Disruption of glucocorticoid action by environmental chemicals: Potential mechanisms and relevance

Journal of Steroid Biochemistry & Molecular Biology 102 (2006) 222–231

Disruption of glucocorticoid action by environmental chemicals: Potential mechanisms and relevance夽 Alex Odermatt ∗ , Christel Gumy, Atanas G. Atanasov, Anna A. Dzyakanchuk Department of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland

Abstract Glucocorticoids play an essential role in the regulation of key physiological processes, including immunomodulation, brain function, energy metabolism, electrolyte balance and blood pressure. Exposure to naturally occurring compounds or industrial chemicals that impair glucocorticoid action may contribute to the increasing incidence of cognitive deficits, immune disorders and metabolic diseases. Potentially, “glucocorticoid disruptors” can interfere with various steps of hormone action, e.g. hormone synthesis, binding to plasma proteins, delivery to target cells, pre-receptor regulation of the ratio of active versus inactive hormones, glucocorticoid receptor (GR) function, or export and degradation of glucocorticoids. Several recent studies indicate that such chemicals exist and that some of them can cause multiple toxic effects by interfering with different steps of hormone action. For example, increasing evidence suggests that organotins disturb glucocorticoid action by altering the function of factors that regulate the expression of 11␤-hydroxysteroid dehydrogenase (11␤-HSD) pre-receptor enzymes, by direct inhibition of 11␤-HSD2-dependent inactivation of glucocorticoids, and by blocking GR activation. These observations emphasize on the complexity of the toxic effects caused by such compounds and on the need of suitable test systems to assess their effects on each relevant step. © 2006 Elsevier Ltd. All rights reserved. Keywords: Endocrine disruptor; Glucocorticoid; Cortisol; Environmental chemical; 11␤-hydroxysteroid dehydrogenase; Glucocorticoid receptor

1. General aspects of glucocorticoid action The accumulated exposure to environmental chemicals may cause serious health problems. Naturally occurring compounds and industrial chemicals mimicking endogenous hormone action disturb the endocrine regulation of various biological processes including development, growth, reproduction and behavior. Such endocrine disruptors are taken up orally from contaminated food and drinking water, by the respiratory tract from polluted air, or via the skin from dust and soil. Other potential sources include the exposure to chemicals released from clothes or taken up from perfumes, soaps and body lotions. Interference with biological processes occurs during fetal development through exposure to 夽 Lecture presented at the 17th International Symposium of the Journal of Steroid Biochemistry & Molecular Biology “Recent Advances in Steroid Biochemistry & Molecular Biology”, 31 May–3 June 2006, Seefeld, Tyrol, Austria. ∗ Corresponding author. Tel.: +41 31 632 9438; fax: +41 31 632 9444. E-mail address: [email protected] (A. Odermatt).

0960-0760/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2006.09.010

maternal nutrients and hormones, in the post-natal phase during breast-feeding and in the pubertal phase or in adolescence through exposure to chemicals in food, water and air. There is increasing evidence for an association of the exposure to endocrine disrupting chemicals with the increasing incidence of disorders of sexual and behavioral development, asthmatic and allergic diseases as well as certain forms of cancer. Many endocrine disruptors are known to interfere with mechanisms regulated by sex steroid hormone receptors (mainly ER and AR), and there is a fast growing literature on environmental chemicals with effects on sex steroid hormone action [1,2]. However, disturbances of ER- and ARmediated processes alone cannot explain the complex toxic effects of most of the compounds disrupting endocrine regulation, and disturbances of the function of other proteins is likely to occur [3,4]. Most nuclear hormone receptors can be modulated by several ligands and, in addition, a given ligand may modify more than one receptor. Similarly, many of the known endocrine disruptors exert a complex pattern of toxicity, and they may interfere with more than one nuclear hormone receptor and with other proteins including steroid

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Fig. 1. Schematic representation of important steps involved in glucocorticoid homeostasis.

hormone metabolizing enzymes, transport proteins, binding proteins or proteins involved in signaling pathways. In contrast to chemicals disrupting estrogen and androgen action, relatively little is known about the interference of environmental chemicals with non-sex steroid hormone responses including glucocorticoid-mediated responses. Thus, there is a great need to investigate the impact of endocrine disruptors on the modulation of responses mediated by steroid hormone receptors other than ER and AR as well as on enzymes involved in the control of steroid hormone homeostasis. Glucocorticoids play a pivotal role for the regulation of a variety of physiological processes. They are essential for the modulation of the immune system, the maintenance of electrolyte concentrations and blood pressure, appropriate brain function, as well as for the regulation of cell proliferation and differentiation. The multiple effects mediated by GR indicate that a tightly regulated network of associated proteins and factors is required for the time-dependent and tissue-specific modulation of the transcriptional regulation of GR target genes. Disturbed glucocorticoid action has been associated with several disease states including osteoporosis, cataract formation, obesity, type 2 diabetes, cardiovascular disease and inflammatory and autoimmune diseases [5–9]. Potentially, disruption of glucocorticoid hormone action by environmental chemicals can occur at various steps (Fig. 1) at the: (1) regulation of the hypothalamus–pituitary–adrenal (HPA)-axis, (2) activity of enzymes with a role in steroidogenesis, (3) binding capacity of serum proteins, (4) uptake into the target cell, (5) intracellular metabolism by 11␤HSD enzymes, (6) activation of the GR, (7) function of GR-associated proteins, (8) binding to the promoter of a given

target gene, (9) export from the cell, and (10) degradation and excretion of the steroid hormone. Several recent reports provide evidence for the existence of chemicals that disturb different steps of glucocorticoid action, thus emphasizing on the need of additional test systems to understand their mechanisms of action and to assess their health risks.

2. Interference of chemicals with the HPA-axis Under normal conditions, the amount of glucocorticoids produced per day corresponds to approximately 15 mg of cortisol and 2 mg of corticosterone in humans [10–12]. The regulation of glucocorticoid concentrations during circadian rhythm and after metabolic and environmental challenges requires a tightly controlled hormone synthesis in the adrenal glands. Glucocorticoid synthesis in the zona fasiculata of the adrenal cortex is regulated by adrenocorticotrophic hormone (ACTH), a hormone produced in the pituitary glands and controlled by the corticotrophin releasing factor (CRF), which is secreted from the hypothalamus. Glucocorticoids inhibit CRF production, thereby reducing their own synthesis and preventing excessive levels via a negative feedback mechanism. There are several studies providing evidence for the existence of environmental chemicals that disturb the HPA-axis, although the underlying mechanisms are mostly unknown. A tight regulation of glucocorticoid levels and GR activity is essential for the appropriate development and function of the brain. The exposure to excessive glucocorticoid concentrations immediately after birth, where glucocorticoid levels are

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low and the feedback regulation by the HPA-axis is not fully developed, can cause irreversible disturbances in learning and memory, behavior and motor activity [13,14]. Importantly, deficits in learning, memory and behavior have also been observed in adrenalectomized animals, indicating that both excessive and insufficient glucocorticoid levels have a negative impact on brain development and function. Thus, chemicals that inhibit glucocorticoid synthesis, reactivation of glucocorticoids by 11␤-HSD1 or activation of GR, as well as chemicals that inhibit glucocorticoid inactivation by 11␤-HSD2 or activate GR can cause permanent functional alterations and cognitive deficits. Disturbances in ACTH and glucocorticoid concentrations are most critical during development. Post-natal treatment of female rats with ACTH resulted in enhanced corticosterone levels and caused a delayed sexual maturation with deficits in female sexual behavior compared to control rats [15]. These studies demonstrate that altered ACTH and corticosterone concentrations interfere with reproductive maturation and behavior. A study in rats treated from day 7 in utero for 70 days with the plant-derived isoflavonoid genistein revealed a significant increase of vasopressin levels [16]. Vasopressin, which is synthesized in the hypothalamus, stimulates ACTH production in the pituitary glands, enhances adrenal corticosteroid production and plays an important role in the regulation of the cardiovascular system and blood pressure. Exposure to polychlorinated biphenyls (PCBs) early during development can alter the function of the HPA-axis and suppress basal and stimulated corticosterone levels. In monkeys, the perinatal exposure to a mixture of PCB congeners led to long-term neurobehavioral changes with learning deficits [17,18]. These observations were confirmed by studies in rats treated with ortho-substituted PCB congeners [19–22]. Rats exposed to Aroclor 1254 showed impaired working and reference memory on the radial arm maze test as well as a deficit on the first reversal of the spatial reversallearning task. This deficiency was sex-specific and mainly observed in males. An impaired adrenocortical response to stress was observed in fish living in environments polluted by polycyclic aromatic hydrocarbons (PAHs), PCBs, and heavymetals such as mercury, cadmium and zinc [23,24]. Fish from the most polluted sites had atrophied pituitary glands with a delayed rise in plasma cortisol levels after acute stress of capture; despite ACTH levels were initially elevated. It was suggested that the overall HPA-axis-dependent response to severe, short-term confinement stress was depressed in fish that were chronically exposed to heavy-metal ions. Treatment of anadromous Arctic charr with the PCB Aroclor 1254 resulted in a higher accumulation of the compound in fasted compared with fed fish [25]. High doses of Aroclor 1254 resulted in significantly reduced expression of GR, hsp70 and hsp90 in the brain of fasted fish. The exposure to the PCB impaired the elevation of plasma cortisol concentrations and up regulation of the expression of brain GR usually observed upon fasting. These findings suggested that PCBs disrupt the

HPA-axis and impair the adaptive response that allows these fish to cope with fasting stress during winter emaciation. Organotin compounds are ubiquitous environmental chemicals that are used in industry as stabilizers and catalysts in various products including polyvinyl chloride. Organotins cause multiple toxicity. Compounds with short alkyl groups such as trimethyltin and triethyltin are highly neurotoxic, while compounds with intermediate alkyl groups such as tributyltin (TBT) and dibutyltin (DBT) are highly immunotoxic and cause thymus involution and impaired cellmediated immunity [26–28]. It has been shown that treatment of rats with food containing TMT resulted in a loss of pyramidal neurons, mainly in the hippocampal CA3 region, which started 3–4 days after ingestion and continued thereafter [29]. TMT intoxication is characterized by seizure, aggressive behavior, hyperactivity and memory deficits. Neuronal toxicity and behavioral effects were significantly reduced when animals were simultaneously treated with corticosterone or dexamethasone. On the other side, toxic effects were aggravated in adrenalectomized animals, suggesting that glucocorticoids partially prevented TMT-induced toxicity. Plasma corticosterone concentrations were significantly increased 3–4 days after TMT ingestion, followed by normalization after 5 days. It was suggested that induction of the expression of the cytokines IL-1␣ and IL-1␤ might be responsible for TMT-induced toxicity. Cytokine induction was abolished by glucocorticoid treatment, whereas adrenalectomy strongly aggravated IL-1␣ and IL-1␤ expression. While an intrahippocampal infusion of IL-1␤ was shown to enhance plasma ACTH and corticosterone levels [29], it is also known that glucocorticoids inhibit cytokine production in injured brain [30,31]. Thus, these findings suggest that a disturbed function of the HPA-axis may be involved in TMT-induced neurotoxicity; however, the mechanism underlying TMT-induced cytokine production remains to be elucidated. A toxic substance that most people would not consider as an endocrine disruptor but which has been shown to significantly alter glucocorticoid levels is ethanol. It was demonstrated that the ingestion of moderate levels of alcohol results in an increase in cortisol concentrations [32,33]. Compared with abstinent individuals, chronic alcohol-dependent subjects showed significantly elevated salivary cortisol concentrations both during intoxication and withdrawal. Importantly, a progressive increase of cortisol concentrations was observed after withdrawal, suggesting a link between withdrawal symptoms and cortisol levels. Thus, the elevated cortisol concentrations in chronic alcoholic patients may contribute to the higher incidence of metabolic disease as well as sleep apnoea, cognitive deficits and mood disturbances.

3. Disturbed glucocorticoid action due to altered function of steroidogenic enzymes Several chemicals were shown to inhibit steroidogenesis in general by reducing the transcription of the steroidogenic

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acute regulatory gene (StAR). The StAR protein mediates the rate-limiting and acutely regulated intramitochondrial transfer of cholesterol to the P450 side-chain cleavage enzyme (P450scc), which then catalyzes the formation of pregnenolone. In humans, genetic mutations in StAR cause lipoid congenital adrenal hyperplasia, which leads to general steroid hormone deficiency and is lethal [34]. Lindane, the γ isomer of hexachlorocyclohexane, is an organochlorine pesticide that is widely distributed in ecosystems. It was shown that lindane caused a significant reduction of StAR protein expression in mouse MA-10 Leydig cells, thereby inhibiting dibutyryl-cAMP-induced steroidogenesis [35]. The pesticide roundup, the two imidazole fungicides econazole and miconazole, and the organophosphate insecticide dimethoate all inhibited dibutyryl-cAMP-induced steroid production in mouse MA-10 Leydig cells by disrupting the expression of the StAR gene [36–38]. Dimethoate also directly inhibited P450scc. Dibutyryl-cAMP-induced cortisol secretion was also inhibited by endosulfan, diazinon, mancozeb and atrazine in adrenocortical steroidogenic cells of rainbow trout [39], demonstrating the susceptibility of adrenal steroidogenesis to environmental pollutants. Recent studies in rainbow trout demonstrated an important connection between arylhydrocarbon receptor (AhR) activation and the regulation of cortisol-mediated stress response [40,41]. Trout exposed to the AhR agonist ␤-naphtoflavone showed impaired stressor-induced plasma and interrenal responses. ␤-Naphtoflavone decreased ACTH-mediated cortisol production as a result of a reduced expression of StAR and P450scc. 11␤-hydroxylase expression was not affected. It was suggested that AhR activation might disrupt interrenal corticosteroidogenesis and target tissue responsiveness to glucocorticoid stimulation in trout. Treatment of rainbow trout with high doses of salicylate decreased interrenal cortisol production [42]. While resting plasma cortisol or glucose levels were not changed, the acute ACTH-stimulated cortisol production was significantly reduced. Salicylate treatment resulted in significantly reduced expression of StAR and of the peripheral-type benzodiazepine receptor. The expression of P450scc and 11␤hydroxylase was not affected after salicylate exposure. Trouts exposed to high doses of salicylate showed a reduced expression of brain GR protein, suggesting that glucocorticoiddependent feedback regulation might be disturbed in fish exposed to this drug. An indirect effect on glucocorticoid synthesis is also caused by phytochemicals that alter adrenocortical steroid hormone production. Genistein and daidzein, which are the major isoflavanoids in soy and soy-derived products, inhibit 21-hydroxylase (P450c21), thereby reducing cortisol synthesis and enhancing the synthesis of the androgens dehydroepiandrosterone (DHEA) and DHEA–sulphate [43]. We have recently shown that the administration of DHEA to mice leads to a down regulation of the expression of 11␤-HSD1 [44], which catalyzes the local reactivation of glucocorticoids in peripheral tissues. This further supports the observation

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that genistein and daidzein mediate a shift from glucocorticoid production to the generation of androgens and estrogens. Moreover, it was found that the flavonoids 6-hydroxyflavone, genistein, daidzein, biochanin A and formomonetin significantly inhibit microsomal 3␤-HSD2 activity with IC50 values around 1 ␮M [45,46], providing further evidence that these substances reduce glucocorticoid production. The environmental chemical 3-methylsulfonyl-DDE, a metabolite of the lipophilic insecticide DDT, was found to be present in mother’s milk, blood and adipose tissue [47,48] and was shown to accumulate in the adrenal cortex. Using human H295R and mouse Y1 adrenocortical cells it was shown that several persistent aryl methylsulfone metabolites of PCBs and DDT, including 3-methylsulfonyl-DDE, competitively inhibit mitochondrial 11␤-hydroxylase, which catalyzes the last step of glucocorticoid synthesis by converting 11-deoxycortisol to cortisol. Inhibition of 11␤-hydroxylase by 3-methylsulfonyl-DDE was comparable to that by the known drugs metyrapone and ketoconazole [49,50].

4. Inhibition of 11␤-HSD2 by environmental chemicals The enzyme 11␤-HSD2 is mainly expressed in mineralocorticoid target tissues, where it protects the MR from activation by glucocorticoids and renders specificity of the receptor for aldosterone. A reduced 11␤-HSD2 activity as a result of genetic mutations results in cortisol-dependent MR activation with a severe form of renal sodium retention and hypertension [51,52]. A similar form of hypertension was observed after ingestion of high amounts of licorice, containing glycyrrhetinic acid, which efficiently inhibits both 11␤-HSD enzymes [52–54]. 11␤-HSD2 also plays an essential role in the placenta, where it protects the fetus from elevated maternal glucocorticoid concentrations. The exposure to compounds inhibiting 11-HSD2 is especially critical during pregnancy. On one side, the pregnant mother is facing high levels of progesterone and its metabolites. Some of these metabolites are potent 11␤-HSD2 inhibitors [55]. The impaired inactivation of these metabolites and/or inhibition of 11␤-HSD2 by substances such as glycyrrhetinic acid might contribute to the pathogenesis of pre-eclampsia, which is characterized by sodium retention, hypertension, edema and proteinuria in the third trimester of pregnancy [56]. On the other side, inhibition of 11␤-HSD2 causes an exposure of the fetus to elevated cortisol levels. In humans, increased cortisol plasma concentrations were found in undernourished mothers, and it was suggested that cortisol is one of the factors responsible for the retarded fetal growth [57,58]. Prenatal stressful insults, leading to elevated plasma cortisol levels, have been associated with low birth weight and the development of type 2 diabetes and ischaemic heart disease in prepubertal children and adults, independent of later adult lifestyle influences [59–61]. Experiments in rats

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exposed in utero to high concentrations of dexamethasone, which cannot be sufficiently inactivated by 11␤-HSD2 [62], results in reduced birth weight and an increased risk for cardiovascular and metabolic diseases in the adult offspring [63,64]. Thus, inhibition of maternal 11␤-HSD2 by environmental chemicals is expected to lead to enhanced exposure of the fetus to high maternal glucocorticoids and cause disturbances in the intrauterine development [65]. An impaired 11␤-HSD2 function due to genetic mutations or the presence of inhibitors such as glycyrrhetinic acid strongly correlates with decreased birth weight and metabolic and cardiovascular disease in later life of the offspring [66,67]. Interestingly, the exposure of rats to high doses of the unspecific 11␤HSD inhibitor glycyrrhetinic acid resulted in significantly increased plasma glucocorticoid levels and caused thymocyte apoptosis [68]. Recently, we demonstrated that dithiocarbamate chemicals (DTCs) interfere with the control of local glucocorticoid concentrations by irreversibly inhibiting 11␤-HSD2 [69]. DTCs are widely applied in cosmetics as disinfectants, in agriculture as pesticides and in industry as accelerating agents in rubber products. Large quantities of DTCs are released into the environment every year. DTCs are also used in therapy. The DTC disulfiram is known as Antabuse and is used for treatment of severe alcoholic patients. Pyrrolidine dithiocarbamate is used in chelation therapy to treat metal intoxication, and the use of DTCs for cancer treatment has been considered. DTCs induce various toxic effects in different organs including liver, kidney, testis and placenta [70–73]. In agricultural workers the excessive exposure to the DTCs maneb and zineb caused acute renal failure and nephrotic syndrome [74]. Exposure to these compounds also led to kidney damage and reduced body weights in the offspring from exposed rats [75]. Inhibition of 11␤-HSD2 activity may contribute to some of these toxic effects in the kidney and on blood pressure, as well as in placenta and on fetal development. The present evidence suggests caution in the use of these compounds in clinical applications and in exposure of the general population to cosmetics and other products containing DTCs. Analysis of the mechanism of inhibition suggested an irreversible modification of cysteine residues on 11␤-HSD2, probably by covalent attachment of a carbamoyl group [69]. DTC-mediated inhibition of 11␤-HSD2 was prevented by both dithiothreitol and glutathione, suggesting that inhibition of 11␤-HSD2 by DTCs is most critical when intracellular glutathione is low, for example in situations of oxidative stress. Interference with the function of active sulfhydryl groups is probably also responsible for the observed inhibition of 11␤HSD2 by organotins. Organotins cause multiple toxic effects. Interestingly, among other effects, the exposure of pregnant rats to organotins has been associated with reduced birth weight [76–78]. In contrast to DTCs, the inhibition of 11␤-HSD2 by organotins is reversible [79]. Dithiothreitol but not glutathione was able to prevent organotin-dependent inhibition of 11␤-HSD2,

indicating that there is no intracellular endogenous protection from the toxicity of these compounds. Mutational analysis of the cysteine residues of 11␤-HSD2 revealed several important interactions of Cys90 , Cys228 and Cys264 and showed that they are essential for enzymatic stability and catalytic activity. The disruption of these interactions by organotins, DTCs and other sulfhydryl modifying agents is expected to inhibit 11␤HSD2-dependent glucocorticoid inactivation and contribute to the toxicity of such compounds in glucocorticoid-sensitive tissues, thereby disturbing essential physiological processes such as development and immune system.

5. Effects of chemicals on 11␤-HSD1 function 11␤-HSD1 is expressed in many tissues and converts biologically inactive 11-ketoglucocorticoids (cortisone, 11-dehydrocorticosterone) into active 11␤-hydroxyglucocorticoids (cortisol, corticosterone). The tissue-specific expression level of 11␤-HSD1 essentially regulates GR activation in a given cell and organ. Studies describing the disturbances of 11␤-HSD1 function and the association with diseases have been discussed by several recent reviews [80–82]. The elevated local reactivation of glucocorticoids has been associated with metabolic disease. Transgenic mice over expressing 11␤-HSD1 in adipose tissue developed visceral obesity, glucose intolerance and insulin resistance [83,84], while over expression of 11␤-HSD1 in liver caused metabolic syndrome without obesity [85]. In humans, elevated 11␤HSD1 expression in adipose tissue and in skeletal muscle has been associated with visceral obesity and diabetes, respectively [86–91]. Therefore, the reduction of excessive glucocorticoid action by inhibiting 11␤-HSD1 is considered as a promising strategy to treat patients with metabolic syndrome. To this end, we recently described environmental compounds that inhibit 11␤-HSD1 [92]. Flavanone and 2 hydroxyflavanone selectively inhibited the formation of cortisol in a cell system expressing recombinant 11␤-HSD1 as well as in differentiated adipocytes expressing endogenous 11␤-HSD1. Substances like flavanone might be responsible in part for the anti-diabetic effect of fruits and vegetables, and such compounds might find application as ingredients of functional food products. Other natural compounds including glycyrrhetinic acid, abietic acid, gossypol and naringenin were also found to inhibit 11␤-HSD1, however, these compounds are not selective and inhibit also 11␤-HSD2 [65,92]. Although inhibition of 11␤-HSD1 might be a promising strategy to reduce excessive glucocorticoid reactivation in metabolic tissues such as liver, adipose tissue and skeletal muscle, an inappropriate inhibition may cause adverse effects by disturbances of energy metabolism and immune system. A reduced function of 11␤-HSD1 has been associated with rheumatoid arthritis [93], indicating an insufficient ability of glucocorticoids to orchestrate the immune response during inflammation. A decreased glucocorticoid reactivation cannot only occur upon direct inhibition of 11␤-HSD1

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but also by reduced gene expression. The activation of peroxisome proliferation activated receptor (PPAR)-␣, PPAR␥ and liver-X-receptor (LXR) was shown to down regulate 11␤-HSD1 expression and activity [94–96]. Recent investigations demonstrated that relatively low concentrations of the organotin compounds TBT and TPT activate PPAR␥ and stimulate adipocyte differentiation [97–99]. Our preliminary observations suggest that these organotins also cause a down regulation of 11␤-HSD1 expression and activity in differentiated mouse 3T3-L1 adipocytes (unpublished data). The reduced 11␤-HSD1 expression might be one of the mechanisms underlying organotin toxicity, since glucocorticoids play a crucial role in adipogenesis by controlling cell proliferation and differentiation, and due to the fact that the lipophilic organotins accumulate in fat tissue. There are several reports on alternative functions of 11␤HSD1 by catalyzing the reduction of compounds with reactive carbonyl groups [81]. A variety of chemicals such as metyrapone, p-nitroacetophenone, p-nitrobenzaldehyde, oracin, ketoprofen, DFU-lactol and the tobacco-specific nicotine-derived nitrosamine ketone (NNK) were reported to be metabolized by 11␤-HSD1 into their corresponding hydroxyl metabolites [100–104]. More recently, we and others demonstrated a role of 11␤-HSD1 in the conversion of 7-ketocholesterol to 7␤-hydroxycholesterol [105–107] with kinetic parameters comparable to those obtained for the oxoreduction of cortisone. The metabolism of 7-ketocholesterol might be relevant in the liver to catalyze the first step in the detoxification of oxidized cholesterol taken up from processed cholesterol-rich food [105]. 11␤-HSD1 might also play a role in the detoxification of 7-ketocholesterol in macrophages. Whether an impaired 11␤-HSD1 function might contribute to the formation of macrophages loaded with cholesterol and high levels of oxidized cholesterol, e.g. foam cells, remains to be investigated. Thus, an inappropriately reduced 11␤-HSD1 activity may have adverse effects by disruption of detoxification processes in some situations.

6. Blockade of GR function PCB methylsulfones are ubiquitous pollutants that have been detected at considerable concentrations in mother’s milk. The compound 3-methylsulfonyl-2,5,6,2 ,4 ,5 -hexachlorobiphenyl was shown to compete with dexamethasone for binding to the GR, with an IC50 of 1 ␮M, and to act as an antagonist in a GR-dependent reporter gene assay with an IC50 of 2.7 ␮M [108]. Later on, it was shown that tolylfluanid and other 4-substituted methylsulfonyl-PCPs bind to the GR and act as antagonists with IC50 values in the low ␮M range [109]. Furthermore, these compounds dose-dependently inhibited dexamethasone-induced tyrosine amino transferase (TAT) activity in Reuber rat hepatoma H4IIE-C3 cells. The most potent compound described was 4methylsulfonyl-CB91 with an IC50 of 0.7 ␮M. Importantly,

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the inhibitory effect of several methylsulfonyl PCBs on TAT activity was found to be close to additive. The blockade of GR by these compounds or by mixtures of them might have an impact on humans and wildlife. Therefore, disruption of glucocorticoid action by these chemicals should be investigated in vivo. Recently, altered GR function in the presence of arsenic (As) contamination has been reported [110]. US EPA set the maximum allowable level of As in public drinking water to 10 ppb or 0.13 ␮M. The concentrations of As in drinking water from several different areas exceed this maximum allowable level. Chronic exposure to As has been associated with several forms of cancer, type 2 diabetes, cardiovascular disease and reproductive and developmental disease [111]. At very low doses, As altered GR-mediated gene transcription in cultured rat hepatoma cells and also in chick embryos [112,113]. As interferes with GR function not by mimicking glucocorticoid hormones but rather by altering the function of GR to regulate gene transcription. Although As did not affect glucocorticoid binding, nuclear receptor translocation or binding of the receptor to the DNA, it altered GR-dependent transactivation in a biphasic manner. At low concentrations (up to 0.5 ␮M), an approximately two-fold stimulation of PEPCK gene expression and TAT activity was observed in experiments using EDR3 rat hepatoma cells. A similar activation was observed in a GR-dependent reporter gene assay. At concentrations higher than 2 ␮M, a significant repression of GR-mediated gene transcription was observed. Interestingly, transrepression by AP1 or NF-␬B was not affected by As. A mutational analysis suggested that free cysteine residues in the GR DNA-binding domain (DBD) are not responsible for the As-mediated effect, although the DBD was found to be the minimal region required for the As effect. It seems that As alters a conformational change of the GR upon binding to the DNA. Further experiments are required to understand the mechanism by which As influences GR-dependent transcriptional activation of target genes, which is a highly dynamic process involving several receptor associated proteins. The effect of As is an example that endocrine disruptors can alter receptor-mediated gene transcription without mimicking the steroid hormone and disturbing the binding and activation process. Our most recent experiments demonstrate that some organotin compounds interfere with glucocorticoid action by directly altering GR activation (manuscript in preparation). This effect is highly dependent on the organotin molecule and the target investigated. Thus, the toxicity of these chemicals depends on the tissue analyzed, their stability and metabolism, and on the local concentrations reached in a specific tissue.

7. Conclusions There is increasing evidence that humans and animals are exposed to multiple environmental pollutants that are

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capable of disturbing glucocorticoid action at various steps. As a consequence of the complex regulation of glucocorticoid action, environmental toxicologists and endocrinologists have to establish a whole array of biological test systems to elucidate the glucocorticoid-disrupting potential of environmental chemicals and to assess their impact on human and animal health. Future investigations need to employ both systemic approaches to identify novel targets responsible for the observed toxicity of a given chemical as well as studies with a focus on specific targets to elucidate the molecular mechanisms of toxicity of a compound toward its target.

Acknowledgements A.O. is a Clo¨etta Research Fellow. This work was supported by grants from the Swiss National Science Foundation (no. 310000-112279 and NRP50 “Endocrine Disruptors” no. 4050-066575).

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