* Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Kaohsiung 807, Taiwan, Republic of China; and Division of Metabolism and Endocrinology, Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan, Republic of China
1To whom correspondence should be addressed at Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Rd, Kaohsiung 807, Taiwan, Republic of China. Fax: 88673221912. E-mail: lihann{at}nhri.org.tw.
Received November 12, 2004; accepted January 27, 2005
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ABSTRACT |
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Key Words: coplanar PCB; adrenal steroidogenesis; cAMP induction; steroidogenic genes; diabetes; cardiovascular diseases.
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INTRODUCTION |
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Three types of steroid hormones are synthesized in the human adrenal cortex. Dehydroepiandrosterone (DHEA) and androstenedione (A4) are the major androgens produced by the gland. Despite possessing only minimal androgenic activity, these two adrenal androgens can be converted to more potent androgens and estrogens in the peripheral tissues. In humans, particularly in postmenopausal women, a large proportion of active androgens and estrogens are derived from adrenal androgens locally (Labrie, 1991). Cortisol, involved in a variety of physiological processes including metabolism, stress response, immune response, vasoconstriction, growth, and development, is the primary glucocorticoid synthesized in the human adrenal cortex (Stewart, 2002
). The third type of adrenal steroid is aldosterone, a mineralocorticoid essential for salt and water homeostasis and vascular tone (Osborn, 1991
).
Despite functional differences, all three types of steroids are converted from cholesterol via series of reactions catalyzed by the same group of steroidogenic enzymes, except (1) androgen formation requires both 17-hydroxylase and 17,20-lyase activities of CYP17, whereas cortisol synthesis involves only the 17
-hydroxylase activity and aldosterone synthesis needs neither; (2) 21-hydroxylation catalyzed by CYP21B is a step specific for cortisol and aldosterone biosynthesis; and (3) two similar but distinct 11ß-hydroxylases, CYP11B1 and CYP11B2, are responsible for the final rate-limiting conversion of cortisol and aldosterone, respectively. Adrenocorticotropin (ACTH) secreted from the anterior pituitary plays an important role in stimulating adrenal steroidogenesis. ACTH exercises its steroidogenic effects mainly by activating adenylyl cyclase to generate cAMP after binding to the G proteincoupled membrane receptor. Through the intracellular messenger cAMP, ACTH instantly speeds up the mobilization of cholesterol to the mitochondria, where steroidogenesis is initiated. ACTH/cAMP also raises a delayed increase in steroid yield by transcriptional activation of steroidogenic enzymes (Sewer and Waterman, 2003
). In addition to ACTH, circulating potassium and angiotensin II (Ang II) have decisive effects on aldosterone synthesis. Potassium elevates aldosterone synthesis by activating the voltage-gated Ca2+ channel, whereas Ang II acts by inducing protein kinase C activation and Ca2+ release from the intracellular store via the phosphatidylinositol 4,5-bisphosphate signal transduction system (Foster, 2004
).
In a previous study (Li et al., 2004b), we have employed the human adrenocortical H295R cell model to study the effects of the most toxic coplanar PCB congener PCB126 on adrenal aldosterone biosynthesis. We found that high levels of PCB126 concomitantly stimulated aldosterone production and steady-state mRNA expression of the key gene CYP11B2. When potassium or Ang II was added to induce aldosterone synthesis, the stimulatory effects of PCB126 were enhanced. However, PCB126 exhibited differential interactions with the potassium and Ang II signals. Although PCB126 and potassium synergistically upregulated CYP11B2 mRNA expression, transcriptional induction of the gene seemed less important in the presence of Ang II (Li et al., 2004b
).
This study expands the PCB126 impact investigation to all three types of adrenal steroids. We assessed the production of A4, cortisol, aldosterone, and the biosynthetic intermediates progesterone (P4) and 17-OH-P4 under the influence of PCB126 alone and together with cAMP. We also compared the steroid conversion rates to gene expression levels. The results indicate that PCB126 has differential dose and time effects on basal and cAMP-induced androgen, cortisol, and aldosterone biosynthesis. The alterations in steroid production are closely related to the modulation of PCB126 on mRNA expression and enzyme activity of the pathway-specific steroidogenic genes.
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MATERIALS AND METHODS |
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Steroid measurement.
Cortisol, aldosterone, P4, and 17-OH-P4 secreted to the serum-free medium during the 24-h incubation were measured by radioimmunoassays (Diagnostic Products Corporation, Los Angeles, CA), whereas A4 was quantified with the LC-MS-MS method developed previously (Chang et al., 2003). The yield of each steroid was normalized to the cellular protein content determined by the Micro BCA protein assay (Pierce Biotechnology, Rockford, IL).
Gene expression assay.
The mRNA abundances of steroidogenic genes were measured in pair with the housekeeping gene ß-actin by reverse transcription-polymerase chain reaction (RT-PCR). RNA isolation, reverse transcription, real-time PCR, primer design, and PCR specificity verification were performed as described previously (Li et al., 2004a). Expression of a target gene in a sample was relatively quantified using the software RelQuant (Roche Diagnostics GmbH, Mannheim, German) by calibration against a target:ß-actin ratio curve, which was drawn based on the real-time PCR data of a series of diluted RT controls. The mathematical model used in this relative quantification is described by Pfaffl (2001)
.
Data analysis.
All the data are expressed as means ± S.E. The dose and time effects of PCB126 on steroid yield, gene expression, and product/precursor ratio were analyzed with one-way analysis of variance (ANOVA) in SPSS 10.0 (SPSS INC., Chicago, IL). When the p value of ANOVA was smaller than 0.05, Bonferroni's post-hoc test was performed to analyze the significance of difference between the treatment and control. The significance of 1 mM 8-Br-cAMP stimulation or 105 M PCB126 treatment to the product/precursor ratio was determined with Student's t-test in Excel 2000 (Microsoft Corporation, Redmond, WA).
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RESULTS |
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The basal P4, 17-OH-P4, aldosterone, and cortisol productions of the H295R cells were gradually elevated in response to increasing concentrations of PCB126 supplemented to the medium in a 10-day treatment (p 0.036, one-way ANOVA). The amounts of P4, 17-OH-P4, aldosterone, and cortisol produced within the 24-h period after the 10-day 105 M PCB126 treatment were 1.57 ± 0.14, 1.40 ± 0.14, 3.31 ± 0.85, and 5.03 ± 1.27-fold of the vehicle control, respectively. In contrast, PCB126 suppressed basal A4 synthesis. The 24-h basal A4 yield was lowered by approximately 4050% after 10 days of treatment with 107 M and 105 M PCB126 (Fig. 1).
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PCB126 effects on mRNA expression and enzyme activity of genes required for A4 biosynthesis
A4 formation involves three genes: CYP11A1, HSD3b2, and CYP17 (Fig. 2A). PCB126 had little effect on either basal or cAMP-stimulated mRNA expression of CYP11A1, the common first-step gene for all three steroidogenic pathways (data not shown). The steady-state mRNA abundance of HSD3b2 was dose-dependently increased by PCB126 under the basal condition (p < 0.001, one-way ANOVA). Basal HSD3b2 expression increased 1.86 ± 0.11-fold when the H295R cells were treated with 105 M PCB126 for 10 days. Stimulating the cells with 1 mM 8-Br-cAMP during the last 24 h of treatment blocked the PCB126 dose effect (Fig. 2B). This might explain why the PCB126-elicited P4 and 17-OH-P4 rises in basal production were absent under cAMP stimulation (Fig. 1). PCB126 exerted an obvious dose-dependent inhibition on CYP17 mRNA expression (p = 0.001, one-way ANOVA). Treating with 1 mM 8-Br-cAMP did not alter CYP17 expression. Similar levels of CYP17 mRNA were detected in the absence and presence of cAMP under each examined PCB126 concentration (Fig. 2C).
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The 105 M PCB126 treatment reduced CYP17 mRNA expression progressively with time despite the absence or presence of cAMP (p 0.007, one-way ANOVA) (Fig. 3A). Time-dependent inhibition was also observed in the relative 17-OH-P4/P4 and A4/17-OH-P4 ratios (Fig. 3B and 3C). The latter or 17,20-lyase activity appeared more sensitive to the 105 M PCB126 treatment. The A4/17-OH-P4 ratio declined significantly after one day of treatment, especially in combination with cAMP. However, the PCB126/cAMP-triggered A4/17-OH-P4 reduction recovered to a fair degree when the PCB126 treatment was extended to 10 days (Fig. 3C).
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The time effect analysis showed that basal CYP21B expression had little change after 1 day of 105 M PCB126 treatment, but it exhibited an 1.5-fold induction when the treatment was prolonged to 3 days or longer. In contrast, cAMP-induced CYP21B expression was immediately downregulated after 1 day of PCB126 treatment, but no further decrease was detected in the prolonged treatments (Fig. 5A). Basal CYP11B1 expression was also significantly induced by a 3-day or longer treatment with 105 M PCB126. When stimulated with cAMP, CYP11B1 mRNA expression was above the vehicle control at the time points of 3 days and 6 days of PCB126 treatment, but fell back after a 10-day treatment (Fig. 5B). 105 M PCB126 exerted a time-dependent induction on the CYP11B2 gene under both basal and induced conditions (p < 0.001, one-way ANOVA). However, while 105 M PCB126 substantially elevated cAMP-induced CYP11B2 mRNA expression in 1 day, 10 days of PCB126 treatment were required for a significant increase in basal expression (Fig. 5C).
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Dose and time effects of PCB126 on ACTH receptor mRNA expression
Binding to the membrane receptor is a required step for ACTH to trigger cAMP formation and subsequent steroidogenic induction. The expression level of ACTH receptor on the adrenocortical cell surface is therefore an important factor determining ACTH responsiveness (Slawik et al., 2004). It is possible that PCB126 affects the steroidogenic regulation of ACTH by modulating expression of the ACTH receptor in addition to the steroidogenic enzymes examined above. To comprehensively understand the influence of PCB126 on ACTH-mediated regulation, this study has also examined ACTH receptor mRNA expression with and without cAMP stimulation. The doseresponse assay demonstrated that PCB126 at 105 M significantly elevated both basal and cAMP-induced steady-state mRNA levels of ACTH receptor. The 105 M PCB126-elicited transcript increase appeared much greater in the absence of cAMP (3.32 ± 0.22-fold) than in the presence of cAMP (1.45 ± 0.13-fold) as compared to the vehicle control (Fig. 6A). A concentration of 105 M PCB126 raised ACTH receptor expression gradually under the basal condition, and plateau was reached after 3 days of treatment. In contrast, 105 M PCB126 stimulated inducible expression without delay. However, the inducible mRNA abundance started to decline when the treatment was extended to longer than 6 days (Fig. 6B).
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DISCUSSION |
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High concentrations of PCB126 repressed basal and cAMP-induced CYP17 expression and diminished encoded 17-hydroxylase and 17,20-lyase activities, especially the latter, in the adrenocortical cells. As a consequence, the basal and cAMP-induced androgen production of the adrenocortical cells was greatly reduced. Similar inhibition was observed in the gonadal steroidogenic cells, where gonadotropin regulates steroidogenesis in a mechanism resembling ACTH in the adrenocortical cells (Richards, 2001
). The incubation of rat testicular Leydig cells with a 5.2 µM PCB mixture significantly inhibited CYP17 activity and consequently decreased chorionic gonadotropin (hCG)-stimulated androgen production (Kovacevic et al., 1995
). Exposure of human luteinized ovarian granulosa cells to 10 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) also reduced the hCG-stimulated production of estradiol (E2), a steroid downstream of androgen in the sex steroid biosynthetic pathway. As the action of PCB126 on inducible adrenal androgen synthesis, TCDD diminished inducible E2 production without altering the synthesis of intermediates P4 and 17-OH-P4 (Moran et al., 2000
). Likewise, the reduction in E2 production was mainly due to the inhibitory effects of TCDD on CYP17 expression and its 17,20-lyase activity (Moran et al., 2003
).
Our previous study demonstrated that PCB126 and potassium synergistically stimulated aldosterone synthesis. The synergistic action between PCB126 and potassium primarily involved upregulation of CYP11B2 (Li et al., 2004b). The present study found that high concentrations of PCB126 also activated CYP11B2 expression and elevated aldosterone yield in synergy with cAMP, although the rapid inhibition that PCB126 exerted on cAMP-induced CYP21B expression seemed to slow the conversion of P4 to aldosterone. The control of PCB126 over CYP21B had a more profound effect on the conversion of 17-OH-P4 to cortisol. The suppression of cAMP-induced CYP21B expression by PCB126 apparently neutralized the stimulation of PCB126 on CYP11B1. Hence, PCB126 elevated basal cortisol synthesis but exhibited little effect on cAMP-induced synthesis. Similar results were seen in animal studies. Daily exposure of male Fischer 344 rats to 0.125 mg/kg body weight of the PCB mixture Aroclor 1254 by gavage for 15 weeks elevated basal serum corticosterone (the cortisol counterpart in rodents) but did not affect stress-induced corticosterone rise (a result of stress activation of the pituitary-adrenal axis) (Miller et al., 1993
). Male Sprague-Dawley rats treated with 125 µg/kg of TCDD also displayed elevated basal plasma corticosterone but showed no difference from the control rats in the stress-induced level (Gorski et al., 1988
). At the same time, this study suggested that high concentrations of PCB126 might increase the sensitivity and responsiveness of the adrenocortical cells to ACTH by increasing receptor expression on the membrane. It has been reported that administration of 200 mg/kg of PCB77, a coplanar PCB congener like PCB126, induced similar morphological alterations in rat adrenocortical cells to those detected after ACTH administration (Durham and Brouwer, 1990
).
Coplanar PCBs and dioxins can induce mRNA expression of several xenobiotic-metabolizing enzymes, including CYP1A1 and CYP1B1, through the aryl hydrocarbon receptor (AhR). AhR is a ligand-dependent transcription factor that interacts with specific upstream DNA elements and activates transcription of target genes after association with a ligand (Denison and Whitlock, 1995). However, we doubt that PCB126 alters steroidogenic gene expression directly through AhR. So far, no AhR-binding elements have been located in the promoter regions of steroidogenic genes. Moreover, PCB126 seems to have a more acute effect on the xenobiotic-metabolizing CYP1A1 gene than on the steroidogenic CYP genes (Hestermann et al., 2000
). Even so, we cannot disregard the possibility that the steroidogenic changes we observed are the ripple effect of AhR-dependent gene activation. We are currently examining the role of AhR in the PCB126-modulated steroidogenesis using AhR antagonists.
The rise of cortisol and aldostereone and the fall of androgen after exposure may increase risk for diabetes mellitus and cardiovascular mortality in highly exposed people (Bertazzi et al., 2001; Cranmer et al., 2000
; Fierens et al., 2003
; Flesch-Janys, 1997
; Gustavsson and Hogstedt, 1997
; Hay and Tarrel, 1997
; Henriksen et al., 1997
; Longnecker et al., 2001
; Michalek et al., 1998
; Steenland et al., 1999
; Vena et al., 1998
). It has long been known that the illness of excess cortisol, such as Cushing's syndrome and metabolic syndrome, is associated with glucose intolerance and insulin resistance. Indeed, modulation of the cortisol levels of healthy people, even within the physiological range, can alter the actions of insulin on glucose metabolism (Dinneen et al., 1993
; Nielsen et al., 2004
). Aldosterone also diminishes insulin sensitivity. It has been shown that aldosterone downregulates insulin receptor expression and insulin binding in human U-937 promonocytic cells (Campion et al., 1999
). Potassium depletion in consequence of prolonged aldosterone excesse.g., primary aldosteronismalso impairs glucose tolerance and insulin secretion (Corry and Tuck, 2003
). In contrast, dehydroepiandrosterone (DHEA) increases the binding of insulin to the insulin receptor (Buffington et al., 1991
). The reduction of adrenal androgen synthesis owing to exposure likely minimizes such an interaction and lowers insulin sensitivity.
Diabetes mellitus is a well-recognized risk factor for cardiovascular diseases (Carr and Brunzell, 2004; Grundy, 2004
; Nesto, 2004
). In addition to the injuries secondary to diabetes, steroid hormones have direct effects on the cardiovascular system. Aldosterone regulates vascular electrolyte permeability, blood volume, and vasocontractility. High levels of aldosterone cause hypertension. Chronic animal studies further demonstrate that aldosterone together with high salt intake induces vascular inflammation and causes myocardial ischemia, necrosis, and fibrosis (Rocha and Funder, 2002
). High levels of cortisol also provoke hypertension, although the underlying mechanism is not clear.
The association of adrenal steroids with diabetes and cardiovascular diseases also involves their effects on lipid metabolism and body fat distribution (Carr and Brunzell, 2004). Patients with excess cortisol have increased total cholesterol and low-density lipoprotein cholesterol (LDL cholesterol) and decreased high-density lipoprotein cholesterol (HDL cholesterol) (Colao et al., 1999
; Tauchmanova et al., 2002
). The general population also displays an inverse relationship between cortisol and HDL cholesterol (Fraser et al., 1999
), implying that a small but chronic excess of cortisol would distort lipid metabolism. Furthermore, cortisol activates adipocyte differentiation and lipoprotein lipase expression, especially in the abdominal adipose tissue (Fried et al., 1993
; Hauner et al., 1989
). High lipoprotein lipase activity elevates the release of free fatty acids into circulation as well as fat accumulation in the adipocytes (Mead et al., 2002
). Contrary to cortisol, plasma DHEA shows a negative correlation with abdominal fat deposition in men (Tchernof and Labrie, 2004
).
Our results put forward plausibility that PCBs and dioxins may alter adrenal steroid synthesis and, in turn, damage metabolism and cardiovascular health. Although there are significant data gaps required to be addressed, our study suggests that adrenal endocrine toxicity is an important potential hazard and should not be ignored in the health effect assessment of PCBs and dioxins.
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ACKNOWLEDGMENTS |
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