Bisphenol A

A Multi-modal Endocrine Disruptor

Natalie R Gassman

• Publisher: Royal Society of Chemistry
• Year: 2022
• ISBN:
  9781839166501
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

Bisphenol A (BPA) is a high production volume endocrine-disrupting chemical present in numerous consumer products. Extensive use of BPA has led to wide-spread contamination in the air, soil, and water, leading to ubiquitous human exposure. Research into BPA has grown exponentially over the past ten years, with numerous modes of action being identified that impact human health and disease development. While BPA has estrogenic effects, emerging literature has identified several non-receptor mediated modes of action, such as epigenetic reprogramming, that can affect the long-term health of the population. This book highlights the multiple modes of action BPA can use to reprogram cells genetically and metabolically. By compiling critical studies in BPA and outlining the connections and disparities in the literature to build a broader understanding of this complex endocrine-disrupting chemical and its impact on the environment and human health, this book is an ideal resource for postgraduates and researchers in a range of disciplines from toxicology to epigenetics and cancer epidemiology.

Chapter 1

Classical and Non-classical Estrogen Receptor Effects of Bisphenol A

Manoj Sonavane^a

^a Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA Email: [email protected]

1.1 Introduction

The word estrogen is commonly used to refer to 17β-estradiol (E2) due to its physiological relevance and predominance during reproductive growth. Estrogens are sex steroid hormones primarily synthesized in the ovaries and the adrenal glands, adipose tissue, brain, and testis. Estrogen displays a broad spectrum of physiological functions, including regulation of the menstrual cycle and reproduction, bone density, brain function, cholesterol mobilization, control of inflammation, and development of breast tissue and sexual organs.¹ While estrogens play diverse and similar physiological roles in both sexes,² they control primary and secondary sexual characteristics in females. In puberty, estradiol (E2) promotes epithelial cell proliferation and mammary glands, whereas estrogen helps prepare the mammary gland for milk production during pregnancy.^2–5 The lower levels of estrogens produced in men are essential for sperm maturation, erectile function, and healthy libido.⁶ Besides this sexual and reproductive role, E2 exerts many actions in other systems such as the adipose tissue, bone, brain, cardiovascular system, endocrine system, pancreas, liver, and skeletal muscle.^7,8 It is important to note that any synthetic or semi-synthetic steroid that mimics the effects of natural estrogens is considered an estrogen.

1.2 Mechanism of Estrogen Signaling

All the physiological functions of estrogen are mediated via estrogen receptors (ERs). In 1958, Elwood Jensen discovered ERs by showing that female reproductive tissues could uptake estrogen from the circulation by binding to proteins. Later, those estrogen-bound receptors migrated to the nucleus, stimulating the transcription of various genes.^9,10 To date, several mechanisms for ER transcriptional regulation have been described in the literature. A classical mechanism is where E2 interacts with intracellular estrogen receptor (ERα or ERβ) resulting in receptor dimerization. This complex is then translocated to the nucleus, where it binds to estrogen response element (ERE) sequences through their DNA-binding domains.¹¹

Estrogens are also shown to regulate transcription of several genes that do not contain EREs in their promoter regions, the mechanisms known as “indirect genomic signaling” or “transcriptional cross-talk.” Here, estrogen indirect signaling influences activation or suppression of target gene expression by acting through protein–protein interactions with other transcription factors such as stimulating protein-1 (Sp-1), activating transcription factor (ATF)-2, Fos/c-jun, the ATF-1/cAMP (cyclic adenosine monophosphate) response element binding protein (ATF-1/CREB), and the nuclear transcription factor-Y (NF-Y).^12–16

Yet, not all estrogen effects fit under the transcriptional regulation of steroid action. The observation of extremely fast estrogen-mediated biological responses led to the hypothesis that estrogen could be acting through mechanisms not involving the direct target gene of G Protein-Coupled Estrogen Receptor 1 (GPER1).¹⁷ In addition, both ERα and ERβ have been identified outside the nucleus, i.e. in the cytoplasm, mitochondria, and associated with the plasma membrane,¹⁸ from where they can rapidly activate other signaling cascades. Both the GPER1 and some variants of ERα or ERβ are associated with non-genomic estrogen signaling.^19,20 Non-genomic actions of the ERα or ERβ could be induced via a sub-population of receptors located at the cell membrane which activate intracellular signaling cascades such as the phospholipase C (PLC)/protein kinase C (PKCs) pathways,²¹ the Ras/Raf/MAPK (mitogen-activated protein kinase) cascade,²² the phosphatidyl inositol 3 kinase (PI3K)/Akt kinase cascade,²³ and the cAMP/protein kinase A (PKA) signaling pathway.^24,25

ER can also be activated in the absence of estrogens or other receptor agonists, an interesting phenomenon observed in many cells and is known as “ligand-independent signaling”.^26–28 This ligand-independent ER activation requires the action of regulatory molecules necessary for phosphorylation, such as PKA, PKC, MAPK phosphorylation cascade, inflammatory cytokines (interleukin (IL)-2), cell cycle regulators (RAS p21 protein activator cyclins A and D1), and peptide growth factors (epidermal growth factor (EGF), insulin, insulin-like growth factor-1, and transforming growth factor-β).²⁹

These various mechanisms of action highlight the complex multifactorial processes induced by estrogen, estrogen-like molecules, and their cellular receptors. Several studies have shown the existence of additional convergent pathways involving both genomic and non-genomic factors that result in the regulation of gene transcription.^28,30

1.3 Estrogenic Assessment of Xenoestrogens, and the Case of Bisphenol A

Xenoestrogens are man-made chemicals that disrupt the endocrine system by mimicking or interfering with the actions of estrogen. These disruptions can lead to estrogen dominance as well as developmental, reproductive, neurological, and immune effects. Xenoestrogens encompass a variety of chemicals, which may be of either synthetic or natural origin. Natural xenoestrogens are represented by phytoestrogens (derived from plants) and mycoestrogens (substances produced by fungi). Synthetic xenoestrogens are molecules produced by chemical synthesis, which are widely used in agricultural chemicals (pesticides) and industrial by-products (certain plastics or detergents), along with pharmaceutical estrogens.³¹ Because of the ability of xenoestrogens to interfere with the endocrine system, they are also classified as endocrine-disrupting chemicals (EDCs). The estrogenic activity of some xenoestrogens such as octyl-phenol and bisphenol A (BPA) was accidentally discovered when they disrupted the experiments that studied the effects of natural estrogens.^32,33 Throughout the years, the appearance of adverse developmental and reproductive effects in aquatic and wildlife species living within or near areas contaminated with xenoestrogens was reported.^34–38 However, substantial evidence has pointed to the fact that these chemicals can mimic the action of the natural estrogen, although they do not exhibit a similar structure to that of estrogens. Thus, it became important to develop accurate assays that could evaluate the risk of xenoestrogens.

Commonly used in vitro screening methods are based on the classical concept of estrogenicity, such as competitive ER-binding assays and yeast-based reporter assays. However, as described earlier, E2 can mediate its estrogenic activity by many other signaling pathways, and not all of them are evaluated by these receptor-based assays. In vitro assays cannot detect pro-estrogens metabolized in vivo to estrogen, which further underestimates the potency of pro-estrogens and their metabolites.³⁹

Bisphenol A, also known as BPA, is a synthetic man-made chemical with a molecular weight of 228.29 g mol⁻¹ with the chemical formula (CH₃)₂C(C₆H₄OH)₂. This monomer was first synthesized by Dianin in 1891 and reported to be a synthetic estrogen in the 1930s.⁴⁰ In the 1950s, BPA was rediscovered as a compound that could be used to synthesize the first epoxy resins as protective coatings and later polymerized to make hard plastic called polycarbonate, which is strong enough to replace steel and clear enough to replace glass.⁴¹ Since then, BPA has been used widely in industrial production and has become one of the highest volume chemicals produced worldwide. More than 6 billion pounds of BPA are produced each year, and >100 tons are released into the atmosphere by yearly production.⁴²

Like other chemicals, BPA can be released (or leached) from these materials under heat stress or through acidic and basic conditions, which accelerates the hydrolysis of the ester bond linking BPA monomers and leads to human exposure.^43–45 It is estimated that BPA-contaminated food contributes to >90% of overall BPA exposure, whereas exposure through dental surgery, dermal absorption, and dust ingestion remains <5% in normal situations.⁴⁶ Overall, human exposure to BPA is consistent and widespread, and biomonitoring studies have reported that >90% of individuals have detectable amounts of BPA in urine samples in the United States, Germany, and Canada.^47–49 Exposure to BPA is a major health concern due to its ability to disrupt the endocrine system,^50,51 and, in many ways, it has become a model EDC. BPA has deleterious effects on the cardiovascular system, alters metabolism, contributes to cancer, and changes immune and reproductive systems. Exposure to BPA is associated with several human diseases.⁵² In contrast with these reports, plastic manufacturers have started to release “BPA-free” plastic material, and the scientific community continues to report the risk of BPA for human beings and wildlife health, highlighting the demand for screening BPA exposures as a research priority.^53–55

The dispute over the safety of the use of BPA has resulted in a deep divide between regulatory toxicologists working for federal agencies or chemical industries and scientists trained in the principles of endocrinology. These principles include the understanding of “low-dose” effects, non-monotonic dose responses, and co-exposure effects, as well as the presence of sex-specific and tissue-specific effects of BPA.^56–59 Another subject of significant debate surrounding BPA exposure is the possible mechanisms by which BPA is thought to exert endocrine-disrupting properties. BPA was initially thought to exert EDC actions primarily by disrupting the activity of the classical estrogen signaling pathways, using ERs as transcription factors binding to the ERE site in the DNA.^60,61 Nowadays, increasing BPA r...

Table of contents

• Cover
• Title
• Copyright
• Contents
• Chapter 1 Classical and Non-classical Estrogen Receptor Effects of Bisphenol A
• Chapter 2 Genotoxicity and Mutagenicity of Bisphenol A
• Chapter 3 Bisphenol A Associated Signaling Pathways in Human Diseases
• Chapter 4 Bisphenol A and Its Impact on Human Telomerase, Telomere Length and Cell Aging
• Chapter 5 The Role of Bisphenol A in Development of Autoimmunity
• Chapter 6 A Novel Model for the Estrogenic Action of BPA in Developing Brain Following Maternal Ingestion
• Chapter 7 Pleiotropic Effects of Bisphenol A Alter Milk Synthesis and Production
• Subject Index