Review Article

Yonago Acta medica 2001;44:1–6

Steroid Hormones and Endocrine Disruptors: Recent Advances in
Receptor–Mediated Actions
Dono Indarto* and Masao Izawa
Department of Biosignaling, Tottori University Faculty of Medicine, Yonago 683-0826 Japan
It has been accepted that receptor-mediated action of steroid hormones depends on
both the receptor and the hormonal level. The mechanism of transcription by steroid
receptors is mediated by cofactors, which function as co-activators or co-repressors,
while their non-genomic actions depend on receptors localized to the cell membrane.
Recently, a number of environmental chemicals, which are now termed as endocrine
disruptors, have been identified, and their unwanted effects on our lives have become
serious problems all over the world. Their adverse effects on endocrine systems inanimals, mostly estrogenic or anti-estrogenic, have resulted in reproductive malfunction
and developmental disorders. Although aryl hydrocarbons exhibit estrogenic or antiestrogenic activity through specific interaction with aryl hydrocarbon receptors, otherchemicals seem to interact directly with estrogen receptors, α and β forms. In thispaper, we surveyed the most recent understanding of endocrine disruptors from theviewpoint of steroid receptor systems. We suggest two potential mechanisms of action
for endocrine disruptors. Endocrine distruptors i) directly associate with steroid
receptor systems and/or ii) associate with the growth factor or the neurotransmitter
receptor systems, and then upregulate the mitogen-activated protein kinase signalingcascades, leading to the ligand-independent activation of steroid receptor systems. Using
these steroid receptor-dependent mechanisms, it appears that endocrine disruptors
disorder our endocrine systems. We have proposed future suggestions to further
understand endocrine disruptors from the viewpoint of steroid receptor systems.
Key words: endocrine disruptors; receptor-mediated actions; steroid hormones

Since the cloning of human glucocorticoid receptor (Hollenberg et al., 1985), a number ofnuclear receptors including steroid receptors
have been identified (Mangelsdorf et al., 1995;
Pfaff et al., 1997), and are now understood astranscription factors included in a nuclear receptor superfamily (Freedman, 1999). Recently, estrogen receptors (ERs) have been shown tolocalize to the cell membrane, and their role innon-genomic actions have been demonstrated aswell (Chen et al., 1999; Goetz et al., 1999).

A number of environmental chemicals havebeen identified as endocrine disruptors, and theirunwanted effects on our lives have become serious problems all over the world. At present,
their adverse effects on endocrine systems inanimals, mostly estrogenic or anti-estrogenic,
have resulted in reproductive malfunction anddevelopmental disorders (Keith, 1997). Among
endocrine disruptors identified so far, arylhydrocarbons, dioxins, exhibit estrogenic or
anti-estrogenic activity through specific inter-

Abbreviations: AhR, aryl hydrocarbon receptor; AR, androgen receptor; ARE, androgen responsive element;
DES, diethylstilbeterol; EGF, epidermal growth factor; ER, estrogen receptor; ERE, estrogen responsive element;
IGF, insulin-like growth factor; LBD, ligand binding domain; MAP mitogaen-activated protein; PR, progesterone
receptor; PRE, progestin responsive element; PHA, polycyclic aromatic hydrocarbon* Present address: Sebelas Maret University, Surakarta 57126, Indonesia. Short-term student exchange promotion
program, Tottori University, supported by AIEJ 2000.

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D. Indarto and M. Izawa

action with aryl hydrocarbon receptors (AhRs)(Osteen et al., 1997), while most other chemicals
seem to interact directly with the ER system.
In this paper, we give a brief overview of therecent understanding of the receptor-mediatedactions of steroid hormones, and discuss thereceptor-mediated actions of endocrine disruptors.

gen responsive element (ERE) in responsive
genes (McKenna and O’Malley, 2000; Freedman,1999). When bound by an estrogen antagonist,
ER recruits N-Cor and SMRT, co-repressors,and inhibits the transcription of estrogen responsive genes (McKenna and O’Malley, 2000). The
concept of ER-dependent genomic actions has
been accepted for other steroid receptor systems. Recently, growth factors, neurotransmitters and cyclins have been demonstrated tocrosstalk with steroid receptor systems. Epidermal growth factor (EGF), insulin-likegrowth factor (IGF) (Kato et al., 1995; Bunone
et al., 1996) and dopamine (Mani et al., 1994)
could activate ERα via the mitogen-activatedprotein (MAP) kinase pathway in a ligandindependent manner. Cyclins directly interact
with the unliganded ERα (Zwijsen et al., 1997).
Progesterone receptor (PR) is also activated bydopamine through cAMP-dependent phosphorylation, and associates with SRC-1e, a coactivator specific for PR, to interact with the progestin responsive element (PRE) (Bai et al.,
1997; Brossens et al., 1999). On the other hand,

Recent advances in themechanism of action of steroids
Nuclear receptors including steroid receptors
have been understood as transcription factors,
which mediate extracellular signals to the
nucleus. A carboxy-terminus region of steroid
receptors, the ligand binding domain (LBD), specifically interacts with cognate ligands, while
the AF-2 domain recruits cofactors (Freedman,
1999; also see Fig. 1). Once associated with estrogens, ER is activated and recruits co-activators such as those from the SRC-1 family and
TIF2/GRIP1/NCoA2, to interact with the estro-A

B

Genomic action

Endocrine Disruptors

Non-genomic action

Endocrine Disruptors

Steroid Hormones

Steroid Hormones

Growth factors

Plasma membrane Receptor

Plasma membrane Steroid Receptor

Up-regulation of MAP kinases
Up-regulation of MAP kinases
Ligand-independent activation

Ligand-dependent activation

Intracellular Steroid Receptor

Responses

Association withcoactivators or corepressors
to interact with HREs
in hormone responsive genes

Responses

Fig. 1. Mechanism of action of steroid hormones and endocrine disruptors. A: Genomic action. Steroid
hormones and endocrine disruptors diretly interact with intracellular steroid receptors. This leads to therecruitment of cofactors for specific interaction with hormone responsive elements (HREs) in hormone responsive genes. On the other hand, endocrine disruptors interact with receptors for growth factors or neurotransmitters to up-regulate mitogen-activated protein (MAP) kinase signaling. This leads to the ligandindependent activation of steroid receptors for the association with cofactors as described above. B: Nongenomic action. Steroid hormones and endocrine disruptors associate with steroid receptors localized to thecell membrane. This leads to the intracellular signaling pathways.

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Steroids and endocrine disruptors

androgen receptor (AR) is activated by EGF,
IGF and keratinocyte growth factor (KGF)
through MAP kinase cascades, and binds to AP1 and Ets, a co-activator specific for AR, tointeract with the androgen responsive element(ARE) (Klocker et al., 1999; Culig et al., 1994).
Along with the ligand-dependent and theligand-independent genomic actions, nongenomic actions through the plasma membrane
receptor have recently been demonstrated toplay impotant roles in hormone responsive cells(Chen et al., 1999; Goetz et al., 1999). In summary, the steroid receptor system is not only aligand-induced transcriptional enhancer, butalso a mediator of common intracellular signaling pathways in multiple cell types.

1999), and decrease the estrogen level in the
blood (Kohn et al., 1993; Alvarez et al., 2000),the ER level in the uterus (De Vito et al., 1992;
Alvarez et al., 2000) and the number of matured
follicles associated with the upregulation of thefollicle-stimulating hormone (Alvarez et al.,2000). Endocrine disruptors, which seemed to
be closely related to AR systems are Flutamide,
vinclozolin, p,p'-DDE and procymidone, antiandrogens, which disorder prostate maturation(Gray et al., 1999b), and induce undescended
testis (Gray et al., 1999b), hypospadia (Gray etal., 1999b; Ostby et al., 1999) and permanent
nipples (Gray et al., 1999b; Ostby et al., 1999)
during sex differentiation. In adult animals,
anti-androgens increase the serum levels of
androgens, luteinizing hormone and estrogens(Ladics et al, 1998; Monosson et al., 1999), andinduces spontaneous abortions, stillbirths,
reproductive malfunction, neuroendocrine
alteration, and disorder of immune systems(Goldman, 1997; Palanza et al, 1999; Alvarez etal., 2000).
As demonstrated above, disorder of steroid
receptor-mediated signaling systems by endocrine disruptors leads to abnormal conditions inanimal physiology. It is important to note thatsome endocrine disruptors exhibit potential
activities: (i) to interact directly with endogenous steroids, (ii) to inhibit steroid receptor
binding, non-competetively or (iii) to destroy
receptor molecules or endogenous steroids(Sonnenschein and Soto, 1998; Soto et al.,1998).

Endocrine disruptors
and the mechanism of action
Adverse effects of pharmaceuticals, industrial
waste and environmental pollutants (now all
acknowledged as endocrine disruptors) on ourlives have become a serious problem in theworld. They disorder the endocrine system inanimals directly or indirectly. It is obvious thatthey exert their effects in a receptor-dependent
manner (Brouwer et al., 1998; Chia, 2000;
Fenner-Crisp, 2000).
Endocrine disruptors, which seemed to beclosely related to ER systems, could be classified into three groups: estrogen mimics, antiestrogens and anti-androgens (Sonnenschein
and Soto, 1998; Gray et al., 1999a). An initial
target for these compounds is ER (Nishikawa etal., 1999). Diethylstilbesterol (DES), a synthetic estrogen, behaves as an estrogen agonist(Hunter et al, 1999), and exposure to DES during the fetal period induces urogenital abnormalities in males (Kuiper et al., 1998; Spearow
et al., 1999), oligospermia (Krishnan et al.,
1993; Vom Saal et al., 1997), the increased
incidence of undescended testis (Kuiper et al.,
1998; Spearow et al., 1999) and hypertrophy ofthe prostate (Newbold, 1995). Polycyclicaromatic hydrocarbons (PAHs) have an antiestrogenic activity through AhR (Brouwer etal., 1998; Safe et al., 1998; Loaiza-Perez et al.,Conclusion
Ligand-dependent and -independent signaling
pathways by steroid receptors seem to provide
insights into the understanding of the molecularbasis of endocrine disruptors as summarized inFig. 1. We also summarized representative endocrine disruptors identified so far in Table 1.
Although a number of endocrine disruptors inour daily lives have been identified, little is
known about their molecular basis. It becomesan urgent subject to further understand the molecular basis of the diverse actions of endocrine3

D. Indarto and M. Izawa

Table 1. Representative endocrine disruptors
CompoundUse

Receptor

Reference

DES
Bisphenol A
Nonylphenol

MedicineERα, ERβERα, ERβERα, ERβ23, 3023, 3723, 37

PAHs:HCB, HCHo,p'-DDT
p,p'-DDT
Methoxychlor
Endosulfan
Chlordeconep,p'-DDE
LinuronVinclozolin
Procymidone

Pesticide

AhR
ERα, ERβERα, ERβERα, ERβERα, ERβERα, ERβ
AR
AR
AR
AR

25, 36
23
23
23
23
23
14, 15, 32
14, 15, 32
14, 15, 32
14, 15, 32

PCBs
Industrial waste
ERα, ERβ15, 23
Bisphenol A
ERα, ERβ23, 37
4 Tert-octyphenol
ERα, ERβ23, 374-Octyphenol
ERα, ERβ23, 37
TCDD
AhR
36
AhR, aryl hydrocarbon receptor; AR, androgen receptor; DES, diethylstilbesterol;
ER, estrogen receptor; HCB, hexachlorobenzene; HCH, hexachlorohexane; op'/pp'DDT, dichlorodiphenyltrichloroethane; PAH, polycyclic aromatic hydrocarbon;
PCB, polychlorinated hydroxybiphenyl; p,p'-DDE, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

disruptors. Understanding endocrine disruptors
from the viewpoint of steroid receptor-mediatedsignaling may allow us to overcome these global problems. In addition, it is obviously important to keep up international cooperation.

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Acknowledgments: D. I. thanks Professor Kenzo
Takeshita, former Dean of Tottori University Faculty of Medicine, for arranging the opportunity to visit
Tottori University. We also thank Professor Takeshi
Sairenji, Department of Biosignaling, Tottori University Faculty of Medicine, for his encouragement.

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Received December 27, 2000; accepted January 12, 2001
Correspondence: Masao Izawa, PhD
Department of Biosignaling
Tottori University Faculty of Medicine
86 Nishi-machi, Yonago 683-8503 JAPANTel and Fax: +81-859-34-8042
E-mail: 1mizawa@grape.med.tottori-u.ac.jp6