scholarly journals 1α,25-Dihydroxyvitamin D3 Supplementation during Pregnancy Is Associated with Allergic Rhinitis in the Offspring by Modulating Immunity

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Liqing Zhang ◽  
Haifeng Ni ◽  
Zhen Zhou ◽  
Xiaoyang Yuan ◽  
Junbo Xia ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Low Dose ◽  
Treg Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Dihydroxyvitamin D3 ◽  
Sterile Saline ◽  
Maternal Supplementation ◽  
Ifn Γ ◽  
Dose Dependent

Background. Maternal supplementation with 1α,25-dihydroxyvitamin D3 (VD3) has immunologic effects on the developing fetus through multiple pathways. This study was aimed at investigating the effects of VD3 supplementation on immune dysregulation in the offspring during allergic rhinitis. Methods. Different doses of VD3 as well as control were given to pregnant female mice. Ovalbumin (OVA) challenge and aluminum hydroxide gel in sterile saline were used to induce allergic rhinitis in offspring mice. Nasal lavage fluids (NLF) were collected, and eosinophils were counted in NLF 24 hours after the OVA challenge. Th1, Th2, Th17, and Treg subtype-relevant cytokines, including IFN-γ, IL-4, IL-10, IL-17, TGF-β, and OVA-IgE levels from the blood and NLF of offspring mice, were detected by the enzyme-linked immunosorbent assay (ELISA) method. The Treg subtype was analyzed by flow cytometry. Treg cells were purified from offspring and were adoptively transferred to OVA-sensitized allogenic offspring mice. The outcomes were assessed in allogenic offspring. Results. Our data showed that VD3 supplementation significantly decreased the number of eosinophils, basophils, and lymphocytes in the peripheral blood and NLF. The proportion of CD4+CD25+FoxP3+Tregs had a positive correlation with VD3 in a dose-dependent manner. The levels of serum IgE, IL-4, and IL-17 were decreased while the expressions of IFN-γ, IL-10, and TGF-β were significantly enhanced in VD3 supplementation groups. Adoptive transfer CD4+CD25+FoxP3+Tregs of VD3 supplementation groups promoted Th1 and suppressed Th2 responses in the offspring during allergic rhinitis. Conclusion. Our findings indicated that low dose VD3 supply in pregnant mice’s diet suppressed Th2 and Th17 responses in allergic rhinitis by elevating the Th1 subtype and the proportion of CD4+CD25+FoxP3+Tregs in offspring. It suggested that low dose VD3 supply may have the potential to act as a new therapeutic strategy for allergic rhinitis.

scholarly journals Yiqi Wenyang Fang ameliorates allergic rhinitis through inhibiting inflammatory response and promoting the expression of Foxp3

2016 ◽  
Vol 29 (4) ◽  
pp. 696-706 ◽  
Author(s):  
Jun Shi ◽  
Yu Liu ◽  
Shihai Yan ◽  
Daonan Yan
Keyword(s):  
Allergic Rhinitis ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Treg Cells ◽  
Pcr Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Dose ◽  
Sprague Dawley ◽  
Model Control ◽  
Tgf Β1

Allergic rhinitis (AR) is an inflammatory disease with a hypersensitivity response to environmental stimulus. The aim of this study was to evaluate the effect of Yiqi Wenyang Fang (YWF) on AR and investigate the underlying mechanism. A total of 48 female Sprague-Dawley rats were randomly divided into six groups (normal control, model control, YWF at low dose, YWF at median dose, YWF at high dose, and loratadine). Rats were injected with antigen for sensitization. Then, rats in the YWF groups were treated with different dose of YWF for 28 days. Loratadine was used as a positive control. Number of sneezes, degree of runny nose, nasal rubbing movements, and tissue damage were scored. The protein and mRNA expression of Foxp3 were determined by western blot and real time-PCR analysis, respectively. Flow cytometry was used to detect the number of CD4+CD25+Foxp3+ Treg cells. The content of interleukin (IL)-10, transforming growth factor β1 (TGF-β1), IL-13, and IL-4 in the serum were detected by enzyme-linked immunosorbent assay (ELISA). Scores of symptoms were significantly reduced and nasal mucosa damage was alleviated after YWF administration. YWF increased the expression of Foxp3, IL-10, TGF-β1, and number of CD4+CD25+Foxp3+ Treg cells which were reduced by antigen injection. The expression levels of IL-13 and IL-4 were increased after antigen administration while decreased after YWF treatment. YWF may ameliorate AR through inhibiting inflammatory response and promoting Foxp3 expression.

scholarly journals Effect ofTityus serrulatusvenom on cytokine production and the activity of murine macrophages

2002 ◽  
Vol 11 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Vera L. Petricevich
Keyword(s):  
Cytokine Production ◽  
Peritoneal Macrophages ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
No Production ◽  
Dependent Manner ◽  
Immune Functions ◽  
Macrophage Activity ◽  
Ifn Γ

The purpose of this study was to investigate the effects ofTityus serrulatusvenom (TSV) on murine peritoneal macrophages evaluated in terms of activation. The effects of crude TSV were analysed by detection of cytokines, oxygen intermediate metabolites (H2O2) and nitric oxide (NO) in supernatants of peritoneal macrophages. Several functional bioassays were employed including anin vitromodel for envenomating: cytotoxicity of TSV was assessed using the lyses percentage. Tumor necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, and interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed by enzyme-linked immunosorbent assay, whereas NO levels were detected by Griess colorimetric reactions in culture supernatant of macrophages incubated with TSV and subsequently exposed to either lipopolysaccharide or IFN-γ. Incubation of macrophages with TSV increased production of IL-6 and IFN-γ in a dose-dependent manner. TNF production was not detected in supernatants treated with TSV at any concentration. The increase in IL-6 secretion was not associated with concentration-dependent cytoxicity of TSV on these cells. These data suggest that the cytotoxicity does not appear to be the main cause of an increased cytokine production by these cells. Although NO is an important effector molecule in macrophage microbicidal activity, the inducing potential of the test compounds for its release was found to be very moderate, ranging from 125 to 800 mM. Interestingly, NO levels of peritoneal macrophages were increased after IFN-γ. Moreover, NO production had an apparent effect on macrophage activity. The results obtained here also shown that the TSV induces an important elevation in H2O2release. These results combined with NO production suggest that TSV possesses significant immunomodulatory activities capable of stimulating immune functionsin vitro.

Production and utilization of monoclonal antibodies to human/rat corticotrophin-releasing factor-41

1990 ◽  
Vol 5 (2) ◽  
pp. 159-166 ◽  
Author(s):  
N. G. N. Milton ◽  
E. W. Hillhouse ◽  
S. A. Nicholson ◽  
C. H. Self ◽  
A. M. McGregor
Keyword(s):  
Monoclonal Antibodies ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Corticotrophin Releasing Factor ◽  
Tissue Extracts ◽  
Rat Pituitary ◽  
Hypothalamic Tissue ◽  
Dose Dependent

ABSTRACT Murine monoclonal antibodies against human/rat corticotrophin-releasing factor-41 (CRF-41) were produced and characterized for use in the immunological and biological characterization of CRF-41. Spleen cells from BALB/c mice immunized with CRF-41 conjugated to bovine γ-globulin were fused with a BALB/c-derived non-secretor X-63 myeloma line. Hybridomas were selected for CRF antibody production by enzyme-linked immunosorbent assay, and positive hybridomas cloned twice. Three monoclonal antibodies were obtained (KCHMB001, KCHMB002 and KCHMB003) and characterized as IgG1, IgG1 and IgG2a isotypes respectively, with affinity constants for rat CRF-41 of 30, 53 and 34 nmol/l respectively. All three monoclonal antibodies recognize an epitope contained between residues 34 and 41 of the human/rat sequence. The antibodies were able to neutralize the ACTH-releasing activity of rat CRF-41, applied to rat pituitary fragments in vitro, in a dose-dependent manner. Isoelectric focusing showed that KCHMB 003 detected bands of synthetic rat CRF-41 and rat [Met(O)21,38]-CRF-41 at pH 7·1 and 6·8 respectively. Use of KCHMB003 in a two-site enzyme-amplified immunoassay showed that this antibody recognizes both synthetic rat CRF-41 and immunoreactive CRF-41 in rat hypothalamic tissue extracts.

Detection of α1 Integrin in Urine of Patients With Immunoglobulin A Nephropathy

2008 ◽  
Vol 56 (3) ◽  
pp. 581-586
Author(s):  
Jonathan Bank ◽  
Aharon Ben-David ◽  
Ram Doolman ◽  
Ben-Ami Sela ◽  
Ilan Bank
Keyword(s):  
Mesangial Cells ◽  
Kidney Diseases ◽  
Surface Membrane ◽  
Immunoglobulin A ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Healthy Individuals ◽  
Immunoglobulin A Nephropathy ◽  
A Cell ◽  
Dose Dependent

BackgroundThe α1β1 integrin is a cell surface membrane heterodimer composed of noncovalently linked α1 and β1 polypeptides that is up-regulated on activated and proliferating mesangial cells.MethodsA double-sandwich enzyme-linked immunosorbent assay that detects α1 integrin in a specific and dose-dependent manner at concentrations greater than 150 ng/mL was used to evaluate whether intact α1 polypeptides are secreted in the urine samples of 29 patients with various kidney diseases and in those of 5 healthy individuals.Resultsα1 Integrin was detected in 8 of the 29 patients including 3 of 3 patients with biopsy-proven immunoglobulin A nephropathy and 3 of 3 clinically suspected but non-biopsy-proven immunoglobulin A nephropathy with evidence of active nephritis. No α1 integrins were found in samples of 5 healthy controls.Conclusionsα1 Integrin polypeptides can be detected in human urine, particularly in immunoglobulin A nephropathy. Further extensive studies are required to clarify the significance of secretion of α1 integrins in urine of patients with kidney disease.

Calcitriol Exerts Prophylactic Anti-Mycobacterium Effect In A Dose-Dependent Manner

2021 ◽  
Author(s):  
Jianguo Li ◽  
Zhen Li ◽  
Zefeng Gao ◽  
Juan Xia ◽  
Jia Cui ◽  
...  
Keyword(s):  
Vitamin D ◽  
1H Nmr ◽  
Low Dose ◽  
Bacterial Load ◽  
High Dose ◽  
Dependent Manner ◽  
Prophylactic Effect ◽  
Moderate Dose ◽  
Metabolism Pathway ◽  
Dose Dependent

Abstract Vitamin D was empirically applied for Tuberculosis (TB) treatment in the past, and is currently used as an adjuvant for TB therapy. Although an increasing pile of evidences suggests that vitamin D has no therapeutic effect against TB infection, the prophylactic effect of vitamin D in preventing TB remains largely undetermined. To experimentally valuate the potential prophylactic effect of calcitriol (the active form of vitamin D) against mycobacterium infection, we performed dose-gradient calcitriol soaking in 30-day-old zebrafish before Mycobacterium marinum (M. marinum) challenge through tail vein injection. 1H-NMR metabolomics analysis was further performed for illustration of potential mechanisms underlying the prophylactic effect of calcitriol against M. marinum. The results suggested that calcitriol exerts dose-dependent prophylactic anti-mycobacterium effects, i.e., the bacterial load and the corresponding inflammatory factors (IL-1β, TNF-α, and IFN-γ) expressions in M. marinum challenged zebrafish were reduced by low-dose (25 µg/L) or high-dose (2500 µg/L) calcitriol soaking, rather than by moderate-dose (250 µg/L) calcitriol soaking. Body weight of the M. marinum challenged zebrafish was recovered by high-dose prophylactic calcitriol soaking rather than by low-dose or moderate-dose calcitriol. The 1H-NMR metabolomic profiling identified 29 metabolites with altered abundance among the dose-gradient calcitriol groups, among which 22 metabolites were co-varied with the dose of calcitriol, the rest 7 metabolites were co-varied with the bacterial load and the inflammatory response in term of cytokine expression. Further pathway analysis indicated that the glycine, serine, and threonine metabolism pathway was the activated in both of the two metabolite groups, indicating that the pathway was altered by dose-gradient of calcitriol and was in response to M. marinum infection in zebrafish. The results of the present study suggested that the activation of glycine, serine and threonine metabolism pathway may play a potential role for the dose-dependent anti-mycobacterium effect induced by prophylactic calcitriol soaking.

scholarly journals Honeysuckle extract relieves ovalbumin-induced allergic rhinitis by inhibiting AR-induced inflammation and autoimmunity

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Bin Lin ◽  
Bijuan Cai ◽  
Huige Wang
Keyword(s):  
Allergic Rhinitis ◽  
Nasal Mucosa ◽  
Inflammatory Reaction ◽  
Lavage Fluid ◽  
Nasal Lavage ◽  
Autoimmune Response ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protein Levels ◽  
Nasal Lavage Fluid ◽  
Ifn Γ

Abstract Honeysuckle has antiviral, antioxidative and anti-inflammatory properties. Allergic rhinitis (AR) is induced by immunoglobulin E (IgE)-mediated inflammatory reaction. Our study investigates whether honeysuckle extract (HE) has therapeutic effect on AR. An AR model of mice was established by ovalbumin (OVA). Hematoxylin–Eosin staining was used to assess nasal mucosa damage. Enzyme-linked immunosorbent assay (ELISA) was performed to determine serum histamine, IgE and interleukin (IL)-2, IL-4, IL-17 and interferon-γ (IFN-γ) from nasal lavage fluid. Western blot was carried out to analyze the protein level from nasal mucosa tissue. We found that HE not only decreased nasal rubbing and sneezing in AR mice, but also reduced AR-induced damage to nasal mucosa. Moreover, HE lowered the levels of serum IgE and histamine and inhibited IL-4 and IL-17 levels from AR mice but raised IL-2 and IFN-γ levels in AR-induced nasal lavage fluid. Our results also showed that HE elevated the protein levels of forkhead box P3 (Foxp3) and T-box transcription factor (T-bet) in AR-induced nasal mucosa tissue, whereas it inhibited signal transducer and activator of transcription (STAT) 3 and GATA binding protein 3 (GATA-3) protein levels. By regulating AR-induced inflammatory reaction and autoimmune response, HE also relieved OVA-induced AR. Thus, HE could be used as a potential drug to treat AR.

scholarly journals Streptococcus pneumoniae Autolysis Prevents Phagocytosis and Production of Phagocyte-Activating Cytokines

2009 ◽  
Vol 77 (9) ◽  
pp. 3826-3837 ◽  
Author(s):  
Anna Martner ◽  
Susann Skovbjerg ◽  
James C. Paton ◽  
Agnes E. Wold
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Exact Function ◽  
Ifn Γ ◽  
Dose Dependent

ABSTRACT Streptococcus pneumoniae is a major pathogen in humans. The pathogenicity of this organism is related to its many virulence factors, the most important of which is the thick pneumococcal capsule that minimizes phagocytosis. Another virulence-associated trait is the tendency of this bacterium to undergo autolysis in stationary phase through activation of the cell wall-bound amidase LytA, which breaks down peptidoglycan. The exact function of autolysis in pneumococcal pathogenesis is, however, unclear. Here, we show the selective and specific inefficiency of wild-type S. pneumoniae for inducing production of phagocyte-activating cytokines in human peripheral blood mononuclear cells (PBMC). Indeed, clinical pneumococcal strains induced production of 30-fold less tumor necrosis factor (TNF), 15-fold less gamma interferon (IFN-γ), and only negligible amounts of interleukin-12 (IL-12) compared with other closely related Streptococcus species, whereas the levels of induction of IL-6, IL-8, and IL-10 production were similar. If pneumococcal LytA was inactivated by mutation or by culture in a medium containing excess choline, the pneumococci induced production of significantly more TNF, IFN-γ, and IL-12 in PBMC, whereas the production of IL-6, IL-8, and IL-10 was unaffected. Further, adding autolyzed pneumococci to intact bacteria inhibited production of TNF, IFN-γ, and IL-12 in a dose-dependent manner but did not inhibit production of IL-6, IL-8, and IL-10 in response to the intact bacteria. Fragments from autolyzed bacteria inhibited phagocytosis of intact bacteria and reduced the in vitro elimination of pneumococci from human blood. Our results suggest that fragments generated by autolysis of bacteria with reduced viability interfere with phagocyte-mediated elimination of live pneumococci.

scholarly journals Intravenous administration of sodium propionate induces antidepressant or prodepressant effect in a dose dependent manner

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chunyan Hao ◽  
Zefeng Gao ◽  
XianJun Liu ◽  
Zhijiang Rong ◽  
Jingjing Jia ◽  
...  
Keyword(s):  
Body Weight ◽  
Low Dose ◽  
Antidepressant Effect ◽  
High Dose ◽  
Mild Stress ◽  
Dependent Manner ◽  
Reward Seeking ◽  
Metabolomic Profiling ◽  
Hydroxyanthranilic Acid ◽  
Dose Dependent

AbstractPropionate has been reported to exert antidepressant effects, but high-dose propionate may induce autism-like symptoms in experimental animals through induction of dysbiosis of neurotransmitters. The bi-directional effects of propionate seem to be dose-dependent. However, due to the pathological discrepancies between depression and autism, conclusions drawn from autism may not be simply transferable to depression. The effect and underlying action mechanisms of high-dose propionate on depression remains undetermined. To investigate the effects of propionate on depression, propionate dose gradients were intravenously administrated to rats exposed to chronic unpredictable mild stress (CUMS) for 1 week. Results of these behavioral tests demonstrate that low-dose propionate (2 mg/kg body weight/day) induces antidepressant effect through bodyweight recovery, elevated reward-seeking behaviors, and reduced depression-like behaviors, while high-dose propionate (200 mg/kg body weight/day) induces prodepressant effects opposite of those of low-dose propionate. A comprehensive profiling of neurotransmitters in the hippocampus demonstrated that CUMS induces reduction of NE (Norepinephrine), DA (Dopamine). GABA (γ-aminobutyric acid) was recovered by low-dose propionate, while high-dose propionate exerted more complicated effects on neurotransmitters, including reduction of NE, DA, 5-Hydroxytryptamine and Tryptophan, and increase of GABA, Kynurenine, Homovanillic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine. The neurotransmitters disturbed by high-dose propionate suggest metabolic disorders in the hippocampus, which were confirmed by the clear group separation in PCA of metabolomic profiling. The results of this study demonstrate the double-edged dose-dependent effects of propionate on depression and suggest potential cumulative toxicity of propionate as a food additive to mood disorders.

Lenalidomide Strongly Enhances Natural Killer (NK) Cell Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) of Rituximab Treated Non-Hodkin’s Lymphoma Cell Lines In Vitro.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3714-3714 ◽  
Author(s):  
Lei Wu ◽  
Peter Schafer ◽  
George Muller ◽  
David Stirling ◽  
J. Blake Bartlett
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Dependent Manner ◽  
Activation Markers ◽  
Early Results ◽  
Ifn Γ ◽  
Dose Dependent

Abstract Lenalidomide (Revlimid® is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone is for the treatment of multiple myeloma patients who have received at least one prior therapy. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin’s lymphoma (NHL). Potential mechanisms of action include anti-angiogenic, anti-proliferative and immunomodulatory activities. Lenalidomide has been shown to enhance Th1-type cytokines and T cell and NK cell activation markers in patients with advanced cancers. Furthermore, lenalidomide has been shown to enhance rituximab-mediated protection in a SCID mouse lymphoma model in vivo. We have utilized an in vitro ADCC system to assess the ability of lenalidomide to directly enhance human NK cell function in response to therapeutic antibodies, such as rituximab (chimeric anti-CD20 mAb). Isolated NK cells produced little or no IFN-γ in response to IgG and/or IL-2 or IL-12. However, pre-treatment of NK cells with lenalidomide greatly enhanced IFN-γ production by NK cells in a dose-dependent manner. In a functional ADCC assay, NHL cell lines (Namalwa, Farage & Raji) were pre-coated with rituximab and exposed to NK cells pre-treated with lenalidomide in the presence of either exogenous IL-2 or IL-12. After 4 hours in culture the viability of the tumor cells was assessed. Lenalidomide consistently and synergistically increased the killing of tumor cells in a dose-dependent manner and up to >4-fold compared to rituximab alone. Rituximab alone had only a small effect in this model and there was no killing of cells in the absence of rituximab. The presence of either exogenous IL-2 or IL-12 was required to see enhanced killing by lenalidomide. In cancer patients lenalidomide has been shown to increase serum IL-12 levels and is also known to induce IL-2 production by T cells in vitro. Potential mechanisms for enhanced ADCC include increased signaling through NK FCγ receptors and/or IL-2 or IL-12 receptors. However, we found that these receptors are unaffected by lenalidomide, although downstream effects on NK signaling pathways are likely and are being actively investigated. In conclusion, we have shown that lenalidomide strongly enhances the ability of rituximab to induce ADCC mediated killing of NHL cells in vitro. This provides a strong rationale for combination of these drugs in patients with NHL and CLL.

scholarly journals Perinatal exposure of female rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces central precocious puberty in the offspring

2008 ◽  
Vol 197 (2) ◽  
pp. 351-358 ◽  
Author(s):  
Masaki Kakeyama ◽  
Hideko Sone ◽  
Chiharu Tohyama
Keyword(s):  
Precocious Puberty ◽  
Low Dose ◽  
Female Offspring ◽  
Compensatory Hypertrophy ◽  
Female Rats ◽  
Perinatal Exposure ◽  
Dependent Manner ◽  
Early Maturation ◽  
Long Evans ◽  
Dose Dependent

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during the fetal and neonatal periods has been indicated to alter the development of the offspring later in life. In this study, we determined whether perinatal exposure to a low dose of TCDD affects the onset of puberty in the female offspring of Long-Evans hooded rats. On day 15 of gestation, pregnant female rats were administered TCDD by gavage at a single dose of 0 (vehicle), 200, or 800 ng/kg b.w. In the female offspring born to dams administered with TCDD at either 200 or 800 ng/kg b.w., the vaginal opening and first estrus occurred ∼4–7 days earlier than in the offspring born to vehicle-treated animals. The ovarian weight gain was also accelerated following exposure to TCDD in a dose-dependent manner. We next examined the ovarian compensatory hypertrophy (OCH) as an indicator of the maturation of the LH/GnRH-generating system in the pituitary and the hypothalamus. Exposure to TCDD accelerated the onset of OCH in the female offspring in a dose-dependent manner. In particular, in the offspring born to the dams exposed to TCDD at 800 ng/kg b.w., hypertrophy, which is characterized by hyperovulation and a marked increase in the weight of the remaining ovary after hemi-ovariectomy, was observed on postnatal days 27–30, which was 10 days earlier than in the offspring born to the vehicle-treated dams. These results indicate that perinatal exposure to a low dose of TCDD induces precocious puberty, including early maturation of the hypothalamic–pituitary axis, the gonads and genitals, in female Long-Evans hooded rats.

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