Steroid Hormone Receptors and Dietary Ligands: a Selected Review

Proceedings of the Nutrition Society (2002), 61, 105–122 DOI:10.1079/PNS2001140 © The Authors 2002

CABPNS12218© Nutrition 140PostgraduateInternationalPNSProceedings Society SymposiumM.2002 of N. Nutrition Jacobs andSociety D. F. (2002)0029-651© V. Lewis105 Nutrition Society 2002 611

Steroid hormone receptors and dietary ligands: a selected review

Miriam N. Jacobs* and David F. V. Lewis School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK Miriam Jacobs, fax +44 1483 300374, email [email protected]

Members of the nuclear steroid hormone superfamily mediate essential physiological functions. Steroid hormone receptors (SHR) act directly on DNA, regulate the synthesis of their target genes and are usually activated by ligand binding. Both endogenous and exogenous compounds and their metabolites may act as activators of SHR and disruptors of endocrine, cellular and lipid homeostasis. The endogenous ligands are generally steroids such as 17β-oestradiol, androgens, progesterone and pregnenolone. The exogenous compounds are usually delivered through the diet and include non-steroidal ligands. Examples of such ligands include isoflavanoids or phyto- oestrogens, and food contaminants such as exogenous oestrogens from hormone-treated cattle, pesticides, polychlorinated biphenyls and plasticisers. Certain drugs are also ligands; so nuclear receptors are also important drug targets for intervention in disease processes. The present review summarises recent reports on ligand-activated SHR that describe the selective regulation of a tightly-controlled cross-talking network involving exchange of ligands, and the control of major classes of cytochrome P450 (CYP) isoforms which metabolise many bioactive exogenous compounds. Many CYP have broad substrate activity and appear to be integrated into a coordinated metabolic pathway, such that whilst some receptors are ligand specific, other sensors may have a broader specificity and low ligand affinity to monitor aggregate levels of inducers. They can then trigger production of metabolising enzymes to defend against possible toxic nutrients and xenobiotic compounds. The influence of dietary intakes of nutrients and non- nutrients on the human oestrogen receptors (α and β), the aryl hydrocarbon receptor, the pregnane X receptor, the constitutive androstane receptor, and the peroxisome proliferator-activated receptors (α and γ), can be examined by utilising computer-generated molecular models of the ligand–receptor interaction, based on information generated from crystallographic data and sequence homology. In relation to experimental and observed data, molecular modelling can provide a scientifically sound perspective on the potential risk and benefits to human health from dietary exposure to hormone-mimicking chemicals, providing a useful tool in drug development and in a situation of considerable public concern.

Steroid hormone receptors: Human oestrogen receptors: Ligand–receptor interaction: Endocrine disruption

activatedAhR, aryl receptor; hydrocarbon PXR, receptor; pregnane CAR, X receptor; constitutive SHR, androstanesteroid hormone receptor; Endocrine-disruptingreceptor. CYP, cytochrome P450; DDT, dichlorodiphenyltrichloroethane; EDC, endocrine-disrupting chemicals; ER,chemicals oestrogen receptor; LBD, ligand binding domain; PCB, polychlorinated biphenyls; PPAR, peroxisome proliferator- heavy metals, because they can interfere with normal blood hormone levels or the subsequent action of those hormones, Endocrine-disrupting chemicals (EDC) are substances that but do not have a classical toxic effect. The effects can can cause adverse effects by interfering in some way with influence and disrupt the hormonal regulation and hormonal the body’s hormonal or chemical messengers. Under the imprinting (in the fetus) of normal cell differentiation, control of the central nervous system, hormones are secreted growth, development, metabolism and reproduction by the endocrine glands and exert control on other cells of throughout life. Endocrine disruption can occur at levels far the body. The endocrine system is complex, with many lower than those of traditional concern to toxicologists. organs producing different hormones, contributing to a Sometimes high doses shut off effects that occur at multifaceted feedback regulatory system that is deficient in low levels, and sometimes low and intermediate doses the developing fetus and infant. EDC are differentiated from produce greater effects than those observed at high doses. classical toxicants such as carcinogens, neurotoxicants and Human populations are exposed to complex mixtures of

Abbreviations: AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; CYP, cytochrome P450; DDT, dichlorodiphenyltrichloroethane; EDC, endocrine-disrupting chemicals; ER, oestrogen receptor; LBD, ligand binding domain; PCB, polychlorinated biphenyls; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; SHR, steroid hormone receptor. *Corresponding author: Miriam Jacobs, fax +44 1483 300374, email [email protected]

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environmental and endogenous agents, which may act the delicately balanced compensatory systems are easily together or modulate one another to produce biological perturbed. Hormone dynamics have evolved over a long effects. While exogenous endocrine modulators can involve period of time to deal with hormone and dietary phyto- any hormonal system and be affected by normal physio- chemical exposure, but they are not a rapid response system logical states (such as menstruation and menopause in able to deal effectively with the synthetic chemicals of the women, the andropause in men, and puberty, the somato- twentieth and twenty-first centuries. pause and adrenopause in both sexes), diet, stress and other At the molecular level, receptors mediate alterations of lifestyle factors, the principal focus of the present review is hormone availability, action, excretion and biotransfor- on the effects of sex hormones, and especially oestrogen- mation, in concert with the cytochrome P450 (CYP) enzyme mediated effects, on the steroid hormone receptors (SHR) in system. Many receptors have been identified and are human subjects where the ligands are delivered through the awaiting the recognition of specific ligands and functions, diet. The intention is that the present review will provide a and it is likely that more receptors will be discovered in the basis for understanding some of the critical issues involved future. Each type of receptor has the potential to regulate a in hormone receptor-mediated toxicity, and the broad distinct endocrine signalling pathway, of which we only context involved. have a rudimentary knowledge.

Hormone dynamics Hormone-mimicking chemicals and steroid hormone receptors Accurate assessment of a chemical’s potential to alter the endocrine system depends on consideration of the entire In recent years there have been many reports on the hormone dynamic pathway together with changes in increasing incidence of breast cancer in women (Davis et al. hormone activity. Fig. 1 presents a simplistic model of 1993, 1997; Bradlow et al. 1995, 1997; Davidson & Yager, hormone dynamics, following hormones from production to 1997) and decreased sperm counts and increasing incidence excretion. of testicular cancer in men (Sharpe & Skakkebæk, 1993; After a hormone is produced, circulating and intracellular Adami et al. 1994; Auger et al. 1995), together with adverse binding proteins regulate the hormones bioavailability. Then wildlife effects that include birth defects, reproductive the hormone triggers action by binding to a specific cellular failures, and sexual abnormalities (Colburn et al. 1993, receptor. The hormone is then either excreted in the urine 1999; Guillette & MacLachlan, 1996). These conditions, after conjugation reactions in the liver, or biotransformed related to oestrogen-like compounds, have stimulated into another hormone, which will begin the cycle of bio- research into both the chemical and molecular actions, and availability, action and excretion or biotransformation. the clinical and epidemiological effects of a large variety of Hormones, and hormone-mimicking chemicals, can natural and synthetic oestrogens present in the environment potentially affect each point in the hormone dynamic cycle, (Falck et al. 1992; Hunter & Kelsey, 1993; Wolff et al. and each point in the steroid hormone pathway, and the 1993; Krieger et al. 1994; Stevens et al. 1994; Ahlborg et al. enzyme families associated with the pathway. Assessing the 1995; Wolff & Toniolo, 1995; Gray et al. 1997; Hunter mode of action of an EDC is further complicated by many et al. 1997; Safe, 1997; Bernstein & Press, 1998; Petreas feedback mechanisms within and between the different HW DO .UVWHYVND.RQVWDQWLQRYD HW DO 7KH hormone systems, as well as interconnections with the JURZLQJ ERG\ RI HYLGHQFH RQ WKH KRUPRQHOLNH HIIHFWV RI nervous and immune systems. Current scientific knowledge PDQ\V\QWKHWLFFKHPLFDOVDQGE\SURGXFWVLQILVK#ZLOGOLIH of these systems is fragmentary, but the emerging picture DQGPDQ#KDVOHGWRWKHLQVWLJDWLRQRIHQGRFULQHGLVUXSWLRQ suggests an interlinked fabric of hormone dynamics where VFUHHQLQJ SURJUDPPHV UHODWLQJ WR SHUVLVWHQW RUJDQLF

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Brain and CNS: ERα, ERβ (pituitary: ERα predominates hypothalamus: ERβ predominates) Thymus: ERβ

Breast: Cardiovascular system: α β ERα, ERβ ER , ER

Liver: Lungs: β ERα, ERβ ER

Adrenals and kidneys: ERα, ERβ

Gastrointestinal tract: β Ovaries: ER ERα, ERβ

Uterus: ERα, ERβ Urogenital tract: ERα, ERβ Bladder: ERβ Bone: α β ER , ER Testes: ERα, ERβ Prostate: ERβ

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Brain and CNS: ERα, ERβ

Breast: Cardiovascular system: α β ERα, ERβ, ER , ER , CAR, α γ AhR, PXR, PPAR , PPAR PPARγ

Lungs: Liver: ERβ, CAR ERα, ERβ, AhR, PXR, LXR, FXR, CAR, PPARα, PPARβ, PPARγ Adrenals: GR, ERα, ERβ, AR, CAR

Kidneys: ERβ

Gastrointestinal tract: β γ Ovaries: PXR, ER , PPAR , CAR ERα, ERβ

Uterus: ERα, ERβ, Urogenital tract: PXR, AhR ERα, ERβ

Bone: α β ER , ER Testes: ERα, ERβ, CAR, AR

Prostate: AR, ERβ, PPARα

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