Abstract
With industrialization, the production of chemicals and their introduction into the environment have increased massively. These new agents included many chemical classes and comprise an integral part of the world economy and commerce [1]. Nevertheless, several of the chemicals used today are called endocrine-disrupting compounds (EDCs).
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2.1 Endocrine Disruptors: Impact on Health
With industrialization, the production of chemicals and their introduction into the environment have increased massively. These new agents included many chemical classes and comprise an integral part of the world economy and commerce [1]. Nevertheless, several of the chemicals used today are called endocrine-disrupting chemicals (EDCs).
A chemical agent is classified as an endocrine-disrupting chemical when it can interfere with the synthesis, metabolism, and action of endogenous hormones.
These substances have been even more tested systematically for endocrine-disrupting effects in organisms as the production of large amounts of synthetic industrial and biomedical chemicals, as well as unwanted pollutants, poses destructive consequences to our ecosystem and imposes negative health effects to wildlife and humans [2, 3].
Several compounds have been identified as potential EDCs due to their actions of estrogenic and androgenic gene regulation, altering the synthesis, metabolism, and action of endogenous hormones interfering with different human mechanisms of male and female reproductive systems. The main chemical and natural compounds that are currently classified and approved as EDCs that deserve a special attention are summarized in Table 2.1.
Epidemiological studies suggest an association between the increasing exposure to chemicals and the development of some of the main ailments of the industrialized world (e.g., disturbances in reproduction, hormone-related cancers, and metabolic disorders like obesity and type 2 diabetes) [44]. In particular, some of these chemicals act as endocrine disruptors as they disturb endogenous hormone signaling pathways.
The consequences of endocrine disruption in human health are discussed. In particular, the possible involvement of EDCs’ exposure on the development of metabolic diseases and their possible responsibility in health disorders are the basic reasons for understanding the mechanisms of action of EDCs. This research field is, however, the subject of scientific and public controversy due to the lack of knowledge about the possible molecular mechanisms underlying endocrine disruption and disease development [45].
A recent review reports that about 40% of human death (62 million per year) is attributed to the effect of exposure to chemical pollutants [46]. Moreover, a study from the US Center for Disease Control (CDC) reported that in the bodies of Americans of all ages have been found over 116 extraneous chemicals [47] and in the cord blood of American infants have been detected over 358 industrial chemicals and pesticides [48].
In some cases, it has been suggested that precise diseases (cancer, neurological disorders, allergies, and reproductive disorders) may be associated with exposure to chemical agents, like EDCs [49]. Focusing on the reproductive disorders, according to the World Health Organization (WHO)’s data, about 80 million people worldwide were estimated to be affected by infertility [50] because of the interference with external agents.
According to these evidences, these compounds raise serious concerns about their potential health impact. These chemicals are prevalently synthetic molecules from an industrial origin [51, 52], but also include some natural molecules [53, 54]. In the latter case, the presence of these compounds ubiquitously in the environment makes really difficult to avoid exposure to them.
The endocrine system of vertebrates is an intricate web of stimulatory and inhibitory hormone signals that control basic functions of body such as metabolism, growth, digestion, and cardiovascular function, as well as more specialized processes such as behavior, sexual differentiation (during embryogenesis), sexual maturation (during puberty), and adult reproduction [55]. EDCs affect human health by disturbing normal endocrine activity through interaction with different receptors involved in key metabolic interaction strategies. This detrimental effect is due to the ability of EDCs to interfere with or mimic endogenous hormones and other signaling molecules of the endocrine system [56, 57].
Due to the huge impact of EDCs on hormonal system, these substances can cause different clinical conditions, including infertility, alterations in sperm quality, abnormalities in sex organs and growth, endometriosis, early puberty [58, 59], altered nervous system function, neurological and learning disabilities [60, 61], immune function [62], certain cancers [63, 64], respiratory problems, metabolic issues, diabetes, obesity, cardiovascular problems [44], thyroid function alterations [65], immune diseases [62], and more (Table 2.2). This aspect highlights the importance of the evaluation of EDC exposure on a developing organism in order to prevent the development of diseases or dysfunctions later in life [74].
2.1.1 Effects of EDCs on Metabolism
Due to the ability of EDCs to interfere with hormone signaling and metabolism, exposure to these substances could lead to the development of metabolic diseases.
In particular, these chemicals cause consequences on the metabolic system by interacting with the hormone receptors (HRs) of the nuclear receptor (NR) family [75] that represents a family of structurally related transcription factors that are involved in various essential biological functions (e.g., fetal development, homeostasis, reproduction, metabolism, and response to xenobiotic substances).
Some EDCs can bind directly to these receptors either as agonists or antagonists, thus enhancing or inhibiting the effect of hormones [44]. In this way, EDCs interfere with the process of hormone biosynthesis, transport to the target tissue, levels of hormone-binding proteins, and hormone catabolism and deregulate hormone availability [76, 77]. One of the main alterations involved in the development of metabolic diseases after EDC exposure is represented by the onset of metabolic syndrome (MetS), due to alteration in fat metabolism and glucose uptake because of the engagement of NRs by EDCs [78] (Table 2.2) that lead to obesity [68, 69] (Table 2.2). For this reason, EDCs involved in MetS onset are called “obesogens,” and it was assumed that already in utero and onward exposure may play a role in the development of obesity and related diseases during life [78,79,80] (Table 2.2).
In addition to EDCs–NRs interaction, the involvement of other receptors in the modulation of the metabolic system has been reported, for example, the aryl hydrocarbon receptor (AhR) [81, 82], estrogen receptors (ERs), androgen receptors (ARs), retinoid X receptor (RXR), and peroxisome proliferator-activated receptors (PPARs) [83].
According to the data reported in the literature, there are specific molecules that interact with the aforementioned receptors, causing a negative effect on human metabolism: For example, dioxin exposure has been reported to increase the risk for type 2 diabetes [84] (Table 2.2), while persistent organic pollutants (POPs), a group of AhR ligands, have been found to be associated with both diabetes and MetS in an epidemiological study of human serum samples [70, 85]. Other authors conclude that low-dose exposure to polychlorinated biphenyls-77 (PCB-77), which could be accumulated in the adipose tissue, may contribute to the development of obesity and atherosclerosis [67] (Table 2.2). In particular, it is known that estrogen and its receptors play an important role in adipogenesis, and exogenous estrogens have an impact on adipose metabolism; for example, octylphenol, a chemical widely used as a surfactant and frequently found in wastewater, decreases adipocyte differentiation [86] (Table 2.2).
Again, bisphenol A (BPA), a monomer with strong estrogenic properties, largely used in a lining of food and beverage containers, medical tubing, and dental fillings, has been associated with cardiovascular disease, liver abnormalities, and diabetes [71] (Table 2.2).
2.1.2 EDCs and Cancer
As mentioned earlier, EDCs are substances that interfere with the endocrine system and therefore with hormones, which are involved in the evolution of cancer.
Exposure to EDCs, in particular to estrogen- or androgen-mimicking EDCs, can promote tumor formation, especially prostate and breast cancers, the latter in particular during the prenatal period, whereas the exposure to some EDCs may affect mammary gland development and increase breast cancer risk later in life [72].
Moreover, EDC exposure could also interfere with hormonal cancer therapy (Table 2.2).
Regard the exposure to EDCs in the prenatal period, there are some indications confirming that exposure to endocrine-disrupting substances in utero can confer an increased risk of cancer in humans (Table 2.2). A clear example is the diethylstilbestrol, reported to be associated with increased incidence of clear-cell carcinoma of the vagina when the exposure occurred during fetal life [87].
Moreover, perinatal exposure to low doses of BPA was reported to result in altered mammary gland morphogenesis and carcinoma in situ [88]. Similar to what is reported referring to the mammary gland, the fetal development of the prostate is affected by the exposure to BPA, which increases the adult prostate size, promoting prostate cancer development [89] (Table 2.2).
One of the main mechanisms responsible for tumorigenesis due to EDC exposure involves epigenetic changes on chromatin and DNA [90, 91]. These kinds of modifications, even if are not affecting DNA sequence, are stable over rounds of cell division and could also be heritable. Epigenetic modifications, such as chromatin methylation or histone modifications, lead to alteration in gene expression that may have repercussions at a phenotypical level, inducing syndromes or tumors, during both prenatal period and adult life.
2.1.3 Effects of EDCs on Reproduction, Growth, and Development
The impairment of the endocrine system regulation may raise abnormal function and development of the reproductive systems [59] (Table 2.2).
In particular, early-life exposures to high level of EDCs have been linked to developmental abnormalities and may increase the risk for a variety of diseases later in life [92]. In fact, EDC exposures during fetal development and childhood can cause long-lasting health effects, as during this developmental period, hormones regulate both formation and maturation of organs [57].
In particular, these hormones are subjected to hypothalamic control during fetal and early postnatal life and are crucial to enable a correct sexual differentiation and a successful reproduction in adulthood [93, 94]. Vilahur et al. [95] showed that prenatal exposure to endocrine-disrupting chemicals causes changes in DNA methylation that were manifested as the latent development of male infertility, reproductive cancers, and other dysfunctions (Table 2.2).
Some classes of EDCs (dichlorodiphenyltrichloroethanes [DDTs], BPA, phthalates, PCBs, and others) can mimic or block the effects of male and female sex hormones, exhibiting a diverse effect on the reproductive and development sphere in men and women, leading to various hormonal changes [59]. In the case of women, EDCs are implicated in the development of some gynecologic pathologies and fertility problems: de Cock et al. (1994) found that reduced fecundability ratio and longer time-to-pregnancy are associated with the application of pesticides fecundability [96] (Table 2.2). Moreover, a positive association between EDCs, especially estrogen-like BPA [97], and gynecological problems highlighting recurrent miscarriages was observed.
On the other hand, men are known to be more susceptible to steroidogenesis, the process for steroid hormone production. Several evidences supported the role of EDCs in interfering with steroidogenesis (particularly through interaction with NRs), modulating the release of endogenous steroid hormones that may cause subsequent reproductive dysfunction [58] (Table 2.2).
The effects of EDCs on fetal testis seem to be more striking as the disruption of steroidogenesis at this early developmental stage can also affect the proliferation of germ cells and Sertoli cells [98,99,100] (Table 2.2), which supports the maximum number of sperms that can be produced in adulthood [101, 102].
2.2 Targets of EDCs: Genomic and Nongenomic Modulation
Insecticides, plasticizers, and detergents can be classified as potential EDCs, and the exposure to these chemicals in the environment in the food chain, or occupational exposures, may affect human health inducing developmental effects and birth defects [103].
EDCs act on human health through various mechanisms, which can be classified as genomic and nongenomic (Fig. 2.1). EDCs can affect every possible cellular hormonal pathway: For example, some of these compounds can bind directly to hormone receptors either as agonists or antagonists, thus enhancing or inhibiting the effect of a hormone regulating gene expression [45]. Despite this, nongenomic modulation was observed, referring to epigenetic modifications, as a system of interaction on human health [104] (Fig. 2.1).
Schematic representation of the types of modulation of the EDCs, genomic and nongenomic
2.2.1 EDCs and Genomic Modulation
A wide range of EDCs exert their effects using a hormone-type mimicking mechanism. These synthetic molecules can be present in rather high quantities and therefore can compete with endogenous hormones despite their lower affinity toward hormone receptors (HRs).
EDCs exhibit structures that are similar to hormones [105]; thus, they can interfere with their binding site as a agonist, activating the receptor, or as an antagonist, inhibiting HRs (Fig. 2.1). This mechanism is defined as “genomic” due to the fact that hormone receptors, like androgen receptors (ARs), estrogen receptors (ERs), and aryl hydrocarbon receptors (AhRs), are nuclear receptors (NRs) that have a direct effect into DNA as a transcription factor [75]. In the specific case of estrogen receptors, p-nonylphenol and bisphenol A act as agonists for ERs, and like estradiol [103], vinclozolin [106], DDT [107], atrazine, and lindane [108] are AR antagonists and have antiandrogenic effects, reducing the expression of ARs [56].
In addition to this mechanism, EDCs are able to interact directly with hormonal regulation by acting on the components of the hormonal signaling pathway (Fig. 2.1). The interaction between EDCs and these components involves a modification of the hormone biosynthesis, positively or negatively, or their degradation [45]. Indeed, xenobiotics and many EDCs have an indirectly effect on hormone regulation through the activation/inhibition of receptors that induced the expression of enzymes involved in activation, conjugation, and elimination of endogenous hormone [56] (Fig. 2.1). The most striking example is in the interference of these compounds with enzyme cytochrome P450, modifying the hormone synthesis as in the case of steroid synthesis [109]. Despite this, also many other metabolic enzymes involved in the synthesis, elimination, and conversion of steroid hormones, such as testosterone to 17β-estradiol (E2) and progesterone to testosterone [110], could be affected by EDCs.
EDCs could also disturb the balance of circulating and local tissue concentration of hormones disturbing the normal functions of the endocrine system. In particular, steroid hormones are hydrophobic and require to be bound by blood proteins to be transported. This characteristic is shared also by EDCs, which have this characteristic of hydrophobicity [111]. In this mechanism, EDCs do not compete with hormones at the receptor level, but at the level of their circulating binding proteins; in fact, these endocrine disruptors are susceptible to compete with hydrophobic hormone-binding transport proteins [112]; otherwise, other EDCs can affect the biosynthesis or degradation of hormone-binding transport protein [113] (Fig. 2.1).
Finally, a further mechanism responsible for EDCs alteration with the endocrine system is represented by the inhibition of receptor expression, modifying endogenous hormone receptor turnover [114] (Fig. 2.1).
Each single mechanism of interaction does not exclude the other; EDCs represent a category of compounds with various and complex activities in the endogenous system.
2.2.2 EDCs and Nongenomic Modulation
The conjugation of the term “epigenetics” [115] gives importance to the effects of the environment on the human gene apparatus. Epigenetics relates the changes that occur in gene expression and phenotype with the inheritance of these, not altering the DNA sequences and identifying external agents from the environment as the cause. The environment can be perturbed by EDCs, and endocrine disruptors affect the epigenetic processes such as DNA methylation [116, 117] and histone modification [118]; this can be considered the nongenomic modulation by EDCs.
Nongenomic modulation by EDCs has importance during development, particularly in three windows of exposure when the epigenome is susceptible to reprogramming by EDCs during gamete maturation [119], implantation of fetus [120], and differentiation of pluripotent cells [121].
The reprogram of the epigenome caused by exposure to EDCs is supported by several evidences; in fact, chemical disruptors such as DES [122], BPA, genistein [123], and vinclozolin [124] all have been shown to alter patterns of DNA methylation. Moreover, Newbold [125] and Tang [126] explored DNA methylation changes induced by developmental exposure to EDCs, specifically to DES.
Finally, Anway et al. [31] demonstrated the transgenerational effects of vinclozolin on spermatogenesis and fertility in males after gestational exposure to these EDCs. This supports the fact that EDCs induce transgenerational inheritance by assuming transmission via germ line alterations [127].
2.3 Hormone Mimicry and Disruption by EDCs: Modulation of Hormone Activity
The name “EDCs” itself refers to the ability of a specific group of environmental endocrine-active chemicals to interfere with the endocrine system, as well as other systems (mainly the reproductive system), disturbing endogenous hormone signaling pathways [44]. As already mentioned, EDCs can influence and modulate the hormonal system, by acting as endogenous hormones and other signaling molecules of the endocrine system, or even mimicking them. This particular property represents a great potential risk for human health, and therefore, the increasing release of contaminants in the environment should be a concern of a global interest.
The principal molecular mechanism of action exhibited by EDCs is represented by their interaction with hormone receptors (HRs), influencing hormonal activity directly (Table 2.3). Receptors have evolved to be protected against binding with endogenous molecules other than hormones; however, the growing environmental contamination of synthetic toxicants having the shape and size of the actual hormone could not have been encountered before during receptor evolution. For this reason, even though EDCs have lower receptor affinity compared with physiological hormones, because of their abundance in the environment, these chemicals can compete with endogenous hormones [105].
Endocrine disruptors are notably able to bind to the family of nuclear receptors (NRs), including the estrogen receptors (ERs) and androgen receptors (ARs) [44], but they can also be associated with some membrane receptors. Nevertheless, thyroid hormone receptors, retinoid X receptor (RXR), and peroxisome proliferator-activated receptors (PPARs) have been recently identified as additional binding targets too [44]. This is the case of estradiol and bisphenol A that can bind both the nuclear receptors ERα and ERβ and a transmembrane receptor called G protein-coupled estrogen receptor 1 (GPER) (GPR30) [128, 129].
Importantly, depending on the binding of EDCs with NRs or membrane receptors, it is possible to observe different kinds of effects. In fact, in the case of NR engagement by EDCs, we observe a modulation of gene expression that exerts a long-term effect on target cells’ phenotype [5, 130] due to their transcriptional factor function, while in the case of binding with membrane receptors the result is a short-term and more acute effect [5, 131].
On the other hand, behaving like agonists, EDCs can also hinder endogenous hormones, by occupying HRs and antagonizing the proper ligand–hormone interaction (Table 2.3) [132]. Many of these EDCs showing antiestrogenic, antiandrogenic, antiprogesteronic, and anti-ER activities have been detected in wastewater [133].
The antagonism exerted by EDCs could be explained by the ability of some chemical compounds to block receptor conformation in their inactive state, resulting in the inhibition of their signaling pathways [45]. For example, polychlorinated biphenyls (PCBs) can prevent the association between triiodothyronine (T3) and thyroid hormone receptor (THR), with the consequent dissociation of the transcriptionally active THR/retinoid X receptor heterodimer complex from the thyroid response element (TRE) [113].
Besides the hormonal activity exhibited by EDCs via receptor binding, toxicants can influence hormonal system activating other signaling pathways, that is, interacting with components of hormone signaling pathways downstream of receptor activation (Table 2.3) [45]. Since this phenomenon does not involve any binding with hormone receptors, such EDCs may present different structures from endogenous hormones [45]. An example is represented by fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) active substance present in antidepressant drugs, which has the potential to alter many intracellular signaling pathways in different cellular types, without HR association [134,135,136]. In addition, some bisphenols can interact with Ras small G proteins (e.g., K-Ras4B) and activate the Ras signaling cascade, causing the increase of pERK and pAKT [137]. Finally, the herbicide atrazine can inhibit cAMP-specific phosphodiesterase 4 (PDE4) [130], leading to cAMP intracellular accumulation, and tolylfluanid is able to reduce insulin receptor substrate-1 (IRS-1) levels, downstream from the insulin receptor, in human adipocytes [131].
Another way by which exogenous molecules exert endocrine disruption is by directly affecting the endogenous hormone biosynthesis or degradation (Table 2.3). Again, in this specific case, there is no interaction with hormone receptors; therefore, chemicals can exhibit different structures than physiological hormones [45]. Evidences of altered hormone biosynthesis have been shown after exposition to different EDCs; for example, low dose of BPA inhibits adiponectin secretion in vitro in human adipocytes [114, 138, 139], 4-nonyphenol (4-NP) inhibits the synthesis of testosterone by Leydig cells following the stimulation by human chorionic gonadotropin [140], or triclosan stimulates vascular endothelial growth factor (VEGF) secretion by human prostate cancer cells [141]. Concerning EDCs’ influence on hormone degradation, polybrominated diphenyl ethers (PBDEs) have been described to potentially increase thyroxine (T4) elimination, lowering its concentration level in blood [113], while parabens inhibit estrogen degradation [142], increasing the hormone concentration in blood.
Since the majority of the hormones are hydrophobic, like steroids and thyroid ones, they necessarily must be transported in association with specific binding proteins through the bloodstream. Thus, since EDCs present structural similarity to hormones, they are hydrophobic and can bind the same hormone-binding transport proteins, competing with endogenous hormones (Table 2.3) [143,144,145]. The result of the association between binding proteins and toxicants is the decrease in hormone transport that decreased their concentration in blood. Examples of transport proteins that are usually subjected to be bound by chemicals instead of hormones include steroid hormone-binding protein (SHBG) or α-fetoprotein (AFP) [112, 146].
Furthermore, EDCs can modulate endogenous free active hormone concentration not only by taking their place in binding transport protein, but also via the direct modification of these protein levels in the bloodstream, affecting their biosynthesis or degradation (Table 2.3) [45]. In fact, a lower availability of transport proteins means at the same time a lower concentration of hormones. EDCs responsible for this mechanism are binding-independent, so they can exhibit different structures from those of endogenous hormones. The advantage of such mechanism of action is that chemicals mainly target liver because this is the classic degrading organ, and at the same time, liver is the place where binding transport proteins are synthetized and degraded [45]. PBDEs, for example, may downregulate transport protein transthyretin (TTR) level [113] and consequently lower T4 amount in blood.
Among the several mechanisms affecting hormonal system to mention, there is also the ability of EDCs to regulate HR turnover through the stimulation or inhibition of their expression (Table 2.3). The absence of the binding with hormone receptors in this specific mechanism allows such chemicals to exhibit structural differences from hormones [45]. BPA, for example, has been shown to induce leptin receptor expression in ovarian cancer cells in vitro [31], cadmium increased estrogen receptor beta (ERβ) and Cyp19a1 enzymes in endothelial human umbilical vein endothelial cells (HUVECs) in vitro, and a dose-dependent decrease of androgen receptor (AR) expression levels was observed after 24 h of exposure [38]. Conversely, the inhibition of receptors has been shown after the administration of a low oral dose of BPA to rats, which decreased estrogen receptor expression in their hypothalamic cells [39]. The inhibition of androgen receptors by BPA has also been observed in vivo [29] and in vitro cells of patients with breast or prostate cancer [40].
Nowadays, it is well known that EDCs may also influence human epigenome by acting through various mechanisms, such as DNA methylation and histone code alteration [1]. Epigenetic modifications consist of changes in gene expression and resulting phenotype, without any alteration in nucleotide sequence of DNA. The alteration of gene expression can act on differential physiological pathways and can affect normal hormonal activity, for example, by alternating hormone signaling pathway downstream of receptor or provoking aberrant receptor turnover, therefore constituting another nontraditional mechanism of action of EDCs on hormonal system (Table 2.3). Waalkes et al. [147] demonstrated that inorganic arsenic exposure in utero induced a significantly decreased promoter methylation of ER in the liver, resulting in increased ER expression, which also correlated with the increased incidence of hepatocellular carcinoma in exposed animals. The soybean isoflavone genistein (GE) has been shown to prevent breast cancer and to induce epigenetic reactivation of estrogen receptors [148]. Recent studies have suggested that GE, besides its ability to enhance the anticancer capacity of the estrogen antagonist tamoxifen (TAM) in ERα-positive breast cancer cells, can also reactivate ERα expression in ERα-negative breast cancer cells. This positive influence on estrogen receptor expression was enhanced when combined with a histone deacetylase (HDAC) inhibitor, named trichostatin A (TSA). GE treatment also resensitized ERα-dependent cellular responses to the activator 17β-estradiol (E2) and the antagonist TAM. The following research revealed that GE can remodel chromatin structure and consequently reactivate ERα gene expression.
Although the spectrum of chemical compounds to which we may be exposed is broad and can influence human health by multiple mechanisms of action, EDCs can be classified according to their endocrine effect in the main classes of estrogenic, antiestrogenic, androgenic, and antiandrogenic EDCs. The name of the class they belong to suggests the type of endogenous hormonal pathway that is disrupted by those specific chemicals.
Among the endocrine-disrupting chemicals, environmental estrogens were the first to cause concern. Lately, it was discovered that also other hormonal systems are susceptible to disruption, like androgen signaling pathway. At last, thyroid hormone was identified as a target for endocrine disruption too [149], as well as peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) system [150, 151].
2.4 Mechanism of Action of EDCs and Estrogens
17-beta-Estradiol (E2) is a key hormone involved in many biological processes in humans, like development and maintenance of the female reproductive tract, brain, bone, and cardiovascular system. Moreover, E2 is a key component in male development too [152]. In female adulthood, estrogen takes part in metabolism and coordinates the morphological alterations occurring during physiological menstrual cycle and pregnancy, together with differentiation and proliferation of target tissues [152].
The classical and conventional estrogenic function is notably mediated by the interaction of E2 with specific estrogen receptors ERα and ERβ, which are steroid receptors belonging to the superfamily of nuclear receptors, in particular type I NRs [152, 153]. ERα and ERβ are tissue-specific; therefore, they are thought to possess distinct physiological roles [154]. ERα is expressed in breast, uterus, pituitary, testis, and kidney, while ERβ is found in cardiovascular system, prostate, hypothalamus, gastrointestinal tract, ovary, kidney, lungs [155,156,157,158,159], and breast [160,161,162]. The tissue distribution pattern of ERβ suggests its role both in male and female reproduction and development and in central neuroendocrine regulation. Even if most tissues show a predominance of either ERα or ERβ, many others coexpress both [163]. To further support the different regulatory roles that distinguish the two types of ERs, ERα contains dissimilar domains compared with ERβ, suggesting a potential for different ligand specificity that results in different effects [103].
As already mentioned before, all nuclear receptors directly participate in the cellular response to hormone, affecting gene expression by acting as transcription factors. Ligand-activated ER generally induces the increase of target gene expression in target tissues, even if in some other cases it can decrease specific gene transcription [164]. However, the mechanism of negative regulation is still less characterized.
Thus, estrogens mainly work through the binding to ERs in order to transactivate the expression of estrogen-responsive genes. The latter contain an estrogen-responsive element (ERE) in their promoters/enhancers, which represents a recognition sequence to which ER binds. Before activation by association with E2 ligand, ERs exhibit inactivation due to the binding with the heat shock protein-90 (HSP90) [152] and display a diffuse nuclear localization [163]. After ER binding with the E2, ER dimerizes and becomes an active transcription factor acting on the expression of several important genes such as progesterone receptor (another nuclear hormone receptors), vascular endothelial growth factor, c-Fos/c-Jun (proto-oncogenes), and cyclin D1 (cell cycle regulators) [152], stimulating proliferation or differentiation at the cellular level. Several coactivators are also recruited to the complex and, together with ER, participate in remodeling of chromatin structure in order to provide access for transcription machinery to the target gene promoter and allow the transcription to begin [165].
Finally, an additional form of nuclear regulation has been discovered via ERs named “composite regulation,” which is based on protein–protein interaction with other transcription factor, requiring the association between activated steroid receptor and members of the activator protein 1 (AP-1) complex, Fos and Jun [103, 166,167,168,169,170], resulting in either gene activation or repression [166]. Nevertheless, it is not still clear how negative, positive, and composite regulations participate together in the complex cellular functions related to the action of estrogens, like differentiation, organ development, and growth.
Among the EDCs, a huge variety of compounds have been identified as estrogenic chemicals, also called “xenoestrogens” [171, 172]. EDCs with the ability to interfere with estrogenic signaling are, for example, genistein, octylphenol, nonylphenol, bisphenol A (BPA), and diethylstilbestrol (DES), and many of these xenoestrogens are ligands for ERs and therefore can act either as agonists (estrogenic) or as antagonists (antiestrogenic) toward endogenous estrogens.
Several EDCs (e.g., DES, BPA, methoxychlor [173], and genistein) show ER-mediated effects on gene expression, competing with E2 for binding to the same ERs. However, xenoestrogens exhibit a different affinity for the two types of ERs: While DES and methoxychlor have a higher affinity for ERα, genistein and BPA mostly bind ERβ [174]. Interestingly, recent studies have identified a natural compound proposed to be an ERβ-specific ligand [175], which may play a role in preventing progression to prostate cancer by activating prostatic ERβ [176]. Differential ERα- or ERβ-mediated effects may partially account for parallel differential effects of EDCs on different target tissues. This is confirmed in the reproductive tract, where the deleterious effects of EDCs are xenoestrogen-specific [177]. Thus, xenoestrogens can disrupt the endocrine system, both showing differential effects on ERα or ERβ or via differential binding affinity.
Similar to the physiological estrogenic pathway, the association between xenoestrogens and ERs leads to the expression of estrogen-responsive genes (Fig. 2.2), as observed following DES, 7-methylbenz[a]anthracene-3,9-diol (MBA), coumestrol, and genistein (GE) [178] exposure. On the contrary, other xenoestrogens can act as hormonal antagonists (Fig. 2.2) employing multiple mechanisms, for example, by preventing the binding of ER to DNA (e.g., BPA) [179] or inhibiting the binding of ER coactivators [174] to avoid transactivation of gene expression.
Summary of the main mechanisms of action of EDCs involved in estrogenic pathway
However, in addition to the classical ER binding, a possible parallel pathway of estrogenic regulation may involve the existence and binding of alternative “estrogenic receptors,” that is, orphan receptors called ER-related receptors (ERRs), -1 and -2 (Fig. 2.2), which share a similar sequence to ER [180]. Several researchers have focused on the nature (constitutive or liganded) of their transcriptional activities. Moreover, it has been showed that ERRs can interfere with estrogen signaling in various ways, either positively or negatively [181]. Therefore, the identification of possible modulators (positive or negative) of ERR activities could be highly useful in understanding some estrogen-related pathologies.
Besides mimicking and antagonizing endogenous estrogens, EDCs may also mediate estrogenic biological effects by inducing enzymes that accelerate the metabolism of estradiol (Fig. 2.2) [103]. Dioxins, for example, have provided additional evidence for their antiestrogenic effects inducing an increased metabolism of E2 [182, 183].
An additional endocrine-disrupting effect of EDCs on estrogenic responses consists in their ability to increase or decrease the amount of available ERs (Fig. 2.2) [184,185,186]. Many members of NR superfamily are degraded by the ubiquitin-proteasome pathway in a ligand-dependent manner, in order to prevent cells from overstimulation by endogenous hormones or other activating signals [187]. Consequently, EDCs might act on proteasome-mediated degradation of nuclear receptors, altering physiological estrogenic pathway. Masuyama et al. [188] compared the effects of BPA and estradiol treatments on ER-mediated transcription, to try to explain the observations relating to differential effects of BPA treatment on ER levels [189]. In the presence of estradiol, both ERα and ERβ interacted directly with suppressor for Gal 1 (SUG1) of the proteasome. In contrast, BPA activated ER-mediated transcription, without enhancing the interaction between ERβ and SUG1. In the presence of BPA, ubiquitination and degradation of ERβ were also slower than those in the presence of estradiol or phthalic acid, suggesting that BPA may affect the ERβ-mediated transcription of target genes by inhibiting ERβ degradation [190].
Lastly, an attractive hypothesis contemplates the conversion of endocrine chemicals from inactive to active ER-binding estrogens, due to the action of a biotransformation happening in vivo (Fig. 2.2) [103]. A phenomenon of biotransformation has been reported for tamoxifen [191], after the isolation of its metabolite 4-OH-tamoxifen from animals and humans treated with the compound. 4-OH-tamoxifen induces antiestrogenic effects, and it has an even higher affinity for ERs compared with its parent compound. Additional EDCs that are metabolically converted into active agents include ethylene glycol monomethyl ether (EGME) [192] and methoxychlor [193].
Endocrine compounds can also exert apparent estrogenic growth effects by interacting with different cellular factors that could occur downstream from ER of the estrogenic regulatory cascade in target cells (Fig. 2.2) [103]. Tamoxifen, for example, affects calmodulin regulation without ER mediation and directly inhibits protein kinase C through non-ER mechanisms [194, 195]. Other xenoestrogens may rapidly modify other signaling pathways, such as DES, nonylphenol (NP), BPA, and polychlorinated biphenyl (PCB), which are able to alter phosphorylation state of proteins belonging to the large family of mitogen-activated protein kinases (MAPK) in mussel hemocytes [196, 197]. Finally, phytoestrogens possess a variety of nonhormonal properties; for example, dietary phytoestrogens are capable of inhibiting tyrosine kinase activity, which are involved in various growth factor signaling pathways implicated in control of cell growth and differentiation [163]. Anyway, some phytoestrogens, like isoflavones in soy and resveratrol in grapes, have been identified as active agents responsible for benefits to human health exerting hormonal mimicry or antagonism through endocrine pathways or endocrine disruption. Recently, the Food and Drug Administration recognized that the Asian diet, high in soy consumption [198], can be associated with lowered cholesterol and reduction in cardiac risk [199], and the same was sustained by the “French Paradox” that associates red wine consumption to decreased cardiac risk [200]. New scientific data would link the dietary assumption of phytoestrogens with the epigenetic mechanism of histone acetylation (Fig. 2.2) through the phenomenon of gene superinduction. The term “superinduction” means the increased expression of nuclear receptor-activated genes to higher levels than those observed with the established ligand, for example, estradiol for ERs [103]. These observations could explain how soy phytoestrogens and grape may act as nontraditional molecular mechanism, leading to health benefits and anticancer effects. In fact, some of these beneficial effects are now associated with a particular family of histone deacetylases (HDACs), including the human SirT1. Again, the action of fiber assumption in lowering colon cancer incidence has been explained by the presence of butyrate and through the effects on histone acetylation status [201, 202]. Lately, several investigations have asserted that the soy isoflavone phytoestrogens, genistein and daidzein, can be linked to resveratrol, butyrate, and histone acetylation state. Both the isoflavone phytoestrogens act as superinducers of estrogen signaling pathways [203]. This evidence could be the proof that histone acetylation status can also be affected by these compounds. Furthermore, similar superinduction properties are also seen with grape phytoestrogen, resveratrol [103, 204], which has been linked to the effects on HDAC Sir2/SirT1 and, thus, also histone acetylation status [205, 206].
2.5 Mechanism of Action of EDCs and Androgens
Testosterone constitutes the key hormone of androgen hormonal pathway in human, and male testis already produces it around gestational day 65 [207], in order to guarantee the proper establishment of sexual behaviors, male reproductive tract development, and masculinization of other organs. In fact, androgens mediate a wide range of biological responses, such as testicular and accessory sex gland development and function, pubertal sexual maturation, maintenance of spermatogenesis and maturation of sperm, male gonadotropin regulation through feedback loops, and various male secondary characteristics like bone mass, musculature, fat distribution, and hair patterning [208]. Moreover, testosterone becomes critical for brain development too, thanks to its aromatization in 17β-estradiol (E2) by the action of the aromatase CYP19 [209].
Similar to estrogens, both testosterone and its metabolite dihydrotestosterone (DHT) can bind type I NRs, called androgen receptors (ARs). ARs, as well as all the members included in the family of nuclear receptors, are a class of ligand-activated proteins that can enter the nucleus functioning as transcription factors and regulating specific gene expression. ARs can be found in multiple organs, such as hypothalamus [210], pituitary, kidney, prostate, and adrenals (and ovary) [211, 212].
During the perinatal period of programming of the endocrine axis, the hormonal feedback from the gonads to the hypothalamus and pituitary gland represents an event of extreme importance and sensitivity toward endogenous and exogenous stimuli [152]. While female sexual differentiation is considered as a default developmental pathway since it is independent of estrogens and androgens, male sexual differentiation is driven by the fetal testes and it is entirely androgen-dependent [213]. For this reason, male sexual differentiation is highly susceptible to androgen disruptors that could affect developmental programming and reproductive tract maturation [214]. In fact, the eventual lack of testosterone in male fetus due to antiandrogenic exposure, to a genetic mutation in AR or to a blocked metabolism of the hormone, can induce the development of phenotypic female with testes.
The exposure to EDCs during male reproductive tract development may alter testosterone–AR association or the endogenous hormone metabolism, resulting in permanent reprogramming of male reproductive tract and its hormonal communication with the entire hypothalamic–pituitary–gonadal (HPG) axis. In adulthood, HPG axis is already established, and antiandrogen compounds can cause aberration in sperm production and libido in males [215, 216].
The mechanisms of action exploited by endocrine compounds to disrupt androgen pathway are multiple. Among these, we can mention the influence on receptor turnover by decreasing AR levels (Fig. 2.3), the alteration of luteinizing hormone (LH) stimulation (Fig. 2.3), the interference with androgen synthesis, metabolism and clearance (Fig. 2.3), and the alteration of proper folding of the ligand-binding domain (LBD) in ARs after EDC binding [107, 214, 217,218,219,220,221]. Aberrant LBD misfolding means AR inactivity, due to its inability to recruit coactivators and to initiate transcription.
Summary of the main mechanisms of action of EDCs involved in the androgenic pathway
Although there are many sites of action for chemicals to interfere with androgen signaling, endocrine chemicals are classified into two main categories: those that interfere with androgen biosynthesis or metabolism (non-receptor-mediated disruptors) (Fig. 2.3) and those that interact with ARs to interfere with the ligand-dependent transcriptional function (receptor-mediated disruptors) (Fig. 2.3). Despite these two principal classes, some chemicals such as PCBs [219], DES [222], cyproterone acetate (CPA), and hydroxyflutamide (OHF) [217] affect AR activity through the reduction of its expression and level. In addition, another group of EDCs disrupts androgen pathway by inhibiting AR ligand, binding, dimerization, and DNA binding or by silencing expression of AR target genes affecting downstream cellular response.
Androgen receptor–mediated disruptors can be further divided into agonists and antagonists. Agonists bind to androgen receptors and activate a response mimicking the action of endogenous androgens; on the contrary, antagonists block AR transactivation.
A pilot study by Araki et al. [223] reported that some industrial or environmental chemicals show AR agonist activity, and in particular, the compound 1,2-dibromo-4-(1,2-dibromoethyl) cyclohexane (DBE-DBCH) was recently identified as the first potent environmental activator of the human AR [224, 225]. DBE-DBCH can exist in four diastereoisomeric forms: α and β that can be converted into γ and δ at specific conditions [226]. Several analyses showed that diastereomers γ and δ are more potent activators of human AR than α and β, but all the DBE-DBCH diastereomers induced the expression of the downstream target prostate-specific antigen (PSA) in vitro [227].
Contrariwise, EDCs with antiandrogenic action are, for example, dichlorodiphenyltrichloroethanes (DDTs), whose isomers [228] and metabolite [41] were shown to reduce the association between DHT and AR in vivo and to inhibit DHT-induced transcriptional activation in vitro [107]. In addition to AR antagonistic effects of DDT, high concentrations of its metabolite have been shown to function as inhibitors of 5α-reductase that converts testosterone to DHT [229], providing a clear example of how chemical compounds can affect androgen signaling at multiple sites of action. Fetal and neonatal DDT exposure in male produced demasculinizing effects with a high incidence of epididymal and testicular lesions [107, 230] and reduced prostate growth and inflammation [231]. Methoxychlor has a similar structure to DDT and, beyond its well-known estrogenic activity, also shows affinity to the AR at comparable or even higher levels than DDTs [41]. In addition to methoxychlor, BPA is first believed to act in estrogen signaling pathway; however, many scientific evidences have shown its association with AR [41] and its antagonist activity [232]. Lastly, vinclozolin also exerts an endocrine-disrupting potential as an AR antagonist through its primary metabolites [233]. Its mechanism of action consists of inhibiting AR transactivation and androgen-dependent gene expression. In vivo administration of vinclozolin at different doses, routes, and periods (gestation, lactation, puberty, and adulthood) is closely related to a different kind of effect on the male reproductive tract [214]. In addition, vinclozolin exposure during sex determination in developing male germ cells (fetal days 8–14) may lead to transgenerational effect. This phenomenon is based on epigenetic modification on male germ cells that consist of perturbations in DNA methylation patterns, underlining the presence of a relationship between this antiandrogenic compound and epigenetics [38].
2.6 Conclusions
Today, several compounds are classified as endocrine disruptor compounds (EDCs), intended as chemical agents that can interfere with the synthesis, metabolism, and action of endogenous hormones [56]. The EDCs are present in the environment ubiquitously and include both natural molecules [53, 54] and synthetic molecules [51, 52]. Several of these compounds used today have been tested systematically for endocrine-disrupting effects in organisms, as demonstrated by epidemiological studies that suggest an association between the exposure to chemicals and the development of some of the main ailments (e.g., metabolic disorders like obesity and type 2 diabetes) [44] (Table 2.2). This action is due to the ability of EDCs to interfere, with different strategies, with endogenous hormones and other signaling molecules of the endocrine system [56, 57].
The effect of these compounds on the endocrine system contributes to the emergence of several problems in the metabolism and systems of the human body. The first system to be negatively affected by these compounds is the metabolic system, through the interaction of EDCs with the hormone receptors (HRs) of the nuclear receptor (NR) family [75], mainly estrogen receptors (ERs) and androgen receptors (ARs) [103]. The direct receptor interaction of EDCs as agonists or antagonists enhances or inhibits the hormones’ action [44], leading to the development of conditions such as the metabolic syndrome (MetS) [78, 79, 125] (Table 2.2). Another negative manifestation of the effect of EDCs on health is the development of cancer [72], caused by both the induction due to these substances of epigenetic changes [54] and the interference of these with the endocrine system and hormones, which are involved in the evolution of cancer (Table 2.2).
EDCs, in addition to the evolution of cancer and problems related to metabolism, affect most of all reproduction, growth, and development. In particular, early-life exposures to high level of EDCs have been associated with developmental abnormalities and may increase the risk for a variety of diseases later in life [23]. In particular, some classes of EDCs can mimic or block the effects of male and female sex hormones, reducing fecundability and alternating reproductive development in men and women [59] (Table 2.2).
Due to the importance and the impact on human health of EDCs, even more studies have begun to focus on potentially harmful compounds.
As illustrated in Table 2.3, endocrine-active compounds can exert their disrupting potential toward hormonal signaling through a huge variety of mechanisms acting at different levels.
According to their endocrine effect, EDCs can be classified as estrogenic, antiestrogenic, androgenic, and antiandrogenic based on their effects on the hormone system.
Of course, the main classification of EDCs is represented by division between estrogenic and androgenic compounds, intended as products that bind estrogen receptors (ERs) and androgen receptors (ARs) with an activating or inhibiting function (Table 2.1). The EDCs–hormone receptor interaction causes various effects, especially on the reproductive system [56]. Within this classification of EDCs, there are several compounds that are included in the classes of pesticides [49], phytoestrogens [26], plastics or associated chemicals (such as phthalates) [23], and drugs (especially anticancer) [234] (Table 2.1). These molecules have effects on human health mainly through two mechanisms: genomic and nongenomic (Fig. 2.1). The genomic modulation induces the regulation of hormone gene expression [45] due to the fact that hormone receptors bound by EDCs are nuclear receptors (NRs) and have a direct effect on DNA as transcription factors [75]. Despite this, EDCs also show nongenomic modulation, referring to epigenetic modifications [127] (Fig. 2.1).
EDCs have the ability to modulate endocrine system and hormonal activity by hormone mimicry and disruption as the type of genomic modulation mechanism [44]. In fact, EDCs may act as endogenous hormones and other signaling molecules of the endocrine system or even mimic them.
EDCs that compete with endogenous hormones as agonists bind HRs inducing their activation and the initiation of the hormonal signaling pathway [105]. On the contrary, EDCs can also act as antagonists of endogenous hormones (Table 2.3), by binding the same hormone receptors but occupying receptor binding site and antagonizing the proper ligand–hormone interaction [132].
Besides the hormonal activity exhibited by EDCs via receptor binding, toxicants can influence hormonal system activating other signaling pathways, that is, interacting with components of hormone signaling pathways downstream of receptor activation (Table 2.3) [45]. A parallel way to modulate hormonal system consists of altering endogenous hormone biosynthesis or degradation (Table 2.3). Again, EDCs can affect hormonal activity by regulating HR turnover through the stimulation or inhibition of their expression (Table 2.3) [45]. Finally, some EDCs exert endocrine disruption on hormonal system via epigenetic modifications as nongenomic modulation (Table 2.3), via DNA methylation and histone code alteration [1] that occurs during the development, when the epigenome is more susceptible to reprogramming by EDCs [119, 120].
This chapter introduced the general characteristics of endocrine-disrupting chemical compounds and summarized their main molecular mechanisms of action, which involve both genomic and nongenomic modulations. Endocrine disruption is associated with inappropriate regulation of hormone activity, underlining the complexity of physiological hormonal signaling and suggesting a large number of potential targets for EDC disruption. Increased studies concerning EDCs’ action in hormone effects, signaling, and transcriptional regulation could provide a better understanding of the danger and their potential consequences of endocrine-active substances in human health.
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Rizzo, R., Bortolotti, D., Rizzo, S., Schiuma, G. (2023). Cellular Mechanisms of Endocrine Disruption. In: Marci, R. (eds) Environment Impact on Reproductive Health. Springer, Cham. https://doi.org/10.1007/978-3-031-36494-5_2
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