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1.
Environ Mol Mutagen ; 48(9): 744-53, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18008354

RESUMO

Azathioprine (Aza), a prodrug of 6-mercaptopurine, is used in human medicine to prevent transplant rejection and for the treatment of autoimmune diseases. Extremely high HPRT lymphocyte mutant frequencies (MFs) are found in humans and mice chronically treated with Aza, and these elevated MFs appear to be caused by selection and amplification of pre-existing HPRT mutant lymphocytes. In the present study, we investigated if in vivo selection by Aza also promotes the germ-line transmission of Hprt mutants. Fifty-five male C57BL/6 mice were treated with 10 mg/kg Aza three times/week for 24 weeks; 10 control mice were treated with the vehicle. Each of these males then was bred to unexposed females for a total of 8 weeks. Analysis of the Aza-treated males after the breeding period indicated that 12 had highly elevated Hprt lymphocyte MFs (1 x 10(-4)-2.5 x 10(-1) vs. normal MFs of <1 x 10(-5)), indicating that the Aza treatment successfully selected somatic cell mutants. The female offspring from the breeding were sacrificed at 28 days of age and Hprt MFs were measured in spleen lymphocytes. Most of the 364 female offspring (332 from Aza-treated fathers) had Hprt MFs of 0-6 x 10(-6), but seven of the offspring had moderately elevated MFs of 16 x 10(-6)-55 x 10(-6). Since one of these mice was fathered by a control male, these relatively high MFs appear to be part of the normal variation in lymphocyte Hprt MF. The present results provide no evidence that long-term Aza treatment promotes high levels of germ-line Hprt mutation transmission in mice.


Assuntos
Azatioprina/farmacologia , Células Germinativas , Hipoxantina Fosforribosiltransferase/genética , Mutação , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
2.
Mutat Res ; 578(1-2): 1-14, 2005 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-16107271

RESUMO

Many patients undergoing chronic therapy with the purine analogue Azathioprine (Aza) have highly elevated HPRT lymphocyte mutant frequencies (MFs), and it is likely that these increases are due to selection of pre-existing HPRT mutant lymphocytes. A similar selection in germ cells might result in an increased frequency of the Lesch-Nyhan syndrome. In this study, a mouse model for Aza mutant selection was developed and Aza toxicity was evaluated in the germ cells of treated mice. Groups of 20 male C57BL/6 mice were treated by gavage three times/week with 0, 5, 10, 25, 50, or 100mg/kg Aza, and three to eight mice from each group were sacrificed at various times for up to 23 weeks. Mice treated with 25-100mg/kg Aza were all dead by 14 weeks of treatment. Hprt lymphocyte MF assays indicated that the treated mice had reduced numbers of spleen lymphocytes. Most treated mice had Hprt MFs similar to those of control mice (2.1+/-1.6 x 10(-6)), however, highly elevated MFs were detected in one out of three mice given 5mg/kg for 10 weeks, one out of three mice given 10mg/kg for 10 weeks, and one out of eight mice given 10mg/kg for 23 weeks (e.g., 233 x 10(-6) after 10 weeks of 5mg/kg). Sequence analysis of Hprt cDNA indicated that all mutant clones from one of these mice had a T-->A transversion in the initiation codon. Multiplex-PCR on mutant clones from the other two mice indicated that all the clones from one had a deletion of Hprt exons 2 and 3, while most of the mutants from the other had lost all of the Hprt exons. Measurements of testicular weight, and of sperm count, viability, morphology, and motility found that Aza produced low levels of toxicity in sperm, with the most consistent effect being a reduction in the testicular weight. The data suggest that mice chronically treated with 5 and 10mg/kg Aza (doses similar to those used in humans) have elevated Hprt MFs due to clonal amplification of selected Hprt mutants. The results also suggest that mice treated with these doses of Aza retain reasonable fertility, and will be useful for breeding experiments to examine the possibility of increasing the germ-line transmission of Hprt mutations.


Assuntos
Azatioprina/toxicidade , Hipoxantina Fosforribosiltransferase/genética , Linfócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Mutação , Espermatozoides/efeitos dos fármacos , Animais , Azatioprina/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Éxons , Linfócitos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Mutagênicos/química , Tamanho do Órgão/efeitos dos fármacos , Deleção de Sequência , Baço/citologia , Testes de Toxicidade Crônica
3.
Reprod Syst Sex Disord ; 4(4)2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26844009

RESUMO

BACKGROUND: Obesity has been associated with low testosterone (T) in adult males and in pubertal boys. Therapy for hypogonadism with exogenous T may lead to testicular atrophy and later infertility. Only a few studies have demonstrated that the Selective Estrogen Receptor Modulator (SERM) clomiphene citrate (CC), an estrogen receptor antagonist, increases T in obese hypogonadal men while preventing testicular atrophy. No studies to date using CC have been done in younger obese post-pubertal hypogonadal males. OBJECTIVE: To determine whether CC therapy is effective in increasing serum T levels in hypogonadal post-pubertal obese males 18-21 years. MATERIALS AND METHODS: A retrospective chart analysis of records in obese men aged 18-21 years was done. Patients with early morning T level <350 ng/dl were given 25 mg CC on alternate days. Out of 18 patients found to have low T, 11 were analyzed. Baseline serum T, LH, FSH, weight and BMI were compared at baseline and after 3 months of CC treatment. RESULTS: Baseline T level was 233 ± 66 ng/dl and increased to 581 ± 161 ng/dl (p<0.0001) after 3 months of CC treatment. Baseline LH levels increased from 3.3 ± 1.6 mIU/mL to 5.7 ± 1.7 mIU/mL (p=0.027). Similarly, baseline FSH levels increased from 2.8 ± 1.5 mIU/mL to 6.2 ± 3 mIU/mL after CC treatment (p=0.026). There was no correlation between baseline or post treatment weight or BMI and the T level, LH, or FSH level. CONCLUSION: This is the first study reporting on CC therapy in obese, hypogonadal post-pubertal men 18-21 years. The SERM CC increased T in obese post-pubertal hypogonadal men, similar to efficacy of CC in adult hypogonadal men over the age 21 years. Larger randomized controlled studies to study the safety and potential use of CC to improve T in young obese HG men are needed.

4.
J Endocrinol ; 212(2): 139-47, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22107955

RESUMO

GnRH is the main regulator of the hypothalamic-pituitary-gonadal (H-P-G) axis. GnRH stimulates the pituitary gonadotroph to synthesize and secrete gonadotrophins (LH and FSH), and this effect of GnRH is dependent on the availability of glucose and other nutrients. Little is known about whether GnRH regulates glucose metabolism in the gonadotroph. This study examined the regulation of glucose transporters (Gluts) by GnRH in the LßT2 gonadotroph cell line. Using real-time PCR analysis, the expression of Glut1, -2, -4, and -8 was detected, but Glut1 mRNA expression level was more abundant than the mRNA expression levels of Glut2, -4, and -8. After the treatment of LßT2 cells with GnRH, Glut1 mRNA expression was markedly induced, but there was no GnRH-induction of Glut2, -4, or -8 mRNA expression in LßT2 cells. The effect of GnRH on Glut1 mRNA expression is partly mediated by ERK activation. GnRH increased GLUT1 protein and stimulated GLUT1 translocation to the cell surface of LßT2 cells. Glucose uptake assays were performed in LßT2 cells and showed that GnRH stimulates glucose uptake in the gonadotroph. Finally, exogenous treatment of mice with GnRH increased the expression of Glut1 but not the expression of Glut2, -4, or -8 in the pituitary. Therefore, regulation of glucose metabolism by GnRH via changes in Gluts expression and subcellular location in the pituitary gonadotroph reveals a novel response of the gonadotroph to GnRH.


Assuntos
Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Gonadotrofos/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Regulação para Cima , Animais , Transporte Biológico , Linhagem Celular , Membrana Celular/metabolismo , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Gonadotrofos/citologia , Gonadotrofos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Hipófise/crescimento & desenvolvimento , Hipófise/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
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