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Regulation of Environmental Endocrine Disrupting Chemicals on the Expressions and Transactivation of Estrogen Receptors and the Related Analytical Techniques

Ren Zhihua , Yang Xiaoxi , Sun Zhendong , Ren Jing , Sang Nan , Zhou Qunfang , Jiang Guibin

Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (10) : 2121 -2133.

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Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (10) : 2121-2133 DOI: 10.7536/PC220215
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Regulation of Environmental Endocrine Disrupting Chemicals on the Expressions and Transactivation of Estrogen Receptors and the Related Analytical Techniques
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Abstract

An increasing number of chemicals with endocrine disrupting effects, such as environmental endocrine disrupting chemicals (EDCs), have been emerging in the environment. Diverse molecules, such as natural chemicals existing in food and synthetic chemicals used in daily products, are identified as endocrine disruptors. With the inevitable release of EDCs, these chemicals are found to be distributed in various environmental matrixes including water, soil and sediments, posing a threat to wildlife and humans. The universal contamination of EDCs may disturb the endocrine system of the wildlife and human beings, potentially causing toxicological effects on multiple targets, like cardiovascular, reproductive and nervous systems, and probably inducing the incidence of metabolic syndrome, obesity, neurological disorder, reproductive and developmental toxicity, and even cancer. Among investigations about mechanisms underlying endocrine disrupting effect, the estrogen receptors (ERs) mediated pathway is one of the hotly-discussed aspects in EDC studies. In this review, the basic characteristics of ERs, analytical techniques for ERs expression and transactivation, and biological significance of EDCs via the regulation of ERs in different organisms were systemically introduced, intending to provide promising strategies for screening the endocrine disrupting effects of emerging chemicals of concern and evaluating their hazardous risks from the aspects of ERs agonistic and antagonistic activities.

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emerging chemicals of concern / endocrine disrupting effects / estrogen receptors / different species / transactivation

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Ren Zhihua, Yang Xiaoxi, Sun Zhendong, Ren Jing, Sang Nan, Zhou Qunfang, Jiang Guibin. Regulation of Environmental Endocrine Disrupting Chemicals on the Expressions and Transactivation of Estrogen Receptors and the Related Analytical Techniques. Progress in Chemistry, 2022, 34(10): 2121-2133 DOI:10.7536/PC220215

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Contents

1 Introduction
2 The basic characteristics of ERs
2.1 Structure of ER isoforms
2.2 Tissue-specific expressions of ERs
2.3 ER-mediated signaling
3 Analytical techniques for ERs
3.1 ER binding
3.2 ER expressions
3.3 ER transactivation
4 Regulation of EDCs on ERs
4.1 Reproductive and developmental system
4.2 Neurological system
4.3 Cardiovascular system
4.4 Lipid metabolism
4.5 Liver
4.6 Cancer
5 Conclusion and outlook

Abbreviations

E1,Estrone;E2,17β-Estradiol;DES,Dihydrodiethylstilbestrol;EE2,17α-Ethinylestradiol;BPs,Bisphenols;PCBs,Polychlorinated biphenyls;PFASs,Perfluorinated alkylated substances;APs,Alkyl phenols;DDT,Dichloro-diphenyl-trichloroethane;BPA,Bisphenol A;GPER,G protein-coupled estrogen receptor;PFIs,Perfluorinated iodine alkanes;BFRs,Brominated flame retardants;PAHs,Polyaromatic hydrocarbons;PFOS,Perfluorooctane sulfonates;DBP,Di-N-butyl phthalate;DINP,Diisononyl phthalate;BBP,Butyl benzyl phthalate;D4,Octamethylcyclotetrasiloxane;Cd,Cadmium;As,Arsenic;Pb,Plumbum;TBBPA,Tetrabromobisphenol A;PFOA,Perfluorooctanoic acid;6∶2 FTOH,1H,1H,2H,2H-Perfluorooctanol;PFNA,Perfluorononanoic;PFDA,Perfluorodecanoic;PFUnDA,Perfluoroundecanoic;PFOI,Perfluorooctyl iodide;8∶2 FTOH,1H,1H,2H,2H-Perfluoro-1-decanol;PFBDI,1,4-Diiodooctafluorobutane;PFHxDI,1,6-Diiodooctafluorohexane;PFODI,1,8-Diiodoperfluorooctane;HBCD,Hexabromocyclododecane;GBHs,Glyphosate-based herbicides;DEHP,Di(2-ethylhexyl)phthalate

1 Introduction

Since the end of the 20th century, environmental pollutants with endocrine disrupting activity have attracted more and more public attention. In 2001, Jiang Guibin et al. Scientifically defined Endocrine disrupting chemicals (EDCs), that is, substances existing in the environment that can interfere with various links of the Endocrine system of humans or wildlife and cause abnormal effects[1]. There are many kinds of EDCs, which can be divided into natural hormones and synthetic compounds according to their sources. Natural hormones include hormones secreted by the body itself (such as E1, E2) and phytoestrogens (such as genistein, zearalenone). Synthetic compounds mainly include synthetic steroid drugs such as DES and EE2, various industrial products and their by-products such as BPs, PCBs, PFASs, APs, and pesticides and herbicides such as DDT.
The widespread use of EDCs has brought a series of ecological and environmental pollution problems, which seriously threaten the long-term survival and species reproduction of wildlife, and also cause potential harm to human health. Animal experimental studies have found that experimental animals exposed to dioxins, furans, PCBs, pesticides and other EDCs during pregnancy and lactation have a particularly prominent lack of learning and cognitive ability in the later stage[2]. The reproductive cycle of Longevity Bird in the Arctic is affected by heavy metal EDCs (such as mercury), and the dynamic changes of the whole population have changed to a certain extent[3]. Similarly, the health risks of EDCs to humans cannot be ignored. All hormone-sensitive human physiological systems are susceptible to EDCs, including the brain and hypothalamic neuroendocrine system, pituitary tissue, thyroid tissue, cardiovascular system, breast tissue, adipose tissue, pancreatic tissue, ovary and uterus in women, and testis and prostate tissue in men[4]. A large number of epidemiological studies have shown that EDCs are associated with metabolic syndrome, cancer (especially female breast cancer) and type II diabetes[5]. Parental occupational exposure to environmentally related concentrations of EDCs can lead to developmental malformations and a significant increase in susceptibility to disease in newborns[6]. Exposure to EDCs during the critical period of fetal or pubertal development may induce diseases such as ovulation disorders, lactation disorders, breast cancer, endometriosis and uterine fibroids in adult women, and reproductive system diseases such as hypospadias, cryptorchidism, low sperm count and quality in men[7,8].
EDCs can interfere with the synthesis, transport and secretion of various hormones by binding to target cell receptors, such as Estrogen receptors (ERs), Androgen receptors (AR), progesterone receptors, thyroid hormone receptors and retinoic acid receptors. With the continuous development of endocrine disruption research, many molecular mechanisms have been confirmed.Such as non-nuclear steroid hormone receptors (such as membrane hormone receptors), non-steroid receptors (such as neurotransmitter receptors including 5-hydroxytryptamine receptors, dopamine receptors, norepinephrine receptors), orphan receptors (e.g. aryl hydrocarbon receptors), steroid synthesis or metabolic processes, and other related pathways.These receptors also play an important role in hormone homeostasis[8]. In many molecular mechanism studies, ERs-mediated signaling pathway is one of the most concerned EDCs action pathways. EDCs in the environment can mimic the action of endogenous hormones and affect the endocrine system of organisms by regulating the binding, transcriptional activation, expression and post-translational modification of ERs, resulting in serious consequences such as reproductive and developmental toxicity.
This review focuses on the basic characteristics of ERs, analysis and detection techniques, and the expression regulation and biological significance of ERs from different tissues by EDCs, in order to provide a systematic and comprehensive scientific idea for the study of ERs-mediated endocrine disruption.

2 Basic characteristics of ERs

2.1 Types and functions of ERs subtypes

ERs are protein molecules abundantly expressed in the nucleus, mainly including two different subtypes of ERα and ERβ, which are involved in the regulation of various biological processes such as reproduction, learning, memory and cognition[9]. Different subtypes of ERs have different physiological functions. ERα has the function of initiating the proliferation signal of mammary ductal epithelial cells. ERβ is associated with the expression of cell differentiation-related proteins such as epithelial cell adhesion molecules (E-cadherin and Integrin α2), gap junction proteins (Connexin 32) and tight junction proteins (Occludin), and has the function of promoting cell differentiation[10]. Based on the in vitro study of human breast cancer epithelial cell line MCF-7, it was found that the two ERs also showed opposite regulatory mechanisms, specifically, the introduction of ERβ could inhibit the cell proliferation effect induced by the combination of E2 and ERα[11]. In addition, based on the results of several human colon cancer cell lines that do not express ERα but only ERβ, such as HT29, Colo320, LoVo, SW480 and HCT116, exogenous phytoestrogens such as genistein also showed a slight inhibitory effect on cell proliferation[12]. The deficiency of ERα gene affects the development of reproductive organs (such as mammary gland, reproductive tract and gonad) in female mice and the fertility of male mice[13,14]. ERβ deficient mice have normal sexual behavior and reproductive function, but they have lower ovulation efficiency and fewer litters[15]. Both ERα and ERβ gene knockout mice showed normal growth and development, and had a relatively complete reproductive system, but neither male nor female had fertility[16].

2.2 Differential expression of ERs in species and tissues

The expression of ERs has a certain tissue and cell specificity, and is involved in the regulation of a variety of biological effects in tissues and organs, endocrine system, urinary system and reproductive system[17]. At present, based on the detection of ERs expression levels in some experimental animals (such as rodents, birds and amphibians) and human tissue cells, the results show that the expression of this receptor has obvious species, tissue and cell differences[8]. For example, ERs play important physiological functions in the brain tissues of birds and amphibians, and their expression in these two groups of organisms also shows significant spatial differences. Specifically, in birds, ERs are mainly localized in the limbic forebrain, midbrain striatum, hippocampus, and hindbrain, particularly in the preoptic area and hypothalamic tubercle[18]. In amphibians such as Tungara frog (Physalaemus pustulosus) and Rough-skinned newt (Taricha granulosa), ERs are mainly expressed in the limbic system (lateral anterior area, hypothalamus, nucleus accumbens, striatum, septum, amygdala), thalamus, laminar nucleus of the semicircular protuberance, and cerebral cortex[19].
Studies on the expression of ERs in rodents (such as rats and mice) have shown that the expression patterns of the two subtypes of receptor proteins are also different. In rats, ERα is mainly expressed in stromal cells and epithelial cells of endometrium, while ERβ is more abundant in prostate tissue cells[20]. In rat ovarian tissue, ERα is mainly present in stromal cells, while ERβ exerts its physiological function mainly in granulosa cells of developing follicles[20]. In the urinary system of mice, ERα is highly expressed mainly in tissues such as the ovary, oviduct, uterus, and vagina, whereas ERβ functions in the ovary, oviduct, and bladder[21].
Immunohistochemical results of normal adult tissues and organs showed that ERs were expressed in many tissues, such as brain, heart, blood vessels, liver, ovary, oviduct, uterus, kidney, breast, prostate and testis, but their abundance showed differences[22]. In addition, the expression of ERs in the same tissue also showed diversity. For example, in cerebellar tissue, glial and cerebellar granule cells express only ERβ, and Purkinje cells express only ERα; In cardiac tissue, ERα and ERβ were not expressed in endocardial and epicardial cells, while cardiomyocytes expressed both ERα and ERβ, but Purkinje fiber cells only expressed ERα[22].

2.3 ERs-mediated signaling pathway

Many EDCs in the environment exert endocrine disrupting effects primarily through genomic and nongenomic pathways that act on ERs signaling (Figure 1)[23,24]. Genomic pathway is the main mode of action of EDCs with estrogenic activity, that is, EDCs bind to ERs to induce receptor conformational changes to form dimers, recruit coactivators or corepressors, and then EDCs-ERs ligand-receptor complexes directly bind to Estrogen response elements.ERE) or through transcription factors such as Specificity protein 1 (Sp-1) or Activator protein 1 (AP-1) binding to ERE mediates the transcriptional regulation of downstream genes. The molecular mechanism of the nongenomic pathway has not been fully elucidated, but it has been demonstrated that ERs associated receptors on the cell membrane, such as typical G protein-coupled receptors (GPR30) or microvesicles (Caveolin-1), can mediate rapid estrogen signaling activation in cells.It leads to the cascade amplification of MAPK or PI3K, the change of intracellular calcium flux and the production of cyclic adenosine monophosphate. At present, some EDCs, such as BPA, DES and Benzo [a] pyrene, have been confirmed to disrupt the ERs signaling pathway through non-genomic pathways[23,24].

3 ERs analysis and detection technology

Exogenous EDCs can interfere with the expression and post-translational modification of ERs, or affect the endocrine system of organisms by acting on the binding pocket of ERs and then activating the transcription of downstream response genes of ERs. Based on this, the analysis and detection technology for ERs mainly includes the detection of ERs binding ability, expression and transcriptional activation.

3.1 ERs binding assay

EDCs can directly act on the ligand-binding pocket of ERs and thus affect the ERs signaling pathway.The existing methods for detecting ERs binding ability include radiolabel-based uterine cytosolic ERs binding activity test, ERs competitive binding assay based on enzyme fragment complementation technology, and rodent-based uterine weight gain assay, which can be used to screen the estrogenic or anti-estrogenic activity of exogenous chemicals.
Early ERs competitive binding assay is a classical method to evaluate the estrogenic activity of ERs by detecting the binding constant of the test substance to radiolabeled E2 when added to the uterine extract containing ERs[25]. Using this method, the researchers evaluated the binding strength of exogenous chemicals such as BPA and nonylphenols (such as p-Nonylphenol) to ERs[26]. However, this method can not distinguish between estrogen agonists and antagonists, and has some disadvantages such as radioactive substances that can cause harm to human body. In recent years, researchers have also developed EDCs screening kits based on different principles, which can rapidly and high-throughput detect the competitive binding ability of pollutants to ERs. For example, researchers have established and optimized ERs competitive binding experiments based on enzyme fragment complementation technology, and used this technology to evaluate the differences in the relative binding capacity of chemicals such as E2, genistein and PFIs with ERα and ERβ, revealing the different cytotoxic effects of these chemicals by regulating different subtypes of ERs[27].
Uterine weight gain experiments based on rats or mice are also an in vivo experimental method to evaluate the binding ability of EDCs to ERs, which aims to screen estrogen-like or anti-estrogenic active substances in the environment using immature female mouse models. Studies have shown that EDCs in the environment, such as Coumestrol, can bind to ERs in the uterus, induce intracellular reactions, cause significant increases in endometrial epithelial cells, increase the number of glands and other morphological changes, and ultimately lead to uterine weight gain[28].

3.2 Detection of ERs expression

Interfering with the transcription, translation and phosphorylation of ERs is one of the important ways for EDCs to mediate biological effects through ERs signaling pathway. Immunohistochemistry, Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting (WB) are the common methods to detect the expression of ERs[29,30].
ERs immunostaining analysis technology based on cell and tissue level has been very mature. This technology uses specific ERα and ERβ antibodies labeled with chromogenic reagents to carry out antigen-antibody reaction and histochemical color reaction in situ in tissue cells, which is one of the methods for visual localization and quantitative analysis of ERs. For example, the expression of ERα and ERβ in mouse tissues was detected by this technology, and it was found that ERα and ERβ were highly expressed in the epithelial cells and interstitial cells of the mammary gland of mice aged 2 months. In the mammary gland of adult mice, more than 60% of ductal epithelial cells express ERβ and less than 20% of ductal epithelial cells express ERα; Only ERβ protein is present in the interstitial cells of the mammary gland of adult mice[31].
RT-PCR analysis of ERs can be used to investigate the expression of these proteins at the transcriptional level. The method needs to extract total RNA from tissues or cells, use mRNA as a template, use Oligo (dT) to transcribe into cDNA through reverse transcriptase reaction, and then use cDNA as a template for PCR amplification to obtain the expression level of the target gene. The technology has high sensitivity and wide application. Taking the expression of ERs at the transcription level as the end point, some studies have shown that novel EDCs such as PFIs in the environment can exert endocrine disruption effects by inducing significant up-regulation of ERs (such as ERα and ERβ) at the transcription level in the liver tissue of fish[32].
The WB detection method for quantifying the ERs protein level is to transfer the total protein of cells or tissues separated by electrophoresis from the gel to a solid support such as Nitrocellulose (NC) or Polyvinylidene fluoride (PVDF) membrane, and use the specific ERs antibody to detect the antigen. Compared with immunohistochemistry, this method can be more accurately used for semi-quantitative analysis and detection of ERs, and can also be used for a certain degree of localization analysis, such as extracting cell membrane, nuclear and cytoplasmic proteins to detect antigen content, which indirectly reflects the localization of ERs in cells, but its sensitivity is far lower than that of immunostaining[33].

3.3 ERs transcriptional activation assay

In the screening of endocrine disrupting effects of new chemicals, small differences in the molecular structure of chemicals can lead to different binding strength with ERs, and then affect the transcriptional activation of downstream effector genes of ERs. At present, the commonly used methods to detect the transcriptional activation effect of environmental EDCs on ERs include in vitro (such as luciferase reporter gene assay, recombinant yeast estrogen assay) and in vivo (such as vitellogenin assay in aquatic organisms).
Cell-based green fluorescent protein or luciferase reporter assays are one of the most common methods for screening potential EDCs in the environment and comparing their binding ability to different subtypes of ERs. Typical EDCs in the environment can be used to evaluate the transcriptional activity of ERs by different cell models (such as Ishikawa, Hela, HepG2, zebrafish liver cells and Chinese hamster ovary cells) and reporter gene experiments transfected with ERs-regulated ERE fragments[34⇓⇓⇓⇓⇓⇓~41]. For example, the classical MVLN cell model is a human MCF-7 cell strain stably transfected with a Luc reporter gene system, which contains a synthetic gene fragment containing a Vitellogenin (VTG) promoter controlled by ERs[42,43]. Estrogen compounds can bind to ERs to change the conformation of the receptor, and the receptor complex can regulate the expression of luciferase by binding to the regulatory fragment of the receptor, which can be quantitatively determined by detecting the fluorescence signal of the luciferase catalytic substrate fluorescein, and the fluorescence signal intensity represents the agonistic or antagonistic effect of the compound on ERs. Some EDCs, such as E2, BPs, BFRs, insecticides, PFASs and genistein, can bind to ERs to different degrees in the activation test of ERs in the MVLN model, and then regulate their transcriptional activity[27,37,44,45]. The transcriptional activation of ERs by EDCs with similar chemical structures depends to some extent on the functional group structure of the compounds, such as the carbon chain length of PFIs (six carbons > eight carbons > four carbons) and the degree of iodine substitution (two iodine substitutions > one iodine substitution), which have a certain degree of influence on the activation of estrogen effect in MVLN cells[46].
The recombinant yeast estrogen assay can be used to detect the estrogenic activity of EDCs. In this method, the exogenous compound can activate the gene response fragment of the transfected human ERs in yeast, and the reporter gene of Lac-Z is also activated to transcribe into β-galactosidase during protein transcription and synthesis, and the estrogenic activity of the exogenous compound is evaluated by detecting the activity of β-galactosidase. At present, researchers have used this method to detect the binding ability of genistein and BPs with different subtypes of ERs[45,47].
The detection of VTG gene and protein levels in aquatic organisms, especially fish, is also a good method to evaluate the transcriptional activation effect of EDCs on ERs in the environment. A large number of experiments have shown that the expression of VTG, the downstream effector molecule of ERs, can not be triggered by the low concentration of circulating estrogen in male fish, but the expression of VTG gene and protein can be significantly up-regulated or down-regulated when exposed to exogenous EDCs. Therefore, VTG is often used as a typical biomarker of endocrine disruption through ERs signaling pathway in fish exposed to exogenous EDCs, indicating the degree of water environment polluted by estrogens or estrogen-like EDCs[48,49].

4 Regulation of ERs by EDCs

ERs are key regulators of growth, differentiation, and function in a variety of target tissues such as the reproductive system, mammary gland, skeletal and cardiovascular systems, and even the central nervous system[23,50]. Inappropriate regulation of ERs signaling can lead to the risk of reduced reproductive capacity, abnormal fetal growth and development, glucose and lipid metabolism disorders, and hormone-dependent cancer[23].

4.1 Reproductive and developmental system

Estrogen or androgen plays an important role in gonadal development, secondary sexual characteristics development and gametogenesis. Most EDCs can interfere with the synthesis and secretion of hormones through ERs, causing damage to reproductive and developmental systems. The effects of EDCs on fish are mainly reflected in the delay of growth and development, the disorder of hormone levels in plasma, the increase of the proportion of female fish in the population, the "feminization" of male fish, and the change of reproductive cycle[51][52⇓~54][48][55,56]. ERs play an important regulatory role in this process, for example, EE2 affects the migration of zebrafish primordial germ cells through ERβ, which has a potential impact on the sex differentiation and reproductive system of fish[57]. Shrimp organisms in arthropods are also susceptible species to EDCs in the environment[58]. Studies have shown that pesticides such as chlordane and lindane can affect the appendage morphology, female reproductive capacity and hormone levels of male green shrimp (Neocaridina denticulata) in freshwater systems in Taiwan, China, which may be related to the involvement of these substances in the regulation of the induction of downstream targets of ERs (such as VTG protein)[59,60]. The results of rodent-based studies have shown that the transcriptional activation of ERs in rat tissues and organs by environmental EDCs can cause changes in the development of the corresponding organs. For example, in the uterine nutrition test, Wistar rats exposed to PAHs such as benzopyrene or benzanthracene for three consecutive days showed increased uterine weight and luminal epithelial hypertrophy mediated by ERα[61]. Excessive activation of ERs can also lead to the cessation of differentiation of round spermatids to elongated spermatids in male rats, changes in hormone levels, and a decrease in litter size[62]. Epidemiological studies have found that EDCs interfere with normal hormone pathways through ERs signaling, affecting steroid production and metabolic breakdown in the ovary.It causes reproductive defects (such as malformation of sexual organs, decreased sperm motility and quality), infertility or adverse pregnancy outcomes, and even neonatal development and later reproductive disorders (such as male cryptorchidism and hypospadias, female ovarian dysplasia and decreased fertility)[63,64].
The reproductive and developmental toxicity of EDCs to organisms can also be regulated by directly affecting the expression of ERs themselves. Based on the results of in vitro studies, 0.1 nmol/L E2 or 1 nmol/L BPA exposure can significantly up-regulate the gene expression of AR and ERs in CD-1 mouse embryonic prostate mesenchymal cells, showing a significant endocrine disruption effect[65]. As the largest group of mollusks, shellfish is one of the "sentinel" species in the process of marine EDCs pollution monitoring. The reproductive physiology of shellfish determines that they are vulnerable to environmental pollutants during gametogenesis[66]. It has been found that contamination of mussels with estrogens (such as E2, EE2 and estradiol benzoate) in the early stage of gametogenesis can lead to a significant up-regulation of VTG and ER transcription levels[67]. Rodential-based studies have shown that PFOS can induce down-regulation of ERα and up-regulation of ERβ in male C57 mice, resulting in reproductive toxicity effects such as decreased sperm quality, decreased serum testosterone levels, and decreased sperm cell numbers[68].

4.2 Nervous system

Some EDCs, such as BPA and Phthalates, have been detected in fetal development matrices (such as maternal blood, placenta and amniotic fluid) and even in human fetal serum, indicating that they can cross the placental barrier and may even be transmitted to offspring through breast milk after birth.It then affects the neurodevelopmental process of the fetus, eventually leading to some abnormal behaviors and neurological disorders in later life (such as hyperactivity, aggressive behavior, anxiety, depression and attention problems)[69⇓⇓~72]. ERs, as typical steroid hormone receptors, play an important role in mediating neurotoxicity caused by EDCs. For example, BPA can regulate the signaling of multiple hormone receptors (such as ERα, ERβ and ERRγ) and interfere with their expression levels, resulting in impaired learning, cognition, memory and neurobehavior during neurodevelopment[70]. Phthalate esters (such as DBP, DINP and BBP) were exposed to zebrafish during embryonic development, and the results showed that these substances significantly down-regulated the expression of ERα and ERβa, up-regulated the expression of ERβb, and reduced the brain volume and the number of proliferating neurons in zebrafish, thus affecting the process of neurogenesis[73]. Octamethylcyclotetrasiloxane (D4) also has typical estrogenic activity during mouse neural development, and ERα and ERβ-mediated regulation affects the cell cycle progression of neural progenitor cells, revealing the potential molecular mechanism of EDCs impairing mouse brain development[74]. In a subchronic toxicity study of BPA in Sprague-Dawley (SD) female rats, continuous low-dose oral administration of BPA from day 6 of pregnancy to parturition caused a decrease in ERα expression in the Anteroventral periventricular nucleus (AVPV) of the hypothalamus, which affected the neuroendocrine system[75]. Injection of PCBs such as Aroclor 1221 into the hypothalamus of SD rats significantly reduced the number of ERβ-positive cells in AVPV, but did not affect the expression of ERβ in the supraoptic nucleus, which may cause permanent damage to the brain structure and function of adult rats[76].

4.3 Cardiovascular system

Toxicological and epidemiological studies have shown that EDCs such as BPA can interfere with endogenous hormone levels in rodents and non-human primates, disrupt normal cardiovascular physiology, and lead to increased health risks of cardiovascular diseases such as hypertension, coronary heart disease, angina pectoris, and myocardial infarction[77,78]. The possible mechanism is that the stimulation of BPA interferes with the normal estrogen and ERs signaling pathways in the vasculature of the organism[78]. The number of L-type calcium channels, which are key factors of cardiac excitability and contractility, increased in ER-deficient male mice, indicating that ERs may be potential targets of cardiac excitability abnormalities and arrhythmias[79]. Furthermore, physiological concentrations of (10-9mol/L)BPA and E2 can specifically induce heart rate abnormalities and sarcoplasmic reticulum calcium leakage in female SD rats through ERs, especially ERβ, suggesting that female rats are more susceptible to exogenous EDCs than males[80]. Phytoestrogens have the ability to activate ERs, and the intake of soybean products has been proved to significantly reduce the levels of total cholesterol, low density lipoprotein and triglyceride in serum, which can reduce the incidence of vascular diseases in the population to a certain extent, and reduce the pathological changes of atherosclerosis patients and the impact on vascular endothelial function[78].

4.4 Lipid metabolism

Endogenous estrogens act on the brain, adipose tissue, pancreatic islets, skeletal muscle, liver and so on to regulate glucose and lipid homeostasis in organisms, and avoid the occurrence of metabolic syndrome, type II diabetes and obesity[81]. At present, many environmental EDCs have been proved to interfere with the balance of glucose and lipid metabolism.Such As DES, bisphenols (BPA and its homologues), phthalates, organotin (such as tributyltin and dibutyltin), nonylphenols, pesticides (organochlorine pesticides such as DDT), food additives (such as 3-tert-butyl-4-hydroxyanisole and p-hydroxybenzoate) and heavy metals (such as Cd, As, Pb), which are considered to be typical environmental obesogenic factors or lipid metabolism interfering factors[82⇓⇓~85]. Peroxisome proliferator-activated receptor γ (PPARγ) and steroid receptors such as ERs (including ERα and ERβ), glucocorticoid receptor and AR are the main target receptors of EDCs to interfere with glucose homeostasis and energy metabolism during physiological and menopausal periods[82]. It was found that fulvestrant, a specific inhibitor of ERs, alleviated the directional differentiation of mouse preadipocytes 3T3-L1 into white adipocytes induced by surfactants such as 4-hexylphenol, and inhibited the formation and accumulation of lipids in human hepatoma cell line HepG2, indicating that ERs play an important regulatory role in lipid production and metabolism[86]. E2 and BPA can bind to ERs on β islet cells, especially ERα, and activate its downstream signal transduction pathways such as MAPK/ERK1/2 phosphorylation, resulting in increased insulin synthesis and secretion, leading to insulin resistance and hyperinsulinemia in liver and muscle, thus aggravating the development of type II diabetes mellitus[83,87,88].

4.5 Liver

ERs play an important role in bile acid synthesis, cholesterol and lipid homeostasis in the liver tissue of organisms, and EDCs can be toxic to the liver through the ERs pathway.
Different subtypes of ERs in liver tissue show different characteristics in response to EDCs. For example, endogenous hormones such as E2 and testosterone can increase the expression of ERα66 and ERβ and decrease the expression of ERα36 in human hepatocellular carcinoma cell line HepG2, which affects the growth of cells[89]. ERs in liver tissue also showed gender differences in response to exogenous EDCs. For example, genistein can increase the expression of ERα in the cytoplasmic matrix of liver tissue in female SD rats and decrease it in male SD rats. EE2 had no effect on ERα expression in the liver of female rats, but showed a significant dose-dependent effect in males[90]. EDCs may also interfere with the regulation of other enzymes or factors through ERs signaling, resulting in toxic effects on the liver. For example, the typical carcinogen furan can induce overexpression of ERα in the liver of B3C6F1 mice, and its mechanism of action involves signaling pathways such as stress-activated protein kinase SAPK, death receptor DR5, extracellular signal-regulated protein kinase ERKs, and tumor necrosis factor-α (TNF-α)[91].
Transcriptional activation of ERs also plays an important role in the metabolism of the liver. Triazole fungicides such as Tebuconazole and cyproconazole can induce the transcriptional activation potential of ERα in HepG2 cells, and then interfere with the synthesis and secretion of estrogen, resulting in metabolic disorders of biological macromolecules such as lipids, amino acids and carbohydrates[92]. In addition, EDCs such as E2, APs, BPA, PFASs, TBBPA, organochlorine pesticides and PAHs entering the aquatic environment can induce the up-regulation of VTG expression in the liver tissue of juvenile or adult fish[93,94]. Taking PFASs as an example, the results based on different fish models such as Tilapia (Oreochromis mossambicus), Rare minnows (Gobiocypris rarus), Japanese medaka (Oryzias latipes) and Rainbow trout (Oncorhynchus mykiss) show that PFOA, PFOS, 6 ∶ 2 FTOH, PFNA, PFDA, PFUnDA, PFOI and 8 ∶ 2[32,95,96]. At the same time, the results of PFIs (such as PFBDI, PFHxDI, PFODI) exposure based on zebrafish embryos also showed that the transcription level of ERs in juvenile fish was significantly up-regulated, suggesting the potential endocrine disrupting properties of PFASs[97]. Rodent-based studies have shown that gibberellin induces the development of liver tumors in American hamsters (Cricetulus migratorius) through ERs-dependent transcriptional activation[98]. Nonylphenols can interfere with estrogen signaling pathway through ERs, resulting in the increase of TNF-α and IL-1β secretion in mouse liver[99]. Furthermore, the two ERs sometimes perform different physiological functions at the metabolic level in the liver. EE2 can cause toxicity such as hepatocyte degeneration and intrahepatic cholestasis in mice by inhibiting hepatic transporters and altering bile acid biosynthesis through ERα-mediated signaling pathways[100]. The deletion of ERβ gene can alleviate the disorder of bile acid and cholesterol metabolism caused by PFOS to some extent, and affect the species and composition of intestinal microbiota.

4.6 Cancer

Estrogen and ERs can participate in the occurrence and development of a variety of malignant tumors, and play an important physiological role in breast cancer and gynecological cancer (such as uterine cancer, ovarian cancer), endocrine organ cancer (such as adrenocortical cancer, ovarian cancer, pancreatic cancer, prostate cancer and thyroid cancer), lung cancer and digestive system cancer (including colorectal cancer, esophageal cancer, liver cancer and pancreatic cancer)[101]. Although most of these tumors express both ERα and ERβ, they often perform opposite physiological functions[101,102]. For example, in breast cancer, gynecological cancer and secretory adenocarcinoma, ERα promotes their proliferation, while ERβ inhibits their proliferation; In digestive tract cancer and lung cancer, ERα inhibits their proliferation, while ERβ promotes their proliferation[101]. Furthermore, ERs-mediated downstream signaling pathways also play a role in the development of cancer. For example, in lung cancer, E2 induces the up-regulated expression of Osteopontin, which contributes to the transduction between ERs and epidermal growth factor receptor signaling pathways, and estrogens can promote the migration of cancer cells by activating ERβ of MEK/ERK signaling pathways. In endometrial carcinoma, overexpression of ERα promotes the activation of the PI3K/AKT/mTOR transduction cascade[103].
A large number of in vitro experimental studies based on human breast cancer cells have shown that many EDCs in the environment can mediate ERs signaling pathway to cause cell proliferation, which confirms that EDCs may induce the occurrence and development of breast cancer in vitro. The effect of E2 on the proliferation of breast cancer cells was found to be positively correlated with the content of ERs in the cells, and the order of the proliferation of the three kinds of cells was MCF-7 > T47D > MDA-MB-231[104]. Some EDCs can also cause significant proliferative effects in breast cancer cells with different contents of the two subtypes, including ERα and ERβ. Genistein, BFRs (such as TBBPA and HBCD) and Parabens can promote the proliferation of MCF-7 cells and induce the expression of estrogenic genes such as TFF1, showing a typical estrogenic effect[105⇓~107]. In addition, the effect of ERs-mediated cell proliferation was also verified in another human breast cancer ductal cell line T47D with a low ERα/ERβ ratio. The results showed that specific ligands of ERβ targeted the expression of key genes in the cell cycle, such as c-myc,cyclin D1,cyclin E,cyclin A,Cdc25A,p45Skip2 and p27Kip1, thereby inhibiting the effect of endogenous estrogens (such as E2) on T47D cell proliferation[108]. Regulating the expression of ERs in breast cancer cells is also one of the important mechanisms for exogenous EDCs to exert their endocrine disrupting effects. It has been found that genistein, E2 and insecticides (such as fenarimol, endosulfan, pirimicarb) can rapidly down-regulate the ER transcription level and affect the growth of MCF-7 cells or breast fibroblast MCF-7 BUS cells[109,110]. Other studies have found that the expression of ERα in MCF-7 cells increased slightly at first and then decreased significantly after 48 H under the continuous stimulation of hydroxybenzoates (such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, etc.), indicating that ERs can mediate the proliferation effect of cells[106]. The results of simulated exposure to herbicides (such as Glyphosate-based herbicides, GBHs) in prepubertal and postpubertal Wistar male rats showed that the development of mammary tissue was blocked, which may be related to the down-regulation of ERα transcription and protein levels, and the biological effects of mammary tissue cells further indicated that the expression response of ERs was directly related to the exposure of exogenous compounds[111].
Glioma is the most common endocrine gland malignancy of the central nervous system. There are two receptors in glioma, ERα and ERβ (mainly ERα), and the expression of both receptors decreases with the increase of tumor malignancy[50]. Previous studies have shown that endogenous estrogen E2 interact with ERα to recruit steroid receptor coactivators (such as SRC-1 and SRC-3) to promote the growth of astrocytes[112]. Based on the in vitro experimental results of neuroblastoma SH-SY5Y cells, two typical EDCs such as BPA and nonylphenol can recruit ERα or SRC-1 to the promoter of their specific target genes such as Cathepsin D, increase the transcriptional activation of ERα, and then induce the high expression of downstream response gene Cyclin D, and enhance the proliferation, invasion and metastasis of SH-SY5Y cells[113]. ERβ agonists have the potential to inhibit the growth of glioma and promote the death of tumor cells, suggesting that ERβ may have a certain inhibitory effect on the development of neural related tumors[50].
Epidemiological studies have shown that some EDCs, such as BPA, dioxin, and phthalate esters (such as DEHP), can activate ERs signaling pathways, which are closely related to the development of estrogen-dependent cancers (such as ovarian cancer, breast cancer, and prostate cancer)[114]. However, population studies based on data analysis alone are not enough to clarify the mechanism of ERs in the occurrence and development of cancer in various populations, and more clinical studies are needed to confirm it in order to find new cancer treatment methods based on ERs.

5 Summary and Prospect

There are many kinds of EDCs in the environment, and the mechanisms of their endocrine disrupting effects on organisms are very complex. ERs-mediated signaling pathway is one of the main mechanisms by which EDCs regulate the endocrine system to produce toxic effects. When EDCs enter the organism, they can bind to ERs to form a complex, which can directly act on ERE or activate the transcriptional regulation of downstream genes by binding to some transcription factors, resulting in growth and development toxicity and reproductive toxicity to humans and wildlife[116,117]. The binding ability of EDCs to ERs, the transcriptional activation of downstream response genes, and the differential regulation of their own transcription and protein expression are all affected by species, tissue cells, gender, age, and exposure methods.The endocrine disrupting effects produced by EDCs are different, which limits the extrapolation of endocrine disrupting effects produced by EDCs through ERs in different species and under different conditions, and is an urgent problem to be solved in the mechanism of endocrine disrupting effects[118].
More and more studies have shown that the exposure of EDCs in the environment may be closely related to the occurrence and development of early embryonic developmental abnormalities (such as neurodevelopmental abnormalities), reproductive disorders, and some cancers (such as breast cancer, testicular cancer, ovarian cancer), in which the role of ERs is still unclear[119]. At present, the studies on the endocrine disrupting effects of EDCs mediated by ERs are mainly focused on rats, mice, fish and other experimental animals, or based on in vitro human cell models, and the relevant research results can not directly reflect the human health effects of pollutants. However, many EDCs can directly target and bind to ERs in the human body, interfere with the expression of ERs themselves and downstream transcriptional regulation, resulting in endocrine system disorders, and may even lead to cancer risk[117]. Therefore, paying attention to the association between ERs and human diseases related to EDCs exposure will help to understand the intrinsic molecular mechanism of the pathogenic effects of EDCs, and provide scientific data support for the risk assessment of EDCs to human health.
As one of the important signaling pathways of EDCs targeting organisms, the endocrine disrupting effect mediated by ERs can not be ignored, so it is urgent to establish a more complete method evaluation system for screening compounds to regulate the activity of ERs, so as to meet the growing demand for rapid screening of endocrine disrupting effects of new chemicals and the analysis of their molecular mechanisms. In addition to ERs, it is also necessary to carry out parallel studies on endocrine disrupting effects of compounds through other regulatory pathways, which is also an indispensable and important direction for comprehensive screening of EDCs in the environment.

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Funding

National Key R&D Program of China(2018YFA0901101)

National Natural Science Foundation of China(22193050)

National Natural Science Foundation of China(22176203)

National Natural Science Foundation of China(21906180)

National Natural Science Foundation of China(22276212)

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