RESUMEN
Oxidative stress and inflammation are significant causes of aging. At the same time, citrus flavanones, naringenin (NAR), and hesperetin (HES) are bioactives with proven antioxidant and anti-inflammatory properties. Nevertheless, there are still no data about flavanone's influence and its potential effects on the healthy aging process and improving pituitary functioning. Thus, using qPCR, immunoblot, histological techniques, and biochemical assays, our study aimed to elucidate how citrus flavanones (15 mg/kg b.m. per os) affect antioxidant defense, inflammation, and stress hormone output in the old rat model. Our results showed that HES restores the redox environment in the pituitary by down-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein while increasing kelch-like ECH-associated protein 1 (Keap1), thioredoxin reductase (TrxR1), and superoxide dismutase 2 (SOD2) protein expression. Immunofluorescent analysis confirmed Nrf2 and Keap1 down- and up-regulation, respectively. Supplementation with NAR increased Keap1, Trxr1, glutathione peroxidase (Gpx), and glutathione reductase (Gr) mRNA expression. Decreased oxidative stress aligned with NLRP3 decrement after both flavanones and glycogen synthase kinase-3 (GSK3) only after HES. The signal intensity of adrenocorticotropic hormone (ACTH) cells did not change, while corticosterone levels in serum decreased after both flavanones. HES showed higher potential than NAR in affecting a redox environment without increasing the inflammatory response, while a decrease in corticosterone level has a solid link to longevity. Our findings suggest that HES could improve and facilitate redox and inflammatory dysregulation in the rat's old pituitary.
Asunto(s)
Citrus , Flavanonas , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Hipófisis , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratas , Flavanonas/farmacología , Hipófisis/metabolismo , Hipófisis/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Citrus/química , Masculino , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Hormona Adrenocorticotrópica/metabolismo , Hormona Adrenocorticotrópica/sangre , Envejecimiento/metabolismo , Envejecimiento/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ratas Wistar , Hesperidina/farmacologíaRESUMEN
The age-related alterations in pituitary function, including changes in prolactin (PRL) production contributes to the systemic susceptibility to age-related diseases. Our previous research has shown the involvement of Nrg1 in regulating the expression and secretion of PRL. However, the precise role of Nrg1 in mitigating the senescence of pituitary lactotrophs and the underlying mechanisms are yet to be comprehended. Here, data from the GEPIA database was used to evaluate the association between transient receptor potential cation channel subfamily M member 8 (TRPM8) and PRL in normal human pituitary tissues, followed by immunofluorescence verification using a human pituitary tissue microarray. TRPM8 levels showed a significant positive association with PRL expression in normal human pituitary tissues, and both TRPM8 and PRL levels declined during aging, suggesting that TRPM8 may regulate pituitary aging by affecting PRL production. It was also found that treatment with exogenous neuregulin 1 (Nrg1) markedly delayed the senescence of GH3 cells (rat lactotroph cell line) generated by D-galactose (D-gal). In addition, melatonin reduced the levels of senescence-related markers in senescent pituitary cells by promoting Nrg1 / ErbB4 signaling, stimulating PRL expression and secretion. Further investigation showed that Nrg1 attenuated senescence in pituitary cells by increasing TRPM8 expression. Downregulation of TRPM8 activation eliminated Nrg1-mediated amelioration of pituitary cell senescence. These findings demonstrate the critical function of Nrg1 / ErbB signaling in delaying pituitary lactotroph cell senescence and enhancing PRL production via promoting TRPM8 expression under the modulation of melatonin.
Asunto(s)
Senescencia Celular , Lactotrofos , Melatonina , Neurregulina-1 , Prolactina , Transducción de Señal , Canales Catiónicos TRPM , Prolactina/metabolismo , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/genética , Humanos , Senescencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Lactotrofos/metabolismo , Lactotrofos/efectos de los fármacos , Melatonina/farmacología , Animales , Ratas , Neurregulina-1/metabolismo , Neurregulina-1/genética , Hipófisis/metabolismo , Hipófisis/efectos de los fármacos , Envejecimiento/metabolismo , Receptor ErbB-4/metabolismo , Receptor ErbB-4/genética , Línea Celular , Masculino , FemeninoRESUMEN
Betamethasone has been extensively used in medicine in recent years and poses potential hazards to aquatic organisms. This study investigated the reproductive toxic effects of betamethasone exposure in fish, employing female Japanese medaka (Oryzias latipes) as a model. Betamethasone exposure at environmentally relevant concentrations (0, 20, 200, and 2000â¯ng/L) for a period of 15 weeks resulted in its high accumulation in the ovary, leading to abnormal oogenesis in female Japanese medaka. The production of gonadotropins (LH and FSH) in the pituitary gland was inhibited, and sex steroid biosynthesis in the ovary was significantly influenced at the transcriptional level. The imbalance of androgens and estrogens resulted in a decrease in the E2/T ratio and hepatic VTG synthesis, and the suppression of estrogen receptor signaling was also induced. Furthermore, betamethasone exposure delayed spawning and reduced fertility in the F0 generation, and had detrimental effects on the fertilization rate and hatchability of the F1 generation. Our results showed that environmental betamethasone had the potential to adversely affect female fertility and steroid hormone dynamics in fish.
Asunto(s)
Betametasona , Oryzias , Ovario , Reproducción , Contaminantes Químicos del Agua , Animales , Oryzias/fisiología , Femenino , Betametasona/toxicidad , Contaminantes Químicos del Agua/toxicidad , Reproducción/efectos de los fármacos , Ovario/efectos de los fármacos , Hipófisis/efectos de los fármacos , Fertilidad/efectos de los fármacos , Oogénesis/efectos de los fármacos , Exposición a Riesgos Ambientales , Hormonas Esteroides GonadalesRESUMEN
This study aimed to explore the regulating effect of Gegen Decoction(GGD) on the hypothalamic-pituitary-ovarian axis(HPOA) dysfunction in the mouse model of primary dysmenorrhea(PD). The mouse model of PD with periodic characteristics was established by administration of estradiol benzoate and oxytocin. Mice were randomized into control, model, GGD, and ibuprofen groups. The writhing response, hypothalamus index, pituitary index, ovary index, and uterus index were observed and determined. The serum levels of prostaglandin F_(2α)(PGF_(2α)), gonadotropin-releasing hormone(GnRH), follicle-stimulating hormone(FSH), luteinizing hormone(LH), and estrogen(E_2) levels were measured by ELISA kits. Western blot and qPCR were employed to determine the protein and mRNA levels, respectively, of gonadotropin-releasing hormone receptor(GnRH-R) in the pituitary tissue, follicle-stimulating hormone receptor(FSHR) and luteinizing hormone receptor(LHR) in the ovarian tissue, and estrogen receptor(ER) in the uterine tissue. The results showed that the writhing response, serum levels of PGF_(2α), GnRH, FSH, LH, and E_2, ovarian and uterine indexes, the protein and mRNA levels of GnRH-R in the pituitary tissue, FSHR and LHR in the ovarian tissue, and ER in the uterine tissue were significantly increased in the model group compared with those in the control group. GGD inhibited the writhing response, reduced the serum levels of PGF_(2α), GnRH, FSH, LH, and E_2, decreased the ovarian and uterine indexes, and down-regulated the protein and mRNA levels of GnRH-R in the pituitary tissue, FSHR and LHR in the ovarian tissue, and ER in the uterine tissue. The data suggested that GGD can regulate the HPOA and inhibit E_2 generation in the mice experiencing recurrent PD by down-regulating the expression of proteins and genes related to HPOA axis, thus exerting the therapeutic effect on PD.
Asunto(s)
Medicamentos Herbarios Chinos , Dismenorrea , Ovario , Animales , Femenino , Ratones , Ovario/efectos de los fármacos , Ovario/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Dismenorrea/tratamiento farmacológico , Dismenorrea/metabolismo , Dismenorrea/genética , Dismenorrea/fisiopatología , Hormona Luteinizante/sangre , Hormona Folículo Estimulante/sangre , Hipófisis/metabolismo , Hipófisis/efectos de los fármacos , Humanos , Receptores de HFE/genética , Receptores de HFE/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Liberadora de Gonadotropina/genética , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Receptores LHRH/genética , Receptores LHRH/metabolismo , Receptores de HL/genética , Receptores de HL/metabolismoRESUMEN
Exposure to specific pesticides has been demonstrated to alter normal thyroid function of aquatic vertebrates. This study aimed to investigate the impact of penthiopyrad (PO) on the thyroid function of zebrafish, further elucidating its toxic mechanisms on the early developmental stages of zebrafish. Exposure to sublethal doses of PO (0.3-1.2 mg/L) for 8 days from 2 h after fertilization resulted in a significant reduction in larval swim bladder size and body weight, accompanied by developmental abnormalities such as pigment deposition and abnormal abdominal development. Perturbations in the hypothalamic-pituitary-thyroid (HPT) axis in larvae manifested as a marked upregulation of crh, tg, ttr, and ugt1ab expression, alongside downregulation of trß expression, culminating in elevated thyroxine (T4) and triiodothyronine (T3) levels. Additionally, molecular docking results suggest that PO and its metabolites may disrupt the binding of thyroid hormones to thyroid hormone receptor beta (TRß), compromising the normal physiological function of TRß. These findings highlight the PO-induced adverse effects on the HPT axis of larvae under sublethal doses, eventually leading to abnormal development and growth inhibition.
Asunto(s)
Glándula Tiroides , Pez Cebra , Animales , Pez Cebra/metabolismo , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Larva/efectos de los fármacos , Larva/metabolismo , Tiroxina/metabolismo , Triyodotironina/metabolismo , Simulación del Acoplamiento Molecular , Hormonas Tiroideas/metabolismo , Hipófisis/metabolismo , Hipófisis/efectos de los fármacos , Receptores beta de Hormona Tiroidea/metabolismo , Receptores beta de Hormona Tiroidea/genéticaRESUMEN
BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.
Asunto(s)
Acetazolamida , Disruptores Endocrinos , Estro , Ratas Sprague-Dawley , Topiramato , Animales , Femenino , Topiramato/farmacología , Acetazolamida/farmacología , Acetazolamida/toxicidad , Disruptores Endocrinos/toxicidad , Ratas , Estro/efectos de los fármacos , Hormona Luteinizante/sangre , Fructosa/toxicidad , Fructosa/análogos & derivados , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Progesterona/sangre , Hormona Folículo Estimulante/sangre , Hormonas Esteroides Gonadales/sangre , Estradiol/sangre , Ovario/efectos de los fármacos , Ovario/metabolismoRESUMEN
Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 µg), kisspeptin + astressin 2B (1 µg), and kisspeptin + atosiban (300 ng/rat) (n = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.
Asunto(s)
Sistema Hipotálamo-Hipofisario , Kisspeptinas , Sistema Hipófiso-Suprarrenal , Ratas Wistar , Animales , Masculino , Kisspeptinas/administración & dosificación , Kisspeptinas/farmacología , Kisspeptinas/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Fragmentos de Péptidos/administración & dosificación , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Corticosterona/sangre , Vasotocina/farmacología , Vasotocina/administración & dosificación , Testosterona/sangre , Inyecciones Intraventriculares , Gónadas/metabolismo , Gónadas/efectos de los fármacos , Hipófisis/metabolismo , Hipófisis/efectos de los fármacos , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Adrenocorticotrópica/sangre , Hormona Liberadora de Corticotropina , OligopéptidosRESUMEN
Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2â¯mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.
Asunto(s)
Hormona Adrenocorticotrópica , Glucagón , Glicopéptidos , Humanos , Glicopéptidos/metabolismo , Glucagón/metabolismo , Glucagón/sangre , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Masculino , Adulto , Femenino , Hipófisis/metabolismo , Hipófisis/efectos de los fármacos , Hidrocortisona/sangre , Receptores de Glucagón/metabolismo , Hormona de Crecimiento Humana/metabolismo , Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/sangre , Persona de Mediana EdadRESUMEN
Although measurements of blood triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels in rodent toxicity studies are useful for detection of antithyroid substances, assays for these measurements are expensive and can show high variability depending on blood sampling conditions. To develop more efficient methods for detecting thyroid disruptors, we compared histopathological and immunohistochemical findings in the thyroid and pituitary glands with blood hormone levels. Six-week-old male and female Sprague-Dawley rats (five rats per group) were treated with multiple doses of the thyroid peroxidase inhibitors propylthiouracil (PTU) and methimazole by gavage for 28 days. Significant decreases in serum T3 and T4 and increases in TSH were observed in the ≥1 mg/kg PTU and ≥3 mg/kg methimazole groups. An increase in TSH was also detected in male rats in the 0.3 mg/kg PTU group. Histopathological and immunohistochemical analyses revealed that follicular cell hypertrophy and decreased T4 and T3 expressions in the thyroid gland were induced at doses lower than doses at which significant changes in serum hormone levels were observed, suggesting that these findings may be more sensitive than blood hormone levels. Significant increases in thyroid weights, Ki67-positive thyroid follicular cell counts, and TSH-positive areas in the pituitary gland were detected at doses comparable with those at which changes in serum T4 and TSH levels were observed, indicating that these parameters may also be useful for evaluation of antithyroid effects. Combining these parameters may be effective for detecting antithyroid substances without relying on hormone measurements.
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Antitiroideos , Inmunohistoquímica , Metimazol , Hipófisis , Propiltiouracilo , Ratas Sprague-Dawley , Glándula Tiroides , Tirotropina , Tiroxina , Animales , Masculino , Antitiroideos/toxicidad , Femenino , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/patología , Propiltiouracilo/toxicidad , Ratas , Metimazol/toxicidad , Tirotropina/sangre , Tiroxina/sangre , Hipófisis/efectos de los fármacos , Hipófisis/patología , Yoduro Peroxidasa/antagonistas & inhibidores , Triyodotironina/sangre , Hormonas Tiroideas/sangre , Relación Dosis-Respuesta a DrogaAsunto(s)
Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Privación de Tratamiento , Hipófisis/cirugía , Hipófisis/efectos de los fármacosAsunto(s)
Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Hipófisis/cirugía , Hipófisis/efectos de los fármacosRESUMEN
Introduction: Intracellular communication is essential for the maintenance of the anterior pituitary gland plasticity. The aim of this study was to evaluate whether GPCR-Gαi modulates basic fibroblast growth factor (FGF2)-induced proliferative activity in normal pituitary cell populations. Methods: Anterior pituitary primary cell cultures from Wistar female rats were treated with FGF2 (10ng/mL) or somatostatin analog (SSTa, 100nM) alone or co-incubated with or without the inhibitors of GPCR-Gαi, pertussis toxin (PTX, 500nM), MEK inhibitor (U0126, 100µM) or PI3K inhibitor (LY 294002, 10 µM). Results: FGF2 increased and SSTa decreased the lactotroph and somatotroph BrdU uptak2e (p<0.05) whereas the FGF2-induced S-phase entry was prevented by SSTa co-incubation in both cell types, with these effects being reverted by PTX, U0126 or LY294002 pre-incubation. The inhibition of lactotroph and somatotroph mitosis was associated with a downregulation of c-Jun expression, a decrease of phosphorylated (p) ERK and pAKT. Furthermore, SSTa was observed to inhibit the S-phase entry induced by FGF2, resulting in a further increase in the number of cells in the G1 phase and a concomitant reduction in the number of cells in the S phases (p< 0.05), effects related to a decrease of cyclin D1 expression and an increase in the expression of the cell cycle inhibitors p27 and p21. Discussion: In summary, the GPCR-Gαi activated by SSTa blocked the pro-proliferative effect of FGF2 in normal pituitary cells via a MEK-dependent mechanism, which acts as a mediator of both anti and pro-mitogenic signals, that may regulate the principal effectors of the G1 to S-phase transition.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos , Hipófisis , Animales , Femenino , Ratas , Proliferación Celular , Factor 2 de Crecimiento de Fibroblastos/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas Wistar , Hipófisis/citología , Hipófisis/efectos de los fármacosRESUMEN
Anti-vascular endothelial growth factor (VEGF) therapy has been developed for the treatment of a variety of cancers. Although this therapy may be a promising alternative treatment for refractory pituitary adenomas and pituitary carcinomas, the effects of anti-VEGF agents on the pituitary gland are not yet well understood. Here, we found that mice administered with OSI-930, an inhibitor of receptor tyrosine kinases including VEGF receptor 1 and 2, frequently exhibited hemorrhage in the pituitary gland. This is the first report that anti-VEGF therapy can cause pituitary apoplexy. C57BL/6 mice were daily injected intraperitoneally with 100 mg/kg body weight of OSI-930 for one to six days. Pituitary glands were immunohistochemically examined. Four of six mice treated for three days and all of five mice treated for six days exhibited hemorrhage in the pituitary gland. In all cases, the hemorrhage occurred just around Rathke's cleft. In OSI-930-administered mice, the vascular coverage and branching were reduced in the anterior lobe, and capillary networks were also decreased in the intermediate lobe in a treatment-day dependent manner. Few blood vessels around Rathke's cleft of the intermediate lobe express VE-cadherin and are covered with platelet-derived growth factor receptor-ß (PDGFR-ß)-positive cells, which suggests that capillaries around Rathke's cleft of the intermediate lobe were VE-cadherin-negative and not covered with pericytes. The reduction of capillary plexus around Rathke's cleft was observed at the site where hemorrhage occurred, suggesting a causal relationship with the pathogenesis of pituitary hemorrhage. Our study demonstrates that anti-VEGF agents have a risk of pituitary apoplexy. Pituitary apoplexy should be kept in mind as an adverse effect of anti-VEGF therapy.
Asunto(s)
Apoplejia Hipofisaria , Receptores de Factores de Crecimiento Endotelial Vascular , Animales , Ratones , Hemorragia Cerebral/complicaciones , Ratones Endogámicos C57BL , Apoplejia Hipofisaria/inducido químicamente , Apoplejia Hipofisaria/genética , Hipófisis/efectos de los fármacos , Hipófisis/patología , Neoplasias Hipofisarias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/efectos de los fármacosRESUMEN
Introduction: DEHP is an endocrine disruptor widely used in the production of malleable plastics. DEHP exposure was associated with altered hypothalamic-pituitary-thyroid (HPT) axis function. Although previous studies reported deleterious effects of DEHP exposure during the intrauterine period, few studies have evaluated the direct effects triggered by this endocrine disruptor on the offspring animals' thyroid function. This study aimed to investigate the impact of intrauterine exposure to DEHP on the HPT axis function programming of the offspring animals during adulthood. Methods: Pregnant Wistar rats were orally treated with corn oil or corn oil supplemented with DEHP (0.48 or 4.8 mg/kg/day) throughout the gestational period. The offspring rats were euthanized on the 90th postnatal day. Hypothalamus, pituitary, thyroid, and liver were collected to analyze gene expression and protein content through qPCR and Western Blot. Blood was collected to determine TSH and thyroid hormone levels through fluorometric or chemiluminescence immunoassays. Results: In the adult F1 female rats, the highest dose of DEHP decreased TSH serum levels. In the thyroid, DEHP reduced the gene expression and/or protein content of NIS, TSHR, TG, TPO, MCT8, NKX2.1, PAX8, and FOXE1. These data are consistent with the reduction in T4 serum levels of the F1 DEHP-exposed female rats. In the liver, DEHP exposure increased the mRNA expression of Dio1 and Ttr, while the highest dose of DEHP reduced the mRNA expression of Ugt1a1 and Ugt1a6. Conversely, in the F1 male adult rats, TSHB expression and TSH serum levels were increased in DEHP-exposed animals. In the thyroid, except for the reduced protein content of TSHR, none of the evaluated genes/proteins were altered by DEHP. TH serum levels were not changed in the DEHP-exposed F1 male rats compared to the control group. Additionally, there were no significant alterations in the expression of hepatic enzymes in these animals. Discussion/Conclusions: Our results demonstrated, for the first time, that intrauterine exposure to DEHP disrupts the HPT axis function in male and female offspring rats and strongly suggest that DEHP exposure increases the susceptibility of the offspring animals to develop thyroid dysfunctions during adulthood.
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Dietilhexil Ftalato , Disruptores Endocrinos , Hipotálamo , Hipófisis , Efectos Tardíos de la Exposición Prenatal , Glándula Tiroides , Animales , Femenino , Masculino , Embarazo , Ratas , Aceite de Maíz , Dietilhexil Ftalato/toxicidad , Disruptores Endocrinos/toxicidad , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Ratas Wistar , ARN Mensajero/metabolismo , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Tirotropina , Hipófisis/efectos de los fármacos , Hipófisis/metabolismoRESUMEN
Phthalates are chemicals used in products including plastics, personal care products, and building materials, leading to widespread contact. Previous studies on prenatal exposure to Di-(2-ethylhexyl) phthalate (DEHP) in mice and humans demonstrated pubertal timing and reproductive performance could be affected in exposed offspring. However, the impacts at the pituitary, specifically regarding signaling pathways engaged and direct effects on the gonadotropins LH and FSH, are unknown. We hypothesized prenatal exposure to DEHP during a critical period of embryonic development (e15.5 to e18.5) will cause sex-specific disruptions in reproduction-related mRNA expression in offspring's pituitary due to interference with androgen and aryl hydrocarbon receptor (AhR) signaling. We found that prenatal DEHP exposure in vivo caused a significant increase in Fshb specifically in males, while the anti-androgen flutamide caused significant increases in both Lhb and Fshb in males. AhR target gene Cyp1b1 was increased in both sexes in DEHP-exposed offspring. In embryonic pituitary cultures, the DEHP metabolite MEHP increased Cyp1a1 and Cyp1b1 mRNA in both sexes and Cyp1b1 induction was reduced by co-treatment with AhR antagonist. AhR reporter assay in GHFT1 cells confirmed MEHP can activate AhR signaling. Lhb, Fshb and Gnrhr mRNA were significantly decreased in both sexes by MEHP, but co-treatment with AhR antagonist did not restore mRNA levels in pituitary culture. In summary, our data suggest phthalates can directly affect the function of the pituitary by activating AhR signaling and altering gonadotropin expression. This indicates DEHP's impacts on the pituitary could contribute to reproductive dysfunctions observed in exposed mice and humans.
Asunto(s)
Dietilhexil Ftalato/análogos & derivados , Dietilhexil Ftalato/toxicidad , Hipófisis/efectos de los fármacos , Plastificantes/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Femenino , Hormona Folículo Estimulante de Subunidad beta/genética , Expresión Génica/efectos de los fármacos , Hormona Luteinizante de Subunidad beta/genética , Masculino , Intercambio Materno-Fetal , Ratones , Hipófisis/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Receptores de Hidrocarburo de Aril/metabolismo , Reproducción/genéticaRESUMEN
Hypophysitis is defined as inflammation of the pituitary gland that is primary or secondary to a local or systemic process. Differential diagnosis is broad (including primary tumors, metastases, and lympho-proliferative diseases) and multifaceted. Patients with hypophysitis typically present with headaches, some degree of anterior and/or posterior pituitary dysfunction, and enlargement of pituitary gland and/or stalk, as determined by imaging. Most hypophysitis causes are autoimmune, but other etiologies include inflammation secondary to sellar tumors or cysts, systemic diseases, and infection or drug-induced causes. Novel pathologies such as immunoglobulin G4-related hypophysitis, immunotherapy-induced hypophysitis, and paraneoplastic pituitary-directed autoimmunity are also included in a growing spectrum of this rare pituitary disease. Typical magnetic resonance imaging reveals stalk thickening and homogenous enlargement of the pituitary gland; however, imaging is not always specific. Diagnosis can be challenging, and ultimately, only a pituitary biopsy can confirm hypophysitis type and rule out other etiologies. A presumptive diagnosis can be made often without biopsy. Detailed history and clinical examination are essential, notably for signs of underlying etiology with systemic manifestations. Hormone replacement and, in selected cases, careful observation is advised with imaging follow-up. High-dose glucocorticoids are initiated mainly to help reduce mass effect. A response may be observed in all auto-immune etiologies, as well as in lymphoproliferative diseases, and, as such, should not be used for differential diagnosis. Surgery may be necessary in some cases to relieve mass effect and allow a definite diagnosis. Immunosuppressive therapy and radiation are sometimes also necessary in resistant cases.
Asunto(s)
Hipofisitis/diagnóstico , Hipófisis/patología , Enfermedades Raras/diagnóstico , Adulto , Anciano , Autoinmunidad , Diagnóstico Diferencial , Femenino , Humanos , Hipofisitis/etiología , Hipofisitis/patología , Hipofisitis/terapia , Imagen por Resonancia Magnética , Masculino , Hipófisis/diagnóstico por imagen , Hipófisis/efectos de los fármacos , Hipófisis/inmunología , Enfermedades Raras/etiología , Enfermedades Raras/patología , Enfermedades Raras/terapiaRESUMEN
Phthalates are synthetic chemicals widely used to make polyvinylchloride (PVC) soft and flexible. Of these, Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used, with high human exposure occurring as early as the fetal developmental stage and affecting the endocrine system. We focused on the perinatal DEHP effects on pituitary estrogen receptor (ER) expression in male rats, explored their impact on lactotroph and somatotroph cell growth, and evaluated the direct effects of this phthalate on pituitary cell cultures. Our results showed that DEHP perinatal exposure was unable to modify the ERα+ pituitary cell number from prepuberal rats, but increased ERß+ cells. In adulthood, the pituitary ERα+ cells underwent a slight decrease with ERß showing the greatest changes, and with a significant increase observed in somatotroph cells. Also, in vitro, DEHP reduced the ERα+ cells, increased the percentage of ERß+ pituitary cells and modified the Ki67 index, as well as decreasing the lactotrophs and increasing the somatotroph cells. In conclusion, the present study showed that DEHP induced ER expression changes in normal pituitary glands from male rats in in vivo and in vitro conditions, suggesting that DEHP could differentially modulate lactotroph and somatotroph cell growth, possibly as a consequence of ER imbalance.
Asunto(s)
Dietilhexil Ftalato/toxicidad , Disruptores Endocrinos/toxicidad , Hipófisis , Efectos Tardíos de la Exposición Prenatal , Receptores de Estrógenos/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Femenino , Lactotrofos/efectos de los fármacos , Lactotrofos/metabolismo , Masculino , Hipófisis/citología , Hipófisis/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas , Ratas Wistar , Somatotrofos/efectos de los fármacos , Somatotrofos/metabolismoRESUMEN
BACKGROUND: Current guidelines indiscriminately recommend magnetic resonance imaging (MRI) of the pituitary gland in pediatric growth hormone deficiency (GHD). The relationship between abnormal MRI, most importantly a tumor, and peak GH levels is not well known. METHODS: In this retrospective chart review, pituitary MRI results of children, ages of 3-16 years with GHD were collected and divided into 3 groups according to peak stimulated GH levels; ≤5, 5-7.4 and 7.5-10 ng/mL, Groups A, B & C respectively. Clinical and MRI findings were compared between the groups. RESULTS: A total of 399 children were included. Abnormal MRI was found in 36.9% of group A subjects, compared to group B (16.7%) and group C (17.0%), both p values =0.0002. Children with multiple pituitary hormonal deficiencies (MPHD) had a higher rate of abnormalities than those with isolated GHD. Children with isolated GHD were more likely to have abnormal MRI with peak GH level < 5 ng/mL compared to those with levels, 5-7.4 & 7.5-10 ng/mL. 4 children in group A had a craniopharyngioma. ROC analysis comparing peak GH levels with abnormal MRI findings showed an area under the curve (AUC) of 0.614 and 0.728 for IGHD and MPHD, respectively. CONCLUSION: Although abnormal MRI was found in all 3 study groups, it was more likely at GH level < 5 ng/mL and in children with MPHD. To avoid missing a tumor, the importance of imaging in children with GHD and peak GH levels <5 ng/mL cannot be overemphasized.
Asunto(s)
Biomarcadores/análisis , Enanismo Hipofisario/patología , Hormona de Crecimiento Humana/sangre , Imagen por Resonancia Magnética/métodos , Hipófisis/patología , Adolescente , Niño , Preescolar , Enanismo Hipofisario/sangre , Enanismo Hipofisario/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Masculino , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: This study aimed to detect the effect of angiotensin receptor 1 (AT1) knock out (KO) on spermatogenesis and hypothalamic-pituitary-gonadal (HPG) axis hormone expression. METHODS: Normal C57BL/6 male mice were used as control group or treated with angiotensin receptor blocker, in addition heterozygous ± AT1KO mice were generated. After caged at a ratio of 2 to 1 with females, pregnancy rates of female mice were determined by detection of vaginal plugs. Deformity rate of spermatozoa was evaluated by eosin staining and morphology evaluation. The AT1 mRNA expression in the testes of male ± AT1KO mice was detected by quantitative real-time polymerase chain reaction (QRT-PCR). Serum GnRH level was determined by ELISA. RESULTS: Compared to control, ± AT1KO mice showed reduced expression of AT1 in testes, pituitary and hypothalamus. In addition, decreased level of GnRH, but not follicle stimulating hormone (FSH) or luteinizing hormone (LH), in ± AT1KO mice was detected. Treatment with angiotensin receptor blocker (ARB) did not have significant effects on HPG hormones. ± AT1KO mice exhibited male infertility and significant abnormality of sperm morphology. CONCLUSION: Reduced AT1 knockout resulted in male infertility, potentially by inducing abnormal spermatogenesis. Both testis and HPG axis signaling may be involved.
Asunto(s)
Hormona Liberadora de Gonadotropina/metabolismo , Infertilidad Masculina/genética , Receptor de Angiotensina Tipo 1/genética , Espermatogénesis/genética , Testículo/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Hormona Liberadora de Gonadotropina/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Infertilidad Masculina/metabolismo , Losartán/farmacología , Masculino , Ratones , Ratones Noqueados , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacosRESUMEN
In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-ß-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR.