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1.
J Endocrinol Invest ; 43(11): 1571-1576, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32242287

ABSTRACT

AIM: A reticulin staining pattern (RSP) can be used for the differential diagnosis of endocrine gland lesions, as in the adrenal and hypophysis glands. We aimed to use RSP for the differential diagnosis of parathyroid gland lesions. MATERIALS AND METHODS: In this study, we evaluated 97 parathyroid lesions in 85 patients, as well as 29 normal parathyroid glands. All sections were stained with a silver impregnation-based kit for the reticulin stain. The RSPs were classified as short thick fiber-, anastomosing- and nodular/alveolar-pattern. The dominant pattern was accepted as being greater than 50% in each section. RESULTS: Short thick fibers and anastomosing and nodular RSPs were seen in adenomas, but there was no alveolar pattern. Although nodular/alveolar patterns were seen in focal areas in hyperplasia, they never became the dominant pattern. Nodular dominant RSPs were seen in adenomas; however, nodular RSPs were not seen in hyperplasia in a dominant pattern (p = 0.049). While short thick fibers were not seen in normal glands, they could be seen in adenomas (p < 0.001) and in hyperplasia (p < 0.001). CONCLUSION: RSPs can be used in the differential diagnosis of parathyroid lesions. While short thick reticular fibers support adenomas and hyperplasia rather than normal tissue, a nodular dominant pattern supports adenomas rather than hyperplasia.


Subject(s)
Adenoma/diagnosis , Parathyroid Neoplasms/diagnosis , Reticulin/analysis , Staining and Labeling/methods , Adenoma/metabolism , Adenoma/pathology , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Diagnosis, Differential , Female , Humans , Hyperplasia/diagnosis , Hyperplasia/metabolism , Hyperplasia/pathology , Immunohistochemistry , Male , Middle Aged , Parathyroid Glands/metabolism , Parathyroid Glands/pathology , Parathyroid Neoplasms/metabolism , Parathyroid Neoplasms/pathology , Predictive Value of Tests , Reticulin/metabolism
3.
West Indian Med J ; 64(2): 166-7, 2015 Mar.
Article in English | MEDLINE | ID: mdl-26360695
5.
Eur Rev Med Pharmacol Sci ; 18(19): 2895-902, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25339484

ABSTRACT

OBJECTIVE: The effect of vitamin D and renin-angiotensin-aldosterone system blockade medications in pathophysiology of contrast induced nephropathy (CIN) is controversial. The effects of paricalcitol (active vitamin D analogue) and losartan treatments in an experimental model of CIN were investigated in this study. MATERIALS AND METHODS: Thirty-six male Wistar albino rats were examined in five treatment groups. Placebo group (Group A; n = 4) received no active medication; control group (Group B; n = 8) received only contrast media (CM); Group C (n = 8) received paricalcitol; Group D (n = 8) received losartan and Group E (n = 8) received paricalcitol plus losartan. CIN was induced by NG-nitro-L-arginine methyl ester and indomethacin before iohexol injection. Renal histopathological findings were categorized and renal immunohistochemical examinations by caspase-3 rabbit primary antibody were performed. RESULTS: Creatinine and cystatin C levels significantly increased in the treatment groups, compared to Group A. However, creatinine levels were not significantly increased in Groups C, D and E compared to Group B. Compared to Group B, a significant increase of cystatin C levels was observed in Group D (p < 0.01). In Group E, when paricalcitol treatment was added to losartan treatment, cystatin C levels were similar to Group B (p = 1.00). In histopathological and immunohistochemical examination frequency of Grade 2/3 tubular necrosis and renal caspase 3 activity scores were significantly higher in the losartan treatment group compared to the other treatment groups. The histopathological effects related to losartan treatment were found to be reversed when paricalcitol treatment was combined. CONCLUSIONS: Our findings suggest that paricalcitol treatment counteracts increased contrast induced nephropathy caused by losartan. These findings warrant further clinical studies to investigate the benefit of paricalcitol in CIN prophylaxis.


Subject(s)
Contrast Media/toxicity , Disease Models, Animal , Ergocalciferols/administration & dosage , Kidney Diseases/chemically induced , Kidney Diseases/drug therapy , Renin-Angiotensin System/drug effects , Animals , Drug Therapy, Combination , Kidney Diseases/pathology , Losartan/administration & dosage , Male , Rabbits , Rats , Rats, Wistar , Renin-Angiotensin System/physiology
6.
Acta Neurochir (Wien) ; 148(6): 663-9; discussion 669, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16523223

ABSTRACT

Intramedullary mature teratomas particularly in adults are rarely encountered. In this manuscript the authors have reviewed the adult intramedullary lesions of the spinal cord published in the literature that are harbouring the characteristics of a mature teratoma and analysed the results with respect to histopathology, epidemiology, diagnostic methods and treatment. An illustrative case of an extremely unusual localization is also presented.


Subject(s)
Spinal Cord Neoplasms/diagnosis , Spinal Cord Neoplasms/physiopathology , Spinal Cord/pathology , Spinal Cord/physiopathology , Teratoma/diagnosis , Teratoma/physiopathology , Adult , Cervical Vertebrae , Decompression, Surgical , Diagnosis, Differential , Female , Germ Layers/pathology , Humans , Laminectomy , Male , Middle Aged , Neck Pain/diagnosis , Neck Pain/etiology , Neck Pain/physiopathology , Neoplasm Recurrence, Local/prevention & control , Neoplasm Recurrence, Local/radiotherapy , Neurosurgical Procedures , Paraparesis/diagnosis , Paraparesis/etiology , Paraparesis/physiopathology , Radiotherapy/standards , Sensation Disorders/diagnosis , Sensation Disorders/etiology , Sensation Disorders/physiopathology , Spinal Canal/pathology , Spinal Canal/surgery , Spinal Cord/surgery , Spinal Cord Neoplasms/surgery , Teratoma/surgery , Treatment Outcome
7.
Acta Chir Belg ; 105(4): 378-82, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16184720

ABSTRACT

BACKGROUND: Pulmonary adenocarcinomas constitute a different histological subtype among the histological subtypes of non small cell lung carcinomas by showing comparably unfavourable rates of prognosis and different immunobiological features. Autonomous motility of tumour cells plays an important role in the regulation of local invasion and distant metastasis of tumour lesions which have great impact on overall survival. AMF (Autocrine motility factor) is a tumour secreted cytokine that stimulates motility during invasion and metastasis via its receptor, AMFR. We conducted an immunohistochemical study to investigate AMFR expression in pulmonary adenocarcinomas and its effect on survival. MATERIAL AND METHODS: We assessed AMFR expression using a monoclonal antibody (3F3A) in a total of 32 surgical specimens with stage I pulmonary adenocarcinomas that underwent curative resection. We analyzed AMFR expression as a possible prognostic factor on survival and its correlations with clinicopathological features. RESULTS: A total of 19 (59.3%) specimens showed AMFR expression. The 3-year survival rates of AMFR positive and AMFR negative patients were 47.3% and 84.6%, respectively, which was a significant difference (P = 0.0197). The univariate predictors of surgical outcome were AMFR expression (P = 0.032) and perineural invasion (P = 0.038). However, multivariate analysis revealed AMFR expression (P = 0.045) as the only independent prognostic factor. CONCLUSIONS: AMFR expression predicts an unfavourable surgical outcome in patients with stage I pulmonary adenocarcinomas.


Subject(s)
Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Receptors, Cytokine/metabolism , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adult , Aged , Female , Humans , Immunohistochemistry , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Male , Middle Aged , Multivariate Analysis , Prognosis , Receptors, Autocrine Motility Factor , Turkey/epidemiology , Ubiquitin-Protein Ligases
8.
Toxicol Sci ; 64(2): 233-42, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11719706

ABSTRACT

Di(n-butyl) phthalate (DBP) has antiandrogenic-like effects on the developing reproductive tract in the male rat and produces regions of interstitial cell hyperplasia and gonocyte degeneration in the developing fetal testes at maternal doses of 100-500 mg/kg/day. Neither DBP nor its primary metabolites interact with the androgen receptor in vitro. The present study was performed to examine gene expression in the fetal rat testes following in utero DBP exposure. Pregnant Sprague-Dawley rats received corn oil, DBP (500 mg/kg/day), or flutamide (reference antiandrogen, 50 mg/kg/day) by gavage daily from gestation day (GD) 12 to 21. Dose levels were selected to maximize fetal response with minimal maternal toxicity. Testes were isolated on GD 16, 19, and 21. Global changes in gene expression were determined by microarray analysis. Selected genes were further examined by quantitative RT-PCR. DBP, but not flutamide, reduced expression of the steroidogenic enzymes cytochrome P450 side chain cleavage, cytochrome P450c17, and steroidogenic acute regulatory protein. Testicular testosterone and androstenedione were decreased on GD 19 and 21, while progesterone was increased on GD 19 in DBP-exposed testes. Testosterone-repressed prostate message-2 (TRPM-2) was upregulated, while c-kit (stem cell factor receptor) mRNA was downregulated following DBP exposure. TRPM-2 and bcl-2 protein staining was elevated in GD 21 DBP-exposed Leydig and Sertoli cells. Results of this study have led to the identification of several possible mechanisms by which DBP can induce its antiandrogenic effects on the developing male reproductive tract without direct interaction with the androgen receptor. Our results suggest that the antiandrogenic effects of DBP are due to decreased testosterone synthesis. In addition, enhanced expression of cell survival proteins such as TRPM-2 and bcl-2 may be involved in DBP-induced Leydig cell hyperplasia, whereas, downregulation of c-kit may play a role in gonocyte degeneration. Future studies will explore the link between these identified gene expression alterations and ultimate adverse responses.


Subject(s)
Androgen Antagonists/pharmacology , Dibutyl Phthalate/pharmacology , Flutamide/pharmacology , Testis/drug effects , Animals , Clusterin , Female , Fetus/drug effects , Gene Expression Regulation, Developmental/drug effects , Glycoproteins/genetics , Glycoproteins/metabolism , Immunohistochemistry , Male , Maternal Exposure , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Oligonucleotide Array Sequence Analysis , Pregnancy , Prenatal Exposure Delayed Effects , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Testis/metabolism , Uterus/drug effects
9.
Hum Reprod Update ; 7(3): 231-5, 2001.
Article in English | MEDLINE | ID: mdl-11392369

ABSTRACT

Phthalate esters are a large group of chemical agents used predominantly as plasticizers and solvents. Certain members of this chemical class have been shown to cause reproductive and developmental toxicity. Recent attention has focused on the potential of these agents to interfere with male reproductive development through a postulated antiandrogenic mechanism. Observations have focused on di-n-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP) and butyl benzylphthalate, with most information relating to dose-response relationships obtained for DBP. Neither DBP, DEHP nor their major metabolites interacted with human or rodent androgen receptors (AR) in transcriptional activation assays. DBP was administered during the critical window of development of the male reproductive system, after which the resulting offspring were examined until adulthood. DBP elicited marked effects on the developing male reproductive tract, including malformations of the epididymis and vas deferens, and hypospadias. Retention of thoracic nipples/areolae and reductions in anogenital distance were also noted. Surprisingly, Leydig cell adenomas were induced in some male offspring at 100 days of age. All these events occurred in the absence of any toxicity in the pregnant dam. Examination of testes from fetal rats indicated markedly reduced testosterone levels and increased Leydig cell numbers after DBP administration to the dams. Leydig cells were positive for AR and 3-betahydroxysteroid dehydrogenase.


Subject(s)
Aging/physiology , Esters/pharmacology , Genitalia, Male/drug effects , Genitalia, Male/embryology , Phthalic Acids/pharmacology , Animals , Embryo, Mammalian/drug effects , Genitalia, Male/growth & development , Humans , Male , Rats
10.
Mol Cell Endocrinol ; 178(1-2): 207-14, 2001 Jun 10.
Article in English | MEDLINE | ID: mdl-11403911

ABSTRACT

1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE, DDE) is a stable metabolite of the pesticide DDT and a persistent environmental pollutant. Earlier reports have demonstrated that DDE is an endocrine-active compound capable of affecting early-stage sexual differentiation in male rats. Experiments based on receptor binding affinity and receptor-mediated transcriptional activation have identified DDE as an androgen receptor antagonist. Other effects of DDE include modulation of the expression and activity of cytochrome P450 (CYP) enzymes, some of which function as steroid hydroxylases, and elevation of serum estrogen levels in treated male rats. These effects suggest the possibility of DDE-caused induction of aromatase, a member of CYP family that catalyzes the conversion of C19 steroids to estrogens. The present study was conducted to determine whether hepatic aromatase was responsive to DDE treatment. We found that hepatic aromatase protein in adult male rats was greatly increased after seven daily oral treatments of DDE at a dosage of 100 mg/kg wt. per day. This induction was seen in both immunoblot and immunohistochemistry of liver tissue sections. Distribution of the aromatase in the liver corresponded to the distribution of hypertrophic hepatocytes in the tissue. Furthermore, we found a large increase in hepatic microsomal aromatase activity in DDE-treated animals, although the difference in serum 17beta-estradiol concentrations between treated animals and controls was not statistically significant. However, an in vitro experiment using primary culture of rat hepatocytes did not show a change in aromatase level after DDE treatment at four concentrations ranging from 0 to 5x10(-6) M for 24 h. Meanwhile, CYP 2B1 induction, a known DDE effect in primary rat hepatocyte culture, was seen in those cells. This study supports the notion that induction of aromatase by DDE is a contributory factor to its reproductive developmental effects.


Subject(s)
Aromatase/biosynthesis , Dichlorodiphenyl Dichloroethylene/toxicity , Liver/drug effects , Liver/enzymology , Animals , Environmental Pollutants/toxicity , Enzyme Induction/drug effects , Estradiol/blood , Hepatocytes/drug effects , Hepatocytes/enzymology , Immunohistochemistry , Male , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley
11.
Andrologia ; 32(4-5): 295-301, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11021522

ABSTRACT

The cellular localization of two oestrogen receptor (ER) subtypes, ER alpha and ER beta, was investigated in neonatal, postnatal, immature and adult male rats to determine whether these receptor subtypes are differentially expressed in prostate and epididymis. A monoclonal antibody against ER alpha and two polyclonal ER beta antibodies were used. Paraffin sections revealed a specific nuclear immunoreaction product in certain cells but not in others. In the epididymis, nuclear ER alpha immunoreactivity (IR) was detected in epithelial cells of efferent ductules and initial segments as well as in connective tissue surrounding the tubules in caput, corpus and cauda. No IR was observed in rete testis. Epithelial cells of the prostate lacked ER alpha IR, but connective tissue cells surrounding prostatic buds in the early neonatal period revealed IR. In prostate, ER beta IR was expressed in epithelial cells of the ventral and dorsolateral lobes, but the IR intensity was higher in the ventral lobe. In neonatal rats, ER beta was expressed in the epididymis but not in the prostate gland. Weak ER beta expression was found in the prostates of 5-day-old rats, and the reaction increased in intensity thereafter. In the epididymis, a similar developmental expression pattern of ER beta was observed. ER beta expression in prostate and epididymis was similar to expression of androgen receptors reported previously for these organs. The results support that both ER alpha and ER beta may be involved in oestrogen modulation of prostate and epididymal functions.


Subject(s)
Epididymis/metabolism , Prostate/metabolism , Receptors, Estrogen/metabolism , Animals , Animals, Newborn , Epididymis/anatomy & histology , Estrogen Receptor alpha , Estrogen Receptor beta , Immunohistochemistry , Male , Prostate/anatomy & histology , Rats , Rats, Sprague-Dawley , Sexual Maturation , Tissue Distribution
12.
Science ; 286(5448): 2328-31, 1999 Dec 17.
Article in English | MEDLINE | ID: mdl-10600740

ABSTRACT

Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alphabeta estrogen receptor knockout (alphabetaERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alphabetaERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Müllerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.


Subject(s)
Disorders of Sex Development , Molecular Chaperones , Ovary/anatomy & histology , Ovary/physiology , Receptors, Estrogen/physiology , Animals , Anti-Mullerian Hormone , Cell Differentiation , Clusterin , Estradiol/physiology , Estrogen Receptor alpha , Estrogen Receptor beta , Female , Gene Targeting , Glycoproteins/analysis , Growth Inhibitors/analysis , High Mobility Group Proteins/analysis , Luteinizing Hormone/blood , Male , Mice , Mice, Knockout , Ovary/cytology , Ovary/growth & development , Receptors, Estrogen/genetics , SOX9 Transcription Factor , Seminiferous Tubules/anatomy & histology , Seminiferous Tubules/cytology , Sertoli Cells/cytology , Signal Transduction , Testicular Hormones/analysis , Testis/anatomy & histology , Testis/cytology , Testis/growth & development , Testis/physiology , Transcription Factors/analysis
13.
Steroids ; 64(10): 742-51, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10498033

ABSTRACT

The alpha isoform of the glucocorticoid receptor (GRalpha) binds glucocorticoids and functions as a ligand-dependent transcription factor. Although GRalpha is expressed in almost all tissues and cells, its subcellular distribution is controversial. Many studies have reported that GRalpha translocates from the cytoplasm to the nucleus in a hormone-dependent manner whereas others have concluded that GRalpha is constitutively located in the nucleus. These conflicting data may result from the use of antibodies that do not discriminate GRalpha from a splice variant of the GR gene termed GRbeta. Using a GRbeta-specific antibody, we have recently demonstrated that GRbeta resides in the nucleus of cells independent of glucocorticoid treatment. In the following study we have generated a novel GRalpha-specific antibody (AShGR) in order to assess, unambiguously, the subcellular distribution of GRalpha. AShGR recognizes recombinant GRalpha on Western blots and in immunoprecipitation experiments but does not cross-react with recombinant GRbeta. Endogenous GRalpha is detected by AShGR in a variety of human cell lines including HeLa S3, CEM-C7, HEK-293, MCF-7, Hep G2, and secondary lung epithelial cells. In addition, AShGR detects endogenous rat and mouse GRalpha. Immunocytochemistry was performed with AShGR on COS-I cells transfected with human GRalpha and on HTC rat hepatoma cells expressing endogenous GRalpha. In both systems, GRalpha was found in the cytoplasm of cells in the absence of hormone and in the nucleus after hormone treatment. These studies mark the first time a GRalpha-specific antibody has been employed to examine the expression and subcellular distribution of endogenous GRalpha.


Subject(s)
Antibodies/immunology , Protein Isoforms/metabolism , Receptors, Glucocorticoid/metabolism , Amino Acid Sequence , Animals , Cell Line , Cross Reactions , Humans , Immunohistochemistry , Molecular Sequence Data , Protein Isoforms/chemistry , Protein Isoforms/immunology , Receptors, Glucocorticoid/chemistry , Receptors, Glucocorticoid/immunology , Recombinant Proteins/chemistry , Recombinant Proteins/immunology , Recombinant Proteins/metabolism , Subcellular Fractions/metabolism
14.
Endocrinology ; 140(6): 2733-44, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10342864

ABSTRACT

Targeted disruption of the mouse estrogen receptor-alpha gene (estrogen receptor-alpha knockout; ERKO) results in a highly novel ovarian phenotype in the adult. The ERKO mouse model was used to characterize ER alpha-dependent processes in the ovary. Visualization of the ovaries of 10-, 20-, and 50-day-old wild-type (WT) and ERKO mice showed that the ERKO phenotype developed between 20 and 50 days of age. Developmental progression through the primordial, primary, and antral follicle stages appeared normal, but functional maturation of preovulatory follicles was arrested resulting in atresia or in anovulatory follicles, which in many cases formed large, hemorrhagic cysts. Corpora lutea were absent, which also indicates that the normal biochemical and mechanical processes that accomplish ovulation were compromised. Northern and ribonuclease protection analyses indicated that ERKO ovary FSH receptor (FSHR) messenger RNA (mRNA) expression was approximately 4-fold greater than in WT controls. Ovarian LH receptor (LHR) mRNA expression was also higher in the ERKO animals. Cellular localization studies by in situ hybridization analysis of ERKO ovaries showed a high level of LHR mRNA expression in the granulosa and thecal layers of virtually all the antral follicles. Ribonuclease protection analyses showed that ovarian progesterone receptor and androgen receptor mRNA expression were similar in the two groups. These results indicated that ER alpha action was not a prerequisite for LHR mRNA expression by thecal or granulosa cells or for ovarian expression of progesterone receptor mRNA. Ovarian estrogen receptor beta (ER beta) was detected immunohistochemically, was sharply compartmentalized to the granulosa cells, and was expressed approximately equally in the ERKO animals and the WT controls. In contrast, ER alpha staining was present in the thecal cells but not the granulosa cells of the WT animals. The summary findings indicate that in the adult the major cause of the ERKO phenotype is high circulating LH interacting with functional LHR of the theca and granulosa cells. These features result in a failure of the normal maturational events leading to successful ovulation and luteinization and presumably involve both hypothalamic-pituitary and intraovarian mechanisms dependent upon ER alpha action. The presence of ER beta in the granulosa cells did not rescue the phenotype of the ovary.


Subject(s)
Ovary/physiology , Receptors, Estrogen/genetics , Animals , Apoptosis , Estrogen Receptor alpha , Estrogen Receptor beta , Female , In Situ Hybridization , Mice , Mice, Knockout , Ovarian Follicle/pathology , Phenotype , RNA, Messenger/analysis , Rabbits , Receptors, Estrogen/analysis , Receptors, Estrogen/physiology , Receptors, FSH/genetics , Receptors, LH/genetics
15.
Toxicol Appl Pharmacol ; 156(2): 81-95, 1999 Apr 15.
Article in English | MEDLINE | ID: mdl-10198273

ABSTRACT

Gestational and lactational exposure to di(n-butyl) phthalate (DBP) at >/=250 mg/kg/day disrupts male rat reproductive development and function. Although this indicates an antiandrogenic mechanism, DBP and its biologically active metabolite do not interact with the androgen receptor (AR) in vitro. In the present study, we compared the effects of DBP and the antiandrogen flutamide using a shorter exposure during the prenatal period of male sexual differentiation in rats. Pregnant CD rats received DBP at 0, 100, 250, or 500 mg/kg/day po (n = 10) or flutamide at 100 mg/kg/day po (n = 5) from Gestation Days 12 to 21. In F1 males, DBP (500 mg/kg/day) and flutamide caused hypospadias; cryptorchidism; agenesis of the prostate, epididymis, and vas deferens; degeneration of the seminiferous epithelium; and interstitial cell hyperplasia of the testis. Flutamide and DBP (250 and 500 mg/kg/day) also produced retained thoracic nipples and decreased anogenital distance. Interstitial cell adenoma occurred at 500 mg DBP/kg/day in two males. The only effect seen at 100 mg DBP/kg/day was delayed preputial separation. In contrast to flutamide, DBP caused a low incidence of prostate agenesis and hypospadias with no vaginal pouch. The low incidence of DBP-induced intraabdominal testes contrasted with the high incidence of inguinal testes seen with flutamide. Thus prenatal male sexual differentiation is a sensitive period for the reproductive toxicity of DBP. A no observed adverse effect level was not established and the lowest observed (adverse) effect level was 100 mg/kg/day. Flutamide and DBP disrupted the androgen signaling necessary for male sexual differentiation but with a different pattern of antiandrogenic effects. DBP is an example of an environmental antiandrogen that disrupts androgen-regulated male sexual differentiation without interacting directly with the AR, as does flutamide.


Subject(s)
Androgen Antagonists/toxicity , Androgens/physiology , Dibutyl Phthalate/toxicity , Flutamide/toxicity , Genitalia, Male/abnormalities , Sexual Maturation/drug effects , Sexual Maturation/physiology , Teratogens/toxicity , Abnormalities, Drug-Induced/pathology , Animals , Animals, Newborn/physiology , Cryptorchidism/chemically induced , Female , Genitalia, Male/embryology , Genitalia, Male/pathology , Immunohistochemistry , Male , Organ Size/drug effects , Pregnancy , Rats , Receptors, Androgen/biosynthesis , Sex Differentiation/drug effects
16.
Endocrinology ; 140(2): 963-71, 1999 Feb.
Article in English | MEDLINE | ID: mdl-9927330

ABSTRACT

Immunohistochemical localization of two estrogen receptor (ER) subtypes, ER beta and ER alpha, was performed in neonatal, early postnatal, immature, and adult rats to determine whether ER alpha and ER beta are differentially expressed in the ovary. ER beta and ER alpha were visualized using a polyclonal anti-ER beta antibody and a monoclonal ER alpha (ID5) antibody, respectively. Postfixed frozen sections and antigen-retrieved paraffin sections of the ovary revealed nuclear ER beta immunoreactivity (IR) in granulosa cells, which was prevented when peptide-adsorbed antibody was used instead. In immature and adult rat ovaries, ER beta was expressed exclusively in nuclei of granulosa cells of primary, secondary, and mature follicles. Atretic follicle granulosa cells showed only weak or no staining. No specific nuclear ER beta IR was detected in thecal cells, luteal cells, interstitial cells, germinal epithelium, or oocytes. In neonatal rat ovary, no ER beta expression was found. In ovaries of 5- and 10-day-old rats, weak ER beta IR was observed in granulosa cells of primary and secondary follicles, but no staining was detected in the primordial follicles. ER alpha protein exhibited a differential distribution in the ovary with no detectable expression in the granulosa cells but evidence of ER alpha IR in germinal epithelium, interstitial cells, and thecal cells. In the oviduct and uterus, IR for ER alpha, but not ER beta, was found in luminal epithelium, stromal cells, muscle cells, and gland cells. Our present study demonstrates that ER beta and ER alpha proteins are expressed in distinctly different cell types in the ovary. The exclusive presence of ER beta in granulosa cells implies that this specific new subtype of ER beta mediates some effects of estrogen action in the regulation of growth and maturation of ovarian follicles.


Subject(s)
Ovary/metabolism , Receptors, Estrogen/metabolism , Aging/metabolism , Animals , Estrogen Receptor alpha , Estrogen Receptor beta , Female , Genitalia, Female/growth & development , Genitalia, Female/metabolism , Granulosa Cells/metabolism , Immunohistochemistry/methods , Ovarian Follicle/metabolism , Ovary/cytology , Rats , Rats, Sprague-Dawley , Tissue Distribution
17.
Proc Natl Acad Sci U S A ; 95(26): 15677-82, 1998 Dec 22.
Article in English | MEDLINE | ID: mdl-9861029

ABSTRACT

Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERalpha and ERbeta. We previously generated and studied knockout mice lacking estrogen receptor alpha and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor beta (ERbeta -/-) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ERbeta -/- mice lack normal ERbeta RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal breast development and lactate normally. Young, sexually mature male mice show no overt abnormalities and reproduce normally. Older mutant males display signs of prostate and bladder hyperplasia. Our results indicate that ERbeta is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation. Future experiments are required to determine the role of ERbeta in bone and cardiovascular homeostasis.


Subject(s)
Receptors, Estrogen/physiology , Reproduction/genetics , Animals , Estrogen Receptor alpha , Estrogen Receptor beta , Exons , Female , Genes, Reporter , Infertility, Female/genetics , Infertility, Male/genetics , Male , Mice , Mice, Knockout , Ovary/cytology , Ovary/metabolism , Ovary/pathology , Phenotype , Receptors, Estrogen/deficiency , Receptors, Estrogen/genetics , Recombination, Genetic , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/physiology , Transfection
18.
Toxicol Sci ; 45(2): 162-73, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9848123

ABSTRACT

Although the pesticide DDT has been banned in the United States for decades, it remains at low levels in the environment. p,p'-DDE, a metabolite of DDT, was recently shown to inhibit the binding of androgens to the androgen receptor and to exert antiandrogenic effects in perinatal Long-Evans (LE) rats at a dose of 100 mg/kg/day administered to pregnant dams. In this study, we compared the effects of p,p'-DDE on male sexual development in offspring of Sprague-Dawley (SD) and LE rats. The chemical was dosed by gavage to pregnant dams at 10 or 100 mg/kg body wt from gestation day 14 to 18. The developing male rats were examined for sexual developmental landmarks, while the effects of p,p'-DDE on androgen receptor expression were evaluated in the testis and other reproductive organs. The tissue dosimetry of p,p'-DDE was also determined at different stages of development following in utero and lactational exposures. The higher p,p'-DDE dose induced a reduction in the male anogenital distance, an increase in retention of male thoracic nipples and alterations in expression of the androgen receptor in either one or both strains. A much weaker response was seen in the lower dose groups. Tissue and body fluid concentrations of p,p'-DDE were similar in the two strains in some tissues but dissimilar in others, particularly in the serum levels. Higher serum p,p'-DDE levels in the LE strain during pregnancy corresponded with an overall greater sensitivity of the LE strain to the antiandrogenic effects of p,p'-DDE. These results support the previous findings of p,p'-DDE antiandrogenicity in LE rats, extend the findings to SD rats, and suggest that the developmental effects of p,p'-DDE on male rat sexual differentiation are minimal at maternal doses below 10 mg/kg/day.


Subject(s)
Dichlorodiphenyl Dichloroethylene/toxicity , Genitalia, Male/drug effects , Insecticides/toxicity , Prenatal Exposure Delayed Effects , Animals , Animals, Suckling , Brain/metabolism , Dichlorodiphenyl Dichloroethylene/metabolism , Female , Flutamide/toxicity , Genitalia, Male/growth & development , Insecticides/metabolism , Liver/metabolism , Male , Organ Size/drug effects , Pregnancy , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Receptors, Androgen/metabolism , Testosterone/blood
19.
Toxicol Sci ; 41(1): 77-87, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9520343

ABSTRACT

Chronic exposure to methyl tertiary butyl ether (MTBE) altered the rodent tumor incidence of endocrine-sensitive tissues and decreased the incidence of estrogen-dependent uterine cystic hyperplasia in mice. To test the hypothesis that changes in the incidence of tumors in female B6C3F1 mice after MTBE exposure are secondary to endocrine alterations, we exposed female mice to the carcinogenic dose of MTBE vapor (8000 ppm) for 3 or 21 days or 4 or 8 months under conditions similar to a previous 2-year bioassay. MTBE exposure significantly decreased body weight gain and ovary and pituitary weight at 4 and 8 months and uterine weight at all time points. After 8 months of exposure, MTBE significantly increased the length of the estrous cycle by increasing the mean number of days in both the estrus and the nonestrus stages. Histological evaluation of H&E-stained tissues showed a decrease in the number of uterine glands after subchronic MTBE exposure. DNA synthesis, as measured by the incorporation of 5-bromo-2'-deoxyuridine (BrdU), was decreased in uterine glandular and luminal epithelial cells after MTBE exposure for 3 or 21 days or 4 or 8 months. MTBE exposure decreased the number of epithelial layers in the cervix and vagina at all time points. DNA synthesis was decreased in cervical and vaginal epithelium after 21 days of MTBE. Decreased zona reticularis of adrenal glands was found after 4 and 8 months of MTBE exposure without changes in BrdU incorporation. MTBE did not competitively bind to estrogen receptor. MTBE exposure did not alter serum estrogen levels or alter the location or intensity of estrogen receptor immunoreactivity in the uterus, cervix, and vagina. These data indicate that while MTBE exposure causes multiple endocrine-related tissue and cellular responses, these effects are not mediated through the estrogen receptor.


Subject(s)
Carcinogens/toxicity , Endocrine Glands/drug effects , Methyl Ethers/toxicity , Receptors, Estrogen/metabolism , Administration, Inhalation , Animals , Body Weight/drug effects , Cell Division/drug effects , Cervix Uteri/drug effects , Cervix Uteri/pathology , DNA Replication/drug effects , Endocrine Glands/metabolism , Endocrine Glands/pathology , Estradiol/blood , Estrus/drug effects , Female , Mice , Organ Size/drug effects , Vagina/drug effects , Vagina/pathology
20.
Endocrine ; 9(3): 253-61, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10221590

ABSTRACT

The androgen receptor (AR) plays a critical role in sexual differentiation and in the virilization of the male reproductive system. A clear understanding of AR expression at the early stages of sexual development will help elucidate the sensitivity of perinatal animals to endocrine modulation by external agents, such as some environmental chemicals. Immunohistochemistry was used in this study to localize the AR in the differentiating testis and epididymis of Sprague-Dawley rats starting from gestation day 15 until postnatal day 21. Positive AR staining was found on gestation day 15 in the mesenchymal as well as in the epithelial cells in the mesonephros. Weak staining was also observed in a small number of interstitial cells in the primordial testis at this age. The fetal interstitial and peritubular myoid cells showed positive AR immunoreactivity early in development, but the Sertoli cells did not overtly express the receptors until postnatal day 5. The intensity of staining and number of AR-positive cells in the testis and epididymis increased over time. The epithelium in the mesonephros-derived tissues, including rete testis and epididymis, appeared to exhibit a higher capacity to express AR than the rest of the testicular tissue. The results demonstrate that AR expression in the primordial male reproductive system is highly specific to time and cell type and modify previous understanding on the timing of AR expression in the testicular tissue. Since AR-positive cells at various developmental stages may be potential sites of interaction with chemicals that adversely affect sexual differentiation, improved understanding of AR ontogeny will help in investigating the effects of AR-reactive agents, such as environmental antiandrogens, with respect to specific windows of sensitivity.


Subject(s)
Epididymis/metabolism , Receptors, Androgen/biosynthesis , Testis/metabolism , Animals , Animals, Newborn , Epididymis/embryology , Female , Immunohistochemistry , Male , Pregnancy , Rats , Rats, Sprague-Dawley , Testis/embryology
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