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1.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803091

RESUMO

Although melatonin has been extensively studied in animal reproduction, the mechanism of melatonin in puberty remains elusive. This study was designed to explore the effect of intraperitoneal administration of melatonin on puberty onset in female mice. The injection of melatonin into postnatal days 10 mice at a dose of 15 mg/kg accelerated the puberty onset in mice. Mechanistically, there was no difference in physical growth and serum Leptin levels after melatonin administration. Meanwhile, the serum levels of reproductive hormones involved in hypothalamic-pituitary-ovarian axis, such as FSH and estrogen level in serum were increased. The mRNA levels of GnRH and GnRHr were not affected by melatonin, while the expressions of FSHß in pituitary and Cyp19a1 in ovary were significantly up-regulated. In addition, melatonin still promoted FSH synthesis after ovariectomy. Furthermore, the enhanced activity of ERK1/2 signaling verified that the expression of FSHß increased in pituitary. We confirmed that melatonin promoted the FSH synthesis in pituitary, thereby increased serum estrogen levels and ultimately accelerated puberty onset. However, these effects of melatonin may be pharmacological due to the high dose. This study would help us to understand the functions of melatonin in pubertal regulation comprehensively.


Assuntos
Hormônio Foliculoestimulante/metabolismo , Melatonina/farmacologia , Maturidade Sexual/efeitos dos fármacos , Animais , Aromatase/metabolismo , China , Estrogênios/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Injeções Intraperitoneais , Leptina/metabolismo , Hormônio Luteinizante/metabolismo , Melatonina/metabolismo , Camundongos , Ovário/efeitos dos fármacos , Hipófise/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Receptores LHRH/metabolismo , Maturidade Sexual/fisiologia
2.
Toxicology ; 454: 152740, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33662507

RESUMO

Xylene is a cyclic hydrocarbon, which is commonly used as a solvent in dyes, paints, polishes, and industrial solutions. It is a potential environmental pollutant. Here, we report the effect of xylene exposure on Leydig cell development in male rats during puberty. Xylene (0, 150, 750, and 1500 mg/kg) was gavaged to 35-day-old male Sprague Dawley rats for 21 days. Xylene significantly reduced serum testosterone levels at 750 and 1500 mg/kg without affecting serum luteinizing hormone and follicle-stimulating hormone levels. Xylene reduced the number of HSD11B1-positive Leydig cells at the advanced stage at 1500 mg/kg. At 750 and 1500 mg/kg, xylene also reduced the cell size and cytoplasm size. It down-regulated the expression of Leydig cell-specific genes (Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd11b1) and proteins. In addition, xylene significantly reduced the ratio of phosphorus-GSK-3ß (pGSK-3ß/GSK-3ß), phosphorus-ERK1/2 (pERK)/ERK1/2, and phosphorus-AKT1 (pAKT1)/AKT1, and SIRT1 levels in the testes. In vitro Leydig cell culture showed that xylene induced oxidative stress by increasing the production of reactive oxygen species and lowing antioxidant (Sod2), and inhibited the production of testosterone, and down-regulated the expression of genes related to steroidogenesis, while vitamin E reversed the xylene-mediated effect as an antioxidant. In conclusion, xylene exposure may disrupt the development of pubertal Leydig cells by increasing reactive oxygen species production and reducing the expression of GSK-3ß, ERK1/2, AKT1, and SIRT1.


Assuntos
Células Intersticiais do Testículo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Maturidade Sexual/efeitos dos fármacos , Xilenos/toxicidade , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Células Intersticiais do Testículo/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Testosterona/sangue , Vitamina E/farmacologia , Xilenos/administração & dosagem
3.
Toxicology ; 449: 152653, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33309551

RESUMO

Bis(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in several items, non-covalently bound to plastics and easily released, since metabolites were found in human matrices. DEHP is an endocrine disrupter and children are particularly vulnerable and susceptible to DEHP effects due to higher exposure levels and developmental stage. A juvenile toxicity study was performed to identify DEHP hazard and mode of action in Sprague-Dawley rats of both sexes during peri-pubertal period - corresponding to childhood phase - from weaning, post-natal day (PND) 23, to full sexual maturity (PND60); the dose levels of 0, 9, 21 and 48 mg/kg bw/day were derived from LIFE PERSUADED biomonitoring study in children. DEHP was administered by gavage for 28 days (5 days/week); timing of preputial separation and vaginal opening was observed during treatment. Histopathological analysis was performed on: adrenals, spleen, liver, thyroid and reproductive organs. The following serum biomarkers were assessed: estradiol, testosterone, anti-Mullerian hormone, tetraiodothyronine, thyroid stimulating hormone, adiponectin and leptin. Gene expression on hypothalamic-pituitary area was focused on follicle stimulating, luteinizing, and thyroid stimulating hormones. The results showed that main targets of DEHP during juvenile period were liver and metabolic system in both sexes, while sex-specific effects were recorded in reproductive system (male rats) and in thyroid (female rats). DEHP exposure during peri-pubertal period at dose levels derived from biomonitoring study in children can induce sex-specific imbalances identifying the juvenile animal model as a sound tool to identify hazards for a reliable risk assessment targeted to children.


Assuntos
Monitoramento Biológico/métodos , Dietilexilftalato/toxicidade , Reprodução/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Administração Oral , Fatores Etários , Animais , Animais Recém-Nascidos , Criança , Dietilexilftalato/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Plastificantes/administração & dosagem , Plastificantes/metabolismo , Plastificantes/toxicidade , Ratos , Ratos Sprague-Dawley , Reprodução/fisiologia , Maturidade Sexual/fisiologia
4.
Chemosphere ; 258: 127361, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947662

RESUMO

In female mammals, puberty and fertility are regulated by the synthesis of estradiol (E2) by the ovaries at the infantile stage and at the approach of puberty, a process which may be affected by endocrine disrupting chemicals (EDC)s acting through the Aryl hydrocarbon receptor (AhR). However, there is no information on AhR-mediated regulation of ovarian estrogenic activity during these developmental periods. Here, we assessed in mouse models, the intrinsic and exogenous ligand-induced AhR action on E2 synthesis at the infantile stage (14 days postnatal (dpn)) and at the approach of puberty (28 dpn). Intrinsic AhR pathway became activated in the ovary at the approach of puberty, as suggested by the decreased intra-ovarian expression in prototypical and steroidogenesis-related AhR targets and E2 contents in Ahr knockout (Ahr-/-) mice versus Ahr+/+ mice exclusively at 28 dpn. Accordingly, AhR nuclear localization in granulosa cells, reflecting its activity in cells responsible for E2 synthesis, was much lower at 14 dpn than at 28 dpn in C57BL/6 mice. However, AhR signaling could be activated by exogenous ligands at both ages, as revealed by FICZ- and TCDD-induced Ahrr and Cyp1a1 expression in C57BL/6 mice. Nevertheless, TCDD impacted ovarian estrogenic activity only at 28 dpn. This age-related AhR action may be ligand-dependent, since FICZ had no effect on E2 synthesis at 28 dpn. In conclusion, AhR would not regulate ovarian estrogenic activity before the approach of puberty. Its activation by EDCs may be more detrimental to reproductive health at this stage than during infancy.


Assuntos
Ovário/fisiologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Citocromo P-450 CYP1A1/metabolismo , Disruptores Endócrinos/metabolismo , Estradiol/metabolismo , Estrogênios/farmacologia , Feminino , Células da Granulosa/efeitos dos fármacos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Ovário/efeitos dos fármacos , Dibenzodioxinas Policloradas/metabolismo , Maturidade Sexual/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
Life Sci ; 258: 118242, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32784056

RESUMO

AIMS: As the spermatogenesis process is targeted by cisplatin (Cis) that changes testicular morphology, alters sperm quality, and hence causes male infertility. This study investigated the possible therapeutic effects of l-carnitine (LC) on Cis impaired spermatogenesis's establishment during the prepubertal phase. MATERIALS AND METHODS: Ninety-six prepubertal Sprague Dawley male rats were divided into four groups. CONTROL GROUP: rats were injected with 0.9% saline solution intraperitoneally (i.p.). LC group: animals were injected for eight weeks, with 250 mg/kg/wk. LC (i.p.). Cis group: animals were injected with a single dose of 5 mg/kg Cis (i.p.). LC + Cis group: animals were pre-injected with LC 250 mg/kg 2 h before Cis injection. The rats were sacrificed at 37, 60, and 90 days old, and their testes were taken for biochemical, molecular, and histopathological studies. The motility, viability, morphology, and DNA fragmentation of sperm in adult rats were also measured. KEY FINDINGS: Group treated with LC and Cis showed an increase in antioxidant and hormonal activity compared to the Cis treated group in the pre and post-pubertal period. Moreover, there was an increase in sperm survival, motility, and DNA integrity. Furthermore, LC showed an increase in the anti-apoptotic and chromatin remodeling genes and a decrease in the pro-inflammatory genes. SIGNIFICANCE: LC could enhance the spermatogenesis process after exposure to Cis during the prepubertal phase by restoring the balance between reactive oxygen species and antioxidant activity, improving hormonal activity, sperm quality and DNA integrity, promoting protamination and blood-testis barrier integrity, and maintaining the testicular architecture.


Assuntos
Carnitina/farmacologia , Cisplatino/toxicidade , Infertilidade Masculina/prevenção & controle , Infertilidade Masculina/fisiopatologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Carnitina/uso terapêutico , Infertilidade Masculina/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/fisiologia , Espermatogênese/fisiologia
6.
Chem Biol Interact ; 328: 109188, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32679048

RESUMO

We have reported that gestational exposure to hexavalent chromium (CrVI) represses androgen receptor (Ar) and follicle stimulating hormone receptor (Fshr) in Sertoli cells (SCs) of adult rats, while the mechanism underlying remains obscure. We tested the hypothesis "transient gestational exposure to CrVI during the critical embryonic windows of testicular differentiation and growth may have adverse impact on transcription factors controlling the expression of Ar and Fshr in SCs of the F1 progeny". CrVI (K2Cr2O7) was given through drinking water (50 ppm, 100 ppm and 200 ppm), to pregnant rats from gestational day 9-14 (testicular differentiation) and 15 to 21 (prenatal differentiation and proliferation of SC); male progenies were sacrificed on postnatal day 30 (Completion of postnatal SC maturation). A significant increase in free radicals and decrease in enzymatic and non-enzymatic antioxidants were observed in SCs of experimental rats. Real time PCR and western blot data showed decreased expression of Ar, Fshr, Inhibin B, Transferrin, Androgen binding protein, Claudin 11 and Occludin in SCs of experimental rats; concentrations of lactate, pyruvate and retinoic acid also decreased. Serum FSH, luteinizing hormone and estradiol increased, whereas testosterone and prolactin decreased in experimental rats. Western blot detection revealed decreased levels of transcription factors regulating Fshr viz., USF-1, USF-2, SF-1, c-fos, c-jun and GATA 1, and those of Ar viz., Sp-1, ARA54, SRC-1 and CBP in experimental rats, whereas the levels of cyclinD1 and p53, repressors of Ar increased. ChIP assay detected decreased USF-1 and USF-2 binding to Fshr promoter, and binding of Sp-1 to Ar promoter. We conclude that gestational exposure to CrVI affects SC structure and function in F1 progeny by inducing oxidative stress and diminishing the expression of Ar and Fshr through attenuation of their specific transcriptional regulators and their interaction with the respective promoter.


Assuntos
Cromo/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Androgênicos/metabolismo , Receptores do FSH/metabolismo , Células de Sertoli/metabolismo , Maturidade Sexual , Fatores de Transcrição/metabolismo , Animais , Antioxidantes/metabolismo , Disponibilidade Biológica , Feminino , Radicais Livres/metabolismo , Hormônios/sangue , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Ratos Wistar , Receptores Androgênicos/genética , Receptores do FSH/genética , Células de Sertoli/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo
7.
Psychopharmacology (Berl) ; 237(8): 2469-2483, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445054

RESUMO

RATIONALE: MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral effect ultimately relies on monoamine neurotransmission is of dispute. OBJECTIVE: The purpose of this study was to determine whether these psychopharmacological effects and underlying neural mechanisms vary according to sex and age. METHODS: Across four experiments, male and female preweanling and adolescent rats were pretreated with vehicle, the monoamine-depleting agent reserpine (1 or 5 mg/kg), the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), or both AMPT and PCPA. The locomotor activity of preweanling and adolescent rats was then measured after saline or MK801 (0.3 mg/kg) treatment. RESULTS: As expected, MK801 increased the locomotor activity of all age groups and both sexes, but the stimulatory effects were significantly less pronounced in male adolescent rats. Preweanling rats and adolescent female rats were more sensitive to the effects of DA and 5-HT synthesis inhibitors, as AMPT and PCPA caused only small reductions in the MK801-induced locomotor activity of male adolescent rats. Co-administration of AMPT+PCPA or high-dose reserpine (5 mg/kg) treatment substantially reduced MK801-induced locomotor activity in both age groups and across both sexes. CONCLUSIONS: These results, when combined with other recent studies, show that NMDA receptor open-channel blockers cause pronounced age-dependent behavioral effects that can vary according to sex. The neural changes underlying these sex and age differences appear to involve monoamine neurotransmission.


Assuntos
Maleato de Dizocilpina/farmacologia , Dopamina/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Locomoção/fisiologia , Serotonina/fisiologia , Maturidade Sexual/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Antagonistas de Dopamina/farmacologia , Feminino , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Fatores Sexuais , Maturidade Sexual/efeitos dos fármacos
8.
Adv Exp Med Biol ; 1242: 121-143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32406031

RESUMO

What is it about sexuality that makes it such a burning matter since the dawn of mankind? Much was lost of humankind heritage because of society's attitude toward sex and gender, but we've made progress. Medical knowledge progressed incredibly and so did social and cultural norms. In these days, on most places on the planet, there is acceptance. Still, gender issues take a center stage, often inflaming the social and political milieu everywhere. So how informed and prepared is the medical community to deal with these issues? Aside from medical treatments, gender dysphoric patients need mental health and social support throughout life. Do we have enough guidelines for treatments that have life-long effects? Do we actually know all of those effects? There are many issues to consider, like fertility preservation, puberty suppression with its adverse effects, and not in the least, the effects of the hormonal therapy on the target tissues.


Assuntos
Disforia de Gênero/tratamento farmacológico , Terapia de Reposição Hormonal , Transtornos Sexuais e da Identidade de Gênero/tratamento farmacológico , Identidade de Gênero , Humanos , Comportamento Sexual/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos
9.
Gene ; 740: 144535, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32156529

RESUMO

Many human epidemiology and animal model studies have reported that bisphenol A (BPA) exerts adverse effects on reproduction through different regulatory mechanisms and signaling pathways in adults. In recent years, the exposure risk has increased for the general population, and little is known about how BPA affects ovarian development in adolescent animals and humans. In the present study, we aimed to investigate the effects of BPA exposure on ovarian development and the transcriptome in adolescent mice. Four-week-old ICR female mice were randomly divided into two groups and orally administered BPA (200 ng/kg/day) by gavage for 4 weeks. The BPA and estrogen (E2) levels in sera from the two groups were subsequently determined by using enzyme-linked immunosorbent assays (ELISAs). An immunohistochemical study showed that several obvious ovarian structural and developmental abnormalities were observed in the treatment group with changes in the E2 receptor gene and protein expression levels. A total of 4266 differentially expressed genes (DEGs) were identified, and the possible functions of these DEGs were explored by bioinformatics analyses based on the RNA-Seq data. The two most significant expression profiles were identified by Short Time-series Expression Miner (STEM) software, and the genes in these two profiles were enriched in actin filament-based processes, behaviour and membrane potential regulation according to Gene Ontology (GO) enrichment analysis. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEGs are particularly involved in the endocrine system, the calcium and cAMP signaling pathways.


Assuntos
Compostos Benzidrílicos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Fenóis , Maturidade Sexual/efeitos dos fármacos , Animais , Compostos Benzidrílicos/sangue , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/toxicidade , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/sangue , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Imuno-Histoquímica , Camundongos , Ovário/ultraestrutura , Fenóis/sangue , Fenóis/metabolismo , Fenóis/toxicidade
10.
J Endocrinol ; 245(1): 21-37, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31977313

RESUMO

Follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) produced by the gonadotropes play a major role in control of reproduction. Contrary to mammals and birds, Lh and Fsh are mostly produced by two separate cell types in teleost. Here, we investigated gonadotrope plasticity, using transgenic lines of medaka (Oryzias latipes) where DsRed2 and hrGfpII are under the control of the fshb and lhb promotors respectively. We found that Fsh cells appear in the pituitary at 8 dpf, while Lh cells were previously shown to appear at 14 dpf. Similar to Lh cells, Fsh cells show hyperplasia from juvenile to adult stages. Hyperplasia is stimulated by estradiol. Both Fsh and Lh cells show hypertrophy during puberty with similar morphology. They also share similar behavior, using their cellular extensions to make networks. We observed bi-hormonal gonadotropes in juveniles and adults but not in larvae where only mono-hormonal cells are observed, suggesting the existence of phenotypic conversion between Fsh and Lh in later stages. This is demonstrated in cell culture, where some Fsh cells start to produce Lhß, a phenomenon enhanced by gonadotropin-releasing hormone (Gnrh) stimulation. We have previously shown that medaka Fsh cells lack Gnrh receptors, but here we show that with time in culture, some Fsh cells start responding to Gnrh, while fshb mRNA levels are significantly reduced, both suggestive of phenotypic change. All together, these results reveal high plasticity of gonadotropes due to both estradiol-sensitive proliferation and Gnrh promoted phenotypic conversion, and moreover, show that gonadotropes lose part of their identity when kept in cell culture.


Assuntos
Hormônio Foliculoestimulante/metabolismo , Gonadotrofos/metabolismo , Hormônio Luteinizante/metabolismo , Oryzias/metabolismo , Maturidade Sexual/fisiologia , Animais , Animais Geneticamente Modificados , Células Cultivadas , Estradiol/farmacologia , Estrogênios/farmacologia , Feminino , Hormônio Foliculoestimulante/genética , Expressão Gênica , Gonadotrofos/citologia , Gonadotrofos/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Luteinizante/genética , Masculino , Oryzias/genética , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/genética
11.
Res Vet Sci ; 129: 21-27, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31927177

RESUMO

Pediculosis is a parasitic disease that is considered a serious global public health problem. It is caused by the ectoparasite that is popularly known as lice, mainly affecting children in early childhood. The most commonly used treatment to combat this parasitosis is the macrocyclic lactone ivermectin (IVM). However, the use of IVM is contraindicated in children who are younger than 5 years old or who weigh <15 kg because some types of drugs that are used during certain periods of brain maturation can lead to behavioral disorders. The present study evaluated the effects of IVM treatment during the prepubertal and pubertal period on sexual behavior in adulthood in male rats. Genital grooming, preputial separation, sexual behavior, sexual motivation, relative organ weight, the gonadosomatic index, and histopathology were evaluated. Oral dose of 0.2 mg/kg (therapeutic dose) of a commercial IVM formulation was administered. IVM affected genital grooming but did not influence preputial separation in prepubertal rats. Prepubertal IVM administration did not impair sexual behavior in adult rats, with the exception of the time of residence with female rats in the sexual motivation test. It did not affect relative organ weights, with the exception of the relative weight of the full seminal vesicle. It did not alter the gonadosomatic index, and no histopathological alterations were observed in different organs. These results indicate that administration of a therapeutic dose of IVM during the prepubertal and pubertal period does not alter parameters of sexual development or sexual behavior in adult male rats.


Assuntos
Inseticidas/administração & dosagem , Ivermectina/administração & dosagem , Infestações por Piolhos/tratamento farmacológico , Tamanho do Órgão/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Animais , Asseio Animal/efeitos dos fármacos , Masculino , Motivação/efeitos dos fármacos , Ratos , Comportamento Sexual Animal/efeitos dos fármacos
12.
Environ Int ; 136: 105469, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31931345

RESUMO

Phthalates are endocrine disrupting compounds commonly found in consumer products, exposure to which may influence reproductive maturation. Effects from exposure in utero on the onset and progression of sexual development are understudied. We examined longitudinal associations between gestational phthalate exposure and sexual maturation at two points in adolescence (8-14, 9-18 years). Gestational exposure was quantified using the geometric mean of 3 trimester-specific urinary phthalate metabolite measurements. Sexual maturation was assessed using Tanner stages and menarche onset for girls and Tanner stages and testicular volume for boys. Generalized estimating equations for correlated ordinal multinomial responses were used to model relationships between phthalates and odds of transitioning to the next Tanner stage, while generalized additive (GA) mixed models were used to assess the odds of menarche. All models were adjusted for child age (centered around the mean), BMI z-score, change in BMI between visits, time (years) between visits (ΔT), and interactions between ΔT and mean-centered child age and the natural log of exposure metabolite concentration. Among girls, a doubling of gestational MBzP concentrations was associated with increased odds of being at a higher Tanner stage for breast development at 8-14 years (OR = 4.62; 95% CI: 1.38, 15.5), but with slower progression of breast development over the follow-up period (OR = 0.65 per year; 95% CI: 0.46, 0.92) after adjustment for child age and BMI z-score. Similar results were found for ∑DEHP levels and breast development. In boys, a doubling of gestational MBP concentrations was associated with lower odds of being at a higher Tanner stage for pubic hair growth at 8-14 years (OR = 0.37; 95% CI: 0.14, 0.95) but with faster progression (OR: 1.28; 95% CI: 0.97, 1.69). These results indicate that gestational phthalate exposures may impact the onset and progression of sexual development, and that these relationships differ between boys and girls.


Assuntos
Ácidos Ftálicos , Maturidade Sexual , Adolescente , Criança , Cidades , Feminino , Humanos , Masculino , México , Fenóis , Ácidos Ftálicos/toxicidade , Maturidade Sexual/efeitos dos fármacos
13.
J Pediatr Endocrinol Metab ; 33(1): 107-112, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31834861

RESUMO

Background Sex hormones initiate profound physical and physiological changes during the pubertal process, but to what extent are they responsible for continuing the body composition changes of late adolescence and what happens to body composition on sudden sex hormone withdrawal? Methods Thirty-six healthy, phenotypically and chromosomally normal late and post-pubertal individuals aged 15-17 years with gender dysphoria (transgirls - birth-registered males identifying as female n = 11; and transboys - birth-registered females identifying as male n = 25) underwent Tanita body composition analysis at 0, 6 and 12 months during reproductive hormone suppression with Triptorelin as part of the standard therapeutic protocol. Results and conclusions In the transgirl cohort, paired t-test analysis demonstrated a significant decrease in height and lean mass standard deviation scores over the 12-month period, going against an expected trajectory over that time. In contrast, oestrogen suppression appeared not to affect the body composition of transboys; their measurements were not significantly different at baseline and after 12 months of treatment. The withdrawal of sex hormone secretion does not appear to have a significant impact on female post-pubertal body composition, in contrast to that seen at the menopause. This suggests that other factors may preserve normal body balance in adolescents in the absence of sex steroids.


Assuntos
Composição Corporal , Disforia de Gênero/tratamento farmacológico , Disforia de Gênero/fisiopatologia , Hormônios Esteroides Gonadais/administração & dosagem , Hormônio Liberador de Gonadotropina/agonistas , Maturidade Sexual/efeitos dos fármacos , Suspensão de Tratamento/estatística & dados numéricos , Adolescente , Índice de Massa Corporal , Feminino , Humanos , Masculino
14.
Horm Behav ; 119: 104650, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31805280

RESUMO

Male Syrian hamsters (Mesocricetus auratus) administered anabolic/androgenic steroids during adolescent development display increased aggression and decreased anxious behavior during the adolescent exposure period. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts and hamsters exhibit decreased aggression and increased anxious behavior. This study investigated the hypothesis that alterations in anterior hypothalamic signaling through serotonin type-3 receptors modulate the behavioral shift between adolescent anabolic/androgenic steroid-induced aggressive and anxious behaviors during the withdrawal period. To test this, hamsters were administered anabolic/androgenic steroids during adolescence then withdrawn from drug exposure for 21 days and tested for aggressive and anxious behaviors following direct pharmacological manipulation of serotonin type-3 receptor signaling within the latero-anterior hypothalamus. Blockade of latero-anterior hypothalamic serotonin type-3 receptors both increased aggression and decreased anxious behavior in steroid-treated hamsters, effectively reversing the pattern of behavioral responding normally observed during anabolic/androgenic steroid withdrawal. These findings suggest that the state of serotonin neural signaling within the latero-anterior hypothalamus plays an important role in behavioral shifting between aggressive and anxious behaviors following adolescent exposure to anabolic/androgenic steroids.


Assuntos
Agressão/efeitos dos fármacos , Anabolizantes/farmacologia , Ansiedade , Receptores 5-HT3 de Serotonina/fisiologia , Síndrome de Abstinência a Substâncias/psicologia , Androgênios/farmacologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Ansiedade/patologia , Comportamento Animal/efeitos dos fármacos , Cricetinae , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Masculino , Mesocricetus , Receptores 5-HT3 de Serotonina/metabolismo , Serotonina/farmacologia , Maturidade Sexual/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Congêneres da Testosterona/farmacologia
15.
Anim Reprod Sci ; 212: 106252, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31864499

RESUMO

The current study was designed to gain insights into regulatory mechanisms mediating long-term effects of androgen excess or deficiency on corpus luteum function in pigs. Piglets were injected subcutaneously with testosterone propionate (TP, an androgen), flutamide (FLU, an anti-androgen) or corn oil (control) between postnatal Days 1 and 10. Corpora lutea from sexually mature gilts were examined for luteal steroid concentrations and processed for total RNA isolation and subsequent RNA sequencing to determine abundances of mRNA transcripts and microRNAs (miRNAs). Potential miRNA-mRNA interactions were explored in silico. Androstenedione, testosterone and estrone concentrations in corpora lutea were altered due to the disrupted androgen action in neonates. The luteal tissue had 465 and 353 genes for which there were differential mRNA abundances as compared with the control group (P-adjusted < 0.05; log2FC ≥ 1.0) in response to neonatal TP and FLU piglet treatments, respectively. Disruption of androgen signalling in neonates affected mRNA transcript abundance, as compared with the control group, for genes associated with apoptosis, angiogenesis and immune functions in the corpora lutea. Furthermore, there was a differential abundance of a group of miRNAs in the treatment groups compared with the control group. These results indicate the neonatal androgenic milieu affects the onset of luteolysis when these animals are sexually mature, although mechanisms for responses to TP or FLU likely differ. It is proposed that changes in specific miRNAs and mRNAs may, in part, account for long-term effects of androgen excess or androgen deficiency on corpus luteum function in pigs.


Assuntos
Corpo Lúteo/fisiologia , Flutamida/farmacologia , Maturidade Sexual/efeitos dos fármacos , Suínos/fisiologia , Propionato de Testosterona/farmacologia , Transcriptoma/fisiologia , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/farmacologia , Androgênios/administração & dosagem , Androgênios/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
16.
Ecotoxicol Environ Saf ; 188: 109898, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31711775

RESUMO

Gamma-aminobutyric acid (GABA) plays a critical role in regulation of gonadotropin-releasing hormone (GnRH) through GABAA receptor (GABAAR). Nitric oxide (NO) production has correlation with GABA and regulates GnRH secretion. This study was performed to examine the mechanisms by which manganese (Mn) accelerate puberty onset involves GABAAR/NO pathway in the preoptic area-anterior hypothalamus (POA-AH) in immature female rats. First, female rats received daily dose of MnCl2 0 (saline), 2.5, 5 and 10 mg/kg b.w by oral gavage during postnatal day (PND) 21-32. Animals administered with 10 mg/kg MnCl2 exhibited earlier puberty onset age and advanced ovary and uterus development than these in saline-treatment group. Furthermore, we found that decrease of GABAAR result in elevated production of nitric oxide synthase1 (NOS1), NO and GnRH in the POA-AH. Second, we recorded the neuronal spikes alternation after perfusion with GABAAR inhibitor bicuculline (BIC), GABAAR agonist isoguvacine (isog), and MnCl2 from the POA-AH in acute brain slices of PND21 rats. Spontaneous firing revealed a powerful GABAAR-mediated action on immature POA-AH and confirm that MnCl2 has a significant effect on GABAAR. Third, we revealed that decrease in NOS1 and NO production by treatment with isog-alone or isog+MnCl2 contribute to the decrease of GnRH in the POA-AH and a delayed puberty onset age compared to treatment with MnCl2-alone. Together, these results suggested that excessive exposure to MnCl2 stimulates NO production through decreased GABAAR in the POA-AH to advance puberty onset in immature female rats.


Assuntos
Envelhecimento/efeitos dos fármacos , Cloretos/toxicidade , Disruptores Endócrinos/toxicidade , Óxido Nítrico/metabolismo , Área Pré-Óptica/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Maturidade Sexual/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Compostos de Manganês , Neurônios/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Área Pré-Óptica/crescimento & desenvolvimento , Área Pré-Óptica/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Útero/diagnóstico por imagem , Útero/efeitos dos fármacos , Desmame
17.
Theriogenology ; 143: 82-87, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31862671

RESUMO

Well-nourished spring-born female goats reach puberty in the autumn of the same year. Contrastingly, undernourished spring-born females reach puberty in the autumn of the following year. Therefore, in this study, we reared female goats (undernourished) under semi-extensive management and determined whether the introduction of photostimulated, sexually active males, advances puberty in these females, and whether nutritional supplementation increases the proportion of kidding females. Goats were born on March 30 and weaned at 2 months of age. Then, they grazed natural vegetation from 10:00 to 18:00 each day. Starting in December, two groups did not receive feed supplementation after grazing, whereas two other groups received 600 g daily supplements of a commercial concentrate. In April, one non-supplemented (n = 10) and other supplemented groups (n = 11) were moved indoors and kept in separate pens, where they were joined with sexually active bucks (n = 1 per group). Males were rotated daily between groups for 7 days. Other non-supplemented (n = 8) and supplemented groups (n = 11) were not joined with males. Most of the female goats under study reached puberty (70-100%). However, in supplemented and non-supplemented groups joined with males, puberty commenced much earlier (April) than in those non-exposed to males (September) (P < 0.001). The proportion of pregnant goats did not differ between groups joined with males (P > 0.05), but the proportion of goats that kidded was higher in supplemented (7/11) than in non-supplemented goats (2/10) (P < 0.05). In conclusion, in spring-born goats, the male effect using sexually active males advanced puberty, and nutritional supplementation increased the proportion of kidding goats in females reared under semi-extensive management.


Assuntos
Ração Animal/análise , Dieta/veterinária , Cabras/fisiologia , Maturidade Sexual/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Feminino , Masculino , Fotoperíodo , Estações do Ano
18.
J Pediatr Endocrinol Metab ; 33(1): 113-120, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31809263

RESUMO

Background Some studies have examined the effect of gonadal suppression on insulin-like growth factor-1 (IGF-1) levels and the growth velocity (GV) with conflicting results. Methods Forty-four girls treated with gonadotropin-releasing hormone analogue (GnRHa) for central precocious puberty (CPP) were included in the study. IGF-1 levels were examined at the beginning and after 12 months of treatment. Results IGF-1 and IGF-1 standard deviation score (SDS) according to chronological age (CA-IGF-1 SDS) at diagnosis were positively correlated with chronological age (CA), anthropometric measurements, stage of puberty, bone age (BA), BA-CA, follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, uterus length, endometrium thickness and ovarian volume (OV) at diagnosis (p < 0.05). There was no significant difference in IGF-1 levels after treatment. However, there was a negative correlation between ΔIGF-1 SDS and IGF-1 level, CA-IGF-1 SDS and BA-IGF-1 SDS at diagnosis (p < 0.05). There was no correlation between GV and IGF-1, ΔIGF-1. GV was negatively correlated with basal LH level at diagnosis (p = 0.008, r = -0.397). Peak LH levels of the patients who had GV-SDS < 0 were more suppressive than those of the patients who had GV-SDS > 0 after 12 months of treatment. Conclusions It was determined that the IGF-1 level and CA-IGF-1 SDS at baseline were correlated with more advanced pubertal stage prior to treatment. Initiation of treatment with a relatively high level of IGF-1 increased the risk of a decrease in the IGF-1 level. Likewise, the initiation of treatment with a relatively high LH level may increase the risk of low GV, but low GV was not related to the IGF-1 level. Increased sex steroid suppression may increase the risk of low GV.


Assuntos
Estatura/efeitos dos fármacos , Índice de Massa Corporal , Hormônio Liberador de Gonadotropina/agonistas , Crescimento/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/análise , Puberdade Precoce/tratamento farmacológico , Maturidade Sexual/efeitos dos fármacos , Criança , Feminino , Humanos , Prognóstico , Estudos Prospectivos , Puberdade Precoce/sangue
19.
Protein Expr Purif ; 166: 105510, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31628987

RESUMO

GnRH is a neuropeptide known to regulate reproduction in vertebrates. The purpose of this study was to design and produce recombinant gonadotropin-releasing hormone associated peptide (rGnRH/GAP) as an alternative of the previous GnRHs and native extracted hormone from tissue, to induce final maturation in fish. Decapeptide as well as GAP area sequences were compared between GnRH1, GnRH2, and mGnRH from Acipenser sp and Huso huso, respectively. Considering the conserved amino acids and the replacement of un-stable amino acids with those that were more stable against proteolytic digestion as well as had a longer half-life, the sequence was designed. The sequences of decapeptide and GAP region were synthesized and then cloned on pET28a expression vector and transformed into expression host Escherichia coli BL21(DE3). The supernatant of cultured recombinant bacteria was used for purification using TALON Metal affinity resin. The purity of the GnRH/GAP was confirmed by single 8 kDa band on SDS-PAGE and Western blot. Bioinformatics studies were performed for evaluation of homology between GnRH protein sequences and prediction of 3D protein structure using Swiss Model. The result showed that the structure prediction of the recombinant GnRH decapeptide was relatively similar to decapeptide of GnRH2 from Beluga (Huso huso). The GAP structure was similar to GAP1 of Nile tilapia (Oreochromis niloticus) and sturgeon and GnRH2 of Chinese sturgeon (Acipenser sinensis). The mass analysis showed that the sequence was exactly the same as designated sequence. Biology activity of rGnRH/GAP was tested in mature goldfish (Carassius auratus) and results showed that rGnRH/GAP had a positive effect in final maturation. Indeed 17α, 20ß-dihydroxy-4-pregnen-3-one (DHP) was increased 17 h and 24 h after injection with rGnRH/GAP and spawning stemmed from that injection. These novel findings introduce the potential of utilizing rGnRH/GAP in aquaculture.


Assuntos
Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/genética , Oligopeptídeos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Sequência de Aminoácidos , Animais , Cromatografia de Afinidade , Clonagem Molecular , Escherichia coli/genética , Peixes , Vetores Genéticos , Estabilidade Proteica , Maturidade Sexual/efeitos dos fármacos
20.
Environ Pollut ; 256: 112957, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672375

RESUMO

Parabens are class of preservatives used in vast majority of commercial products, and a potential Endocrine Disrupting Chemical (EDC). The present study was undertaken to delineate the effects of n-butylparaben on F1 male progeny exposed maternally through gestation and lactation via subcutaneous route. The F0 dams were given subcutaneous injections of n-butylparaben from gestation day (GD) 6 to postnatal day (PND) 21 with doses of 10, 100, 1000 mg/kg Bw/day in corn oil. The F1 male rats were monitored for pubertal development and sexual maturation; these were sacrificed on PND 30, 45 and 75. On PND 75, these F1 male rats were subjected for fertility assessment with unexposed female rats. A delayed testicular descent at 100 and 1000 mg/kg Bw dose and delayed preputial separation at 10 mg/kg Bw dose was observed in exposed F1 male rats. Decreased sperm count, motility and Daily Sperm Production was observed at 100 mg/kg Bw dose at PND 75. Interestingly, the sperm transit time in the epididymis was accelerated at this dose. Significant perturbed testicular expression of steroid receptors (ERα and ß, AR), INSL3 and StAR genes with increased T and LH levels indicates direct effect on spermatogenesis and steroidogenesis. These F1 generation adult rats were sub-fertile with increased (%) pre- and post-implantation loss at 100 and 1000 mg/kg Bw/day dose. This is the first report on n-butylparaben highlighting the involvement of testicular leydig cells with accelerated sperm transit time leading to reduced fertility in the maternally exposed F1 male rats through estrogenic/anti-androgenic action.


Assuntos
Disruptores Endócrinos/toxicidade , Fertilidade/efeitos dos fármacos , Parabenos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores de Esteroides/metabolismo , Espermatogênese/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Lactação , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Receptores de Esteroides/genética , Maturidade Sexual/efeitos dos fármacos , Contagem de Espermatozoides , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/embriologia , Testículo/crescimento & desenvolvimento
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