Tissue-specific induction of 17 beta-hydroxysteroid dehydrogenase type IV by peroxisome proliferator chemicals is dependent on the peroxisome proliferator-activated receptor alpha

Fan, Ling; Rc, Cattley; Corton, J C

doi:10.1677/joe.0.1580237

Cited by 57 publications

(21 citation statements)

References 22 publications

(36 reference statements)

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“…It is also important to note that 17β-HSD4 is a 80 kDa multi-domain protein, which has previously been reported to undergo processing to the 32 kDa protein detected in target tissues. Evidence for further processing into additional fragments has been demonstrated in rat tissue by peroxisome proliferator chemicals (Fan et al, 1998). Tumour specific processing of this particular isozyme may therefore occur by an as yet unidentified mechanism, resulting in species that competitively alter oestrogen inactivation.…”

Section: Discussionmentioning

confidence: 99%

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

et al. 2000

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Summary Epidemiological data suggest that oestrogen contributes to the aetiology of colonic cancer. Furthermore, recent studies have suggested that local hormone metabolism may play a key role in determining colonic responsiveness to oestrogen. To further clarify this mechanism we have characterized the expression and regulation of isozymes of 17β-hydroxysteroid dehydrogenase (17β-HSD) in vitro and in situ. Immunohistochemistry was used to confirm expression of the type 2 and 4 isozymes of 17β-HSD (17β-HSD2 and 4) in normal colonic epithelial cells. Parallel studies suggested that both isozymes were abnormally expressed in colonic tumours and this was confirmed by Western blot analyses. Abnormal expression of 17β-HSD2 and 4 proteins was also observed in Caco-2, HT-29 and SW620 colonic cancer cell lines, although the overall pattern of oestrogen metabolism in these cells was similar to that seen in primary colonic mucosal tissue. The predominant activity (conversion of oestradiol to oestrone) was highest in Caco-2>SW620>HT-29, which correlated inversely with the rate of proliferation of the cell lines. Regulatory studies using SW620 cells indicated that the most potent stimulator of oestradiol to oestrone inactivation was the antiproliferative agent 1,25-dihydroxyvitamin D 3 (1,25D 3 ), whilst oestradiol itself inhibited 17β-HSD activity. Both oestradiol and 1,25D 3 decreased mRNA for 17β-HSD2 and 4. Data indicate that the high capacity for inactivation of oestrogens in the colon is associated with the presence of 17β-HSD2 and 4 in epithelial cells. MATERIALS AND METHODS Immunohistochemical studiesColonic tumour and paired normal mucosal tissue were obtained with agreement from the local ethical approval committee. Fivemicron thick, formalin-fixed tissue sections were cut and placed on coated glass slides. Sections were de-waxed and endogenous peroxidase activity quenched with 3% hydrogen peroxide. Sections were then incubated in donkey serum (Binding Site, Birmingham, UK) diluted 1/10 in PBS (15 min), followed by primary antibody diluted in PBS (1 hour). Antisera used were as follows: 17β-HSD2 monoclonal antiserum (1/500 dilution), a kind gift of Dr S Andersson (South Western Medical Center, Dallas, USA), was produced with a synthetic carboxyterminal peptide [C]RALRMP-NYKKKAT, corresponding to amino acids 375-387 in the human 17β-HSD2 protein; 17β-HSD4 monoclonal antibody (1:200 dilution), a kind gift of Dr J Adamski (GSF, Neuherberg, Germany) was prepared against the porcine 17β-HSD4 which cross-reacts with human, rat and mouse tissues. After washing, slides were incubated for 30 min with a biotinylated universal secondary antibody (Binding Site), diluted 1/100 in PBS, and binding visualised using ABC reagent (Binding Site) and 3,3′-diaminobenzidine (Sigma Chemical Co, Poole, UK). After staining, slides were washed and counterstained in Mayer's haematoxylin. Cell cultureColonic carcinoma cell lines (SW620, Caco-2 and HT-29) were routinely maintained in Dulbecco's Modified Eagles Medium (DMEM), supplemented wit...

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Section: Discussionmentioning

confidence: 99%

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

et al. 2000

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“…Denatured total RNA was separated on 1.0% formaldehydeagarose gels and transferred to Hybond-N Nylon membranes in 20ϫ standard saline citrate. Hybridization and washing conditions were described previously (Fan et al, 1998). The probes include full-length rat ␣2u-globulin cDNA isolated from a rat heart cDNA library (Corton J. C., unpublished data), an oligonucleotide specific for mouse major urinary protein-I (5Ј-AGGGAATAGGATTGTCTG-3Ј) (GenBank Accession no.…”

Section: Methodsmentioning

confidence: 99%

Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

et al. 1998

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In this study, we show that peroxisome proliferator chemical (PPC) exposure leads to alterations in the expression of genes in rat liver regulated by the sex-specific growth hormone secretory pattern and induced during inflammation. Expression of the male-specific cytochrome P450 (P450) 2C11 and ␣2 urinary globulin (␣2u) genes and the female-specific P450 2C12 gene was down-regulated by some PPC. Expression of P450 2C13, also under control by the sex-specific growth hormone secretory pattern, was not altered by PPC treatment, indicating that regulation of CYP2C family members does not involve perturbation of the growth hormone secretory pattern. In contrast to the increases in expression observed when inflammation was induced in male rats, two positive acute-phase response genes, ␣ 1 -acid glycoprotein and ␤-fibrinogen, were decreased by PPC exposure. The down-regulation of the P450 2C11 by WY-14,643 could be reproduced in cultured rat hepatocytes, indicating the down-regulation is a direct effect. Experiments in wild-type mice and mice that lacked a functional peroxisome proliferator-activated receptor-␣ gene showed that down-regulation by WY of ␣ 1 -acid glycoprotein, ␤-fibrinogen, and a mouse homologue of ␣2u was dependent on peroxisome proliferator-activated receptor-␣ expression. Our results demonstrate that PPC exposure leads to down-regulation of diverse liver-specific genes, including CYP2C family members important in hormonal homeostasis and acute-phase response genes important in inflammatory responses.

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“…PPAR-mediated effects of MEHP in the granulosa cell are consistent with those observed in the liver of rodents. As in the granulosa cell, the induction of 17β-HSD IV by MEHP in the liver depends on PPARα (Corton et al 1997;Fan et al 1998). Increased conversion of estradiol to estrone in both the liver and the granulosa cell contribute to decreased serum estradiol levels after in vivo DEHP treatment.…”

Section: Proposed Model In the Granulosa Cellmentioning

confidence: 99%

Mechanisms of phthalate ester toxicity in the female reproductive system.

Lovekamp-Swan

Davis

2003

Environ Health Perspect

582

288

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Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.

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Tissue-specific induction of 17 beta-hydroxysteroid dehydrogenase type IV by peroxisome proliferator chemicals is dependent on the peroxisome proliferator-activated receptor alpha

Cited by 57 publications

References 22 publications

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

Mechanisms of phthalate ester toxicity in the female reproductive system.

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