposure and its associated health risks by adopting these practices and advocating for stricter regulations.

CONCLUSION

EDCs are widespread and present in everyday items like plastics, food packaging, personal care products, and even water. Their harmful effects can extend across generations, increasing the risk of obesity, T2D, and other chronic conditions. While small changes in daily lifestyle, such as reducing the use of plastics, choosing organic products, and reading product labels, can help reduce exposure at an individual level, a holistic solution requires steps to be taken at governmental level. Regulatory bodies and lawmakers must implement stricter guidelines and promote safer alternatives to mitigate the long-term impact of EDCs. Hence, protecting the current and future generations from these chemicals demands collective efforts from both individuals and policymakers.