Biomedical subjects

G Morel

Publications and source records attributed to G Morel.

At least 19 recordsLinked to original sources

PubMed2006

Developmental toxicity of combined ethylbenzene and methylethylketone administered by inhalation to rats.

Pregnant Sprague-Dawley rats were exposed to ethylbenzene (EB; 0, 250, or 1000 ppm) and methylethylketone (MEK; 0, 1000, or 3000 ppm), alone and in combination, by inhalation, for 6h/day, during days 6-20 of gestation. Maternal toxicity, evidenced by decreased in body weight gain and food consumption, tended to be greater after simultaneous exposures to the high concentrations of 1000 ppm EB and 3000 ppm MEK, when compared to the treatments with individual compounds. No significant increase in embryo/fetal lethality or incidence of malformations and variations was observed in any of the treatment groups. Fetal body weight was significantly reduced after individual treatment with 1000 ppm EB or 3000 ppm MEK, and in the combined groups. There was no evidence of interaction between EB and MEK in causing developmental toxicity.

Animals↗

PubMed2005

Developmental toxicity of two trimethylbenzene isomers, mesitylene and pseudocumene, in rats following inhalation exposure.

The developmental toxicity of two trimethylbenzene isomers, mesitylene (1,3,5-trimethylbenzene) and pseudocumene (1,2,4-trimethylbenzene) was studied in Sprague-Dawley rats following inhalation exposure. Pregnant rats were exposed whole body to vapours of mesitylene (0, 100, 300, 600, and 1200 ppm) or pseudocumene (0, 100, 300, 600, and 900 ppm), 6h/day, on gestational days (GD) 6 through 20. Significant decrease in maternal body weight gain and food consumption was observed at concentrations of 300 ppm mesitylene, 600 ppm pseudocumene, or greater. Fetal toxicity, expressed as significant reduction in fetal body weight, occurred at 600 and 1200 ppm mesitylene, and at 600 and 900 ppm pseudocumene. There was no evidence of embryolethal or teratogenic effects following inhalation exposure to either of these chemicals. In summary, the no-observed-adverse-effect-level (NOAEL) for maternal toxicity was 100 ppm for mesitylene and 300 ppm for pseudocumene, and the NOAEL for developmental toxicity was 300 ppm for mesitylene and pseudocumene.

Abnormalities, Drug-Induced↗

PubMed2005

Cellular distribution of growth hormone-releasing hormone receptor in human reproductive system and breast and prostate cancers.

Growth hormone releasing hormone receptor (GHRH-R) mRNA and protein was first localized to the anterior pituitary gland, consequent with the action of its ligand on GH synthesis and release. Subsequent studies found GHRH-R also expressed in the hypothalamus and in systemic tissues including those of the reproductive system. In the present work, we studied the distribution of GHRH-R in human reproductive system of males and females by immunohistochemical method. GHRH-R immunostaining was localized in male reproductive system: Leydig cells, Sertoli and basal germ cells of the seminiferous tubules and prostate secretory cells. GHRH-R immunostaining was also demonstrated in the ovary: oocytes, follicular cells, granulosa, thecal and corpus luteum cells. Endometrial glands, placenta and normal mammary glands also showed GHRH-R immunostaining. Our results demonstrate the localization of GHRH-R in the reproductive system, which may mediate the direct action of GHRH in these tissues. Moreover, GHRH-R was demonstrated in prostate and breast carcinomas, opening a variety of possibilities for the use of GHRH antagonists in the treatment of prostatic and mammary tumors.

Adenocarcinoma↗

PubMed2003

Suppressor of cytokine signalling gene expression is elevated in breast carcinoma.

Cytokines are important for breast cell function, both as trophic hormones and as mediators of host defense mechanisms against breast cancer. Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines. We examined the expression of SOCS genes in 17 breast carcinomas and 10 breast cancer lines, in comparison with normal tissue and breast lines. We report elevated expression of SOCS-1-3 and CIS immunoreactive proteins within in situ ductal carcinomas and infiltrating ductal carcinomas relative to normal breast tissue. Significantly increased expression of SOCS-1-3 and CIS transcripts was also shown by quantitative in situ hybridisation within both tumour tissue and reactive stroma. CIS transcript expression was elevated in all 10 cancer lines, but not in control lines. However, there was no consistent elevation of other SOCS transcripts. CIS protein was shown by immunoblot to be present in all cancer lines at increased levels, mainly as the 47 kDa ubiquitinylated form. A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter. The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin. However, increased CIS expression in breast cancer lines appears to be a specific lesion, and could simultaneously shut down STAT 5 signalling by trophic hormones, confer resistance to host cytokines and increase proliferation through ERK kinases.

Breast Neoplasms↗

PubMed2003

Leukemia inhibitory factor is a key signal for injury-induced neurogenesis in the adult mouse olfactory epithelium.

The mammalian olfactory epithelium (OE) is composed of primary olfactory sensory neurons (OSNs) that are renewed throughout adulthood by local, restricted neuronal progenitor cells. The molecular signals that control this neurogenesis in vivo are unknown. Using olfactory bulb ablation (OBX) in adult mice to trigger synchronous mitotic stimulation of neuronal progenitors in the OE, we show the in vivo involvement of a cytokine in the cellular events leading to the regeneration of the OE. We find that, of many potential mitogenic signals, only leukemia inhibitory factor (LIF) is induced before the onset of neuronal progenitor proliferation. The rise in LIF mRNA expression peaks at 8 hr after OBX, and in situ RT-PCR and immunocytochemistry indicate that LIF is upregulated, in part, in the injured neurons themselves. This rise in LIF is necessary for injury-induced neurogenesis, as OBX in the LIF knock-out mouse fails to stimulate cell proliferation in the OE. Moreover, delivery of exogenous LIF to the intact adult OE using an adenoviral vector stimulates BrdU labeling in the apical OE. Taken together, these results suggest that injured OSNs release LIF as a stimulus to initiate their own replacement.

Animals↗

PubMed2003

Developmental toxicities of ethylbenzene, ortho-, meta-, para-xylene and technical xylene in rats following inhalation exposure.

The developmental toxicities of ethylbenzene, o-, m-, p-xylene and technical xylene were studied in Sprague-Dawley rats after inhalation exposure. Animals were exposed to either of these agents at 100, 500, 1000 or 2000 ppm, for 6 h/day, during days 6-20 of gestation. All the agents tested caused maternal toxicity expressed as a reduction in maternal body weight gain at 1000 and 2000 ppm. Decreased corrected weight gain and food consumption were observed at 1000 and 2000 ppm ethylbenzene, o-, m- or p-xylene, and at 2000 ppm technical xylene. No evidence of teratogenic effects was found after exposure to any of these agents up to 2000 ppm. Fetal toxicity evidenced by significant decreases in fetal body weights occurred at concentrations of 500 ppm or greater of o-xylene or technical xylene, and 1000 ppm or greater of ethylbenzene, m- or p-xylene. A significant increase in the mean percentage of fetuses per litter with skeletal variations was also noted at 2000 ppm ethylbenzene, o- and p-xylene. In summary, all tested agents produced developmental toxicity at 1000 and 2000 ppm, concentrations that also produced significant maternal toxicity. With o-xylene and technical xylene, developmental toxicity also occurred at 500 ppm, in the absence of maternal toxic effects. However, the only indication of a treatment-related effect was a slight decrease in fetal weight.

Administration, Inhalation↗

PubMed2003

Developmental toxicity of N-methyl-2-pyrrolidone in rats following inhalation exposure.

The developmental toxicity of inhaled N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats. Pregnant rats were exposed whole body to NMP vapours at concentrations of 0, 30, 60 and 120 ppm, 6 h/day, on gestational days (GD) 6 through 20. Maternal body weight gain was significantly decreased at 60 and 120 ppm on GD 6-13 and maternal food consumption was reduced at 120 ppm on GD 13-21. No significant difference in the gestational weight change corrected for the weight of the gravid uterus was observed, whatever NMP concentration. There were no adverse effects on embryo/fetal viability or evidence of teratogenicity at any concentration tested. Fetal toxicity indicated by reduced fetal weight was observed at 120 ppm. Thus, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 30 and 60 ppm, respectively.

Abnormalities, Drug-Induced↗

PubMed2002

Development and validation of a new bitumen fume generation system which generates polycyclic aromatic hydrocarbon concentrations proportional to fume concentrations.

Bitumen fumes emitted during road paving and roofing contain polycyclic aromatic compounds (PACs) of potential health concern. Little information is available for an experimental device devoted to inhalation experiments with animals exposed to bitumen fumes, and in all studies the systems were never validated for a range of fume concentrations, which prohibited their use for toxicological concentration-effect studies. Therefore, the purpose of this study was to validate a new experimental device able to generate bitumen fumes at different total particulate matter (TPM) concentrations with a linear correlation between TPM and the concentrations of different PACs, thus allowing toxicological dose-response studies with fumes representative of those in the field. Atmosphere samples collected from an animal exposure chamber allowed the determination of TPM, toluene soluble matter, polycyclic aromatic hydrocarbons (PAHs) and semi-volatiles. The particulate size distributions were determined in order to assess the deposition pattern in the respiratory tract. The temperature of 170 degrees C was chosen by analogy with the upper range of the temperature used during paving operations. The temperature of the air passing over the fume emission area was regulated to 20 degrees C and stirring of the heated bitumen was restricted to 90 r.p.m. The data show that the objective of developing a static fume generation system that reproducibly produces fumes in the inhalation chamber for specified target concentrations (TPM) were successful. The within-day variation coefficients for TPM were between 2.5 and 6.1%. The day-to-day variations for TPM concentration were between 4.1 and 5.8%. The concentrations of the 4-5 ring PAHs and the polycyclic aromatic sulphur heterocycles were proportional to the TPM concentration. The 2 and 3 ring PAH concentrations showed a deviation from proportionality with the TPM, probably due to their re-evaporation during sampling. The mass median aerodynamic diameter of airborne particles varied from 1.4 micro m at a fume concentration of 5 mg/m(3) to 3.2 micro m at 100 mg/m(3). In conclusion, this equipment was suitable for nose-only inhalation studies in the 5-100 mg/m(3) range of TPM. Bitumen fumes were generated with a good reproducibility under well-controlled conditions. Finally, the PAH profiles from atmospheric samples were in good agreement with those measured during road paving.

Hydrocarbons↗

PubMed2002

High stromal and epithelial human gh gene expression is associated with proliferative disorders of the mammary gland.

We have demonstrated and localized human GH (hGH) gene expression in surgical specimens of normal human mammary gland and in proliferative disorders of the mammary gland of increasing severity using sensitive in situ RT-PCR methodology. hGH mRNA identical to pituitary hGH mRNA was first detected by RT-PCR of RNA derived from samples of normal human mammary gland. Cellular localization of hGH gene expression in the normal mammary gland exhibited restriction to luminal epithelial and myoepithelial cells of the ducts and to scattered stromal fibroblasts. We subsequently examined the expression of the hgh gene in three progressive proliferative disorders of the human mammary gland, i.e. A benign lesion (fibroadenoma), a pre-invasive stage (intraductal carcinoma) and an invasive ductal carcinoma. hGH mRNA was readily detected in the tumoral and non-tumoral epithelial components and also in cells of the reactive stroma including fibroblasts, myofibroblastic and myoepithelial cells, inflammatory infiltrate lymphocytes and endothelial cells in areas of neovascularization. In all three proliferative disorders examined, the intensity of the cellular labeling observed in both the epithelial and stromal compartments was always stronger compared with that in adjacent normal tissue. hGH protein was also present in significantly higher concentration in extracts derived from proliferative disorders of the mammary gland compared with extracts derived from normal mammary gland. We also examined hGH gene expression in axillary lymph nodes not containing and containing metastatic mammary carcinoma. hGH gene expression was evidenced in metastatic mammary carcinoma cells and in reactive stromal cells by both in situ hybridization and in situ RT-PCR. In contrast, in lymph nodes not containing metastatic mammary carcinoma, hGH mRNA was detected only by use of in situ RT-PCR. Thus, increased expression of the hGH gene in the epithelial component and the de novo stromal expression in proliferative disorders of the mammary gland are suggestive of a pivotal role for autocrine hGH in neoplastic progression of the mammary gland.

Breast↗

PubMed2001

Localization of growth hormone receptors in rat and human thyroid cells.

Growth hormone (GH) exerts its multiple actions by binding to a specific receptor (GHR) widely distributed in the organism. It is well established that, in acromegaly, the thyroid gland is larger than normal and that GH increases triiodothyronin concentrations and decreases those of tetraiodothyronin (thyroxine). The aim of the present study was to analyze the presence of GHR and its mRNA in rat and human thyroid gland by Western blot, in situ hybridization techniques, and immunohistochemistry. A band of the expected size for GHR was shown in rat and human thyroid by Western blot. GHR immunoreactivity was found in virtually all follicles. The signal was mainly localized in the cytoplasm, although a nuclear positivity was also found. In situ hybridization techniques demonstrated the presence of GHR messenger RNA in the thyroid gland (cytoplasm of the follicular cells). These results provide direct morphological evidence that GHR is localized in the thyroid gland of mammals and opens up the possibility that GH regulates thyroid cell function directly or via local autocrine or paracrine production of insulin-like growth factor I.

Animals↗

PubMed2001

Autocrine human growth hormone (hGH) regulation of human mammary carcinoma cell gene expression. Identification of CHOP as a mediator of hGH-stimulated human mammary carcinoma cell survival.

By use of cDNA array technology we have screened 588 genes to determine the effect of autocrine production of human growth hormone (hGH) on gene expression in human mammary carcinoma cells. We have used a previously described cellular model to study autocrine hGH function in which the hGH gene or a translation-deficient hGH gene was stably transfected into MCF-7 cells. Fifty two of the screened genes were regulated, either positively () or negatively (), by autocrine production of hGH. We have now characterized the role of one of the up-regulated genes, chop (gadd153), in the effect of autocrine production of hGH on mammary carcinoma cell number. The effect of autocrine production of hGH on the level of CHOP mRNA was exerted at the transcriptional level as autocrine hGH increased chloramphenicol acetyltransferase production from a reporter plasmid containing a 1-kilobase pair fragment of the chop promoter. The autocrine hGH-stimulated increase in CHOP mRNA also resulted in an increase in CHOP protein. As a consequence, autocrine hGH stimulation of CHOP-mediated transcriptional activation was increased. Stable transfection of human CHOP cDNA into mammary carcinoma cells demonstrated that CHOP functioned not as a mediator of hGH-stimulated mitogenesis but rather enhanced the protection from apoptosis afforded by hGH in a p38 MAPK-dependent manner. Thus transcriptional up-regulation of chop is one mechanism by which hGH regulates mammary carcinoma cell number.

Breast Neoplasms↗

PubMed2001

Caveolae and clathrin-coated vesicles: two possible internalization pathways for IFN-gamma and IFN-gamma receptor.

Interferon-gamma (IFN-gamma) elicits a variety of activities following binding to its cell-surface-specific receptor (IFN-gammaR). This complex formation leads to the activation of the Jak-STAT pathway. Several hypotheses have been proposed to explain the role and location of the receptor and its ligand in the signalling pathway. In vivo as well as in vitro, the present study shows that IFN-gamma and its receptor were internalized in different cellular compartments including cytoplasmic matrix, mitochondria and nucleus. In order to analyse the internalization pathway of IFN-gamma and its receptor, we have study in vivo and in vitro their colocalization with clathrin and caveolin by using double immunogold-labelling experiments using electron microscopy. We demonstrate that IFN-gamma and IFN-gammaR were colocalized in the caveolin-containing structures and the clathrin-coated pits suggesting that both internalization pathways may be used. This indicates that IFN-gamma and IFN-gammaR were internalized by these two different pathways, suggesting two different intracellular routes probably for different target cell-compartments.

Animals↗

PubMed2001

Intrauterine oxytocin system. Compartmental distribution of oxytocin and oxytocin receptors in rat endometrial epithelium.

At term, uterine epithelial cells express oxytocin (OT) as well as the OT receptor (OTR). Like other epithelial cells, uterine epithelial cells are polarized and sort secretory and membrane components to the apical or the basolateral cell surface. We have studied the subcellular localization of OT-like immunoreactivity (OT-IR) and OTR-IR in rat uterine epithelium by immuno-gold labelling of ultrathin frozen sections. Our observations indicate that OT and OTR are both distributed preferentially to the apical surface of rat uterine epithelial cells. OT-IR showed a 6-fold apical versus basolateral preference and was localized in apical secretory vesicles, suggesting that uterine OT is released by apical exocytosis. OTR-IR was localized to the apical surface with a 9-fold apical versus basolateral preference and was found specifically in association with apical microvilli. The present findings represent the first example of a G protein-coupled receptor that is preferentially localized on the microvillar compartment and support the concept of an autocrine uterine OT system at the apical side of the uterine epithelium.

Animals↗

PubMed2001

Prenatal and adult growth hormone gene expression in rat lymphoid organs.

Growth hormone (GH) exerts its immune effects on mature lymphocytes through an autocrine/paracrine mechanism. We investigated the prenatal synthesis of GH mRNA in rat lymphoid organs using the sensitive in situ RT-PCR methodology. We show that GH transcripts are detectable in the thymus and liver of the 18-day fetus. At this stage, all thymocytes are immature and express the GH gene. In fetal liver, GH gene expression was localized in circulating lymphocytes and in hematopoietic cells surrounding GH mRNA-negative hepatocytes. In situ GH gene expression in fetal lymphoid organs was confirmed by in vitro RT-PCR showing that the amplified product from fetal lymphoid tissues was similar to the product obtained from the pituitary. Moreover, GH gene expression was detected in the thymus, spleen, and ileum Peyer's patches of adult rat, with a localization restricted to the lymphocytes and endothelial and smooth muscle cells of blood vessels. The autocrine/paracrine expression of the GH gene by lymphoid and hematopoietic cells during fetal growth might influence the generation of regulatory cells involved in immunity and hematopoiesis.

Animals↗

PubMed2001

Cellular localization of orexin receptors in human pituitary.

Orexins-A and -B are hypothalamic peptides derived from a precursor called prepro-orexin and relationated with the stimulation of food intake. They act on G protein receptors named orexin receptor 1 (OX(1)R) and orexin receptor 2 (OX(2)R), respectively. In the present study, we used RT-PCR and immunohistochemical techniques to detect the presence of OX(1)R and OX(2)R in human pituitary. A band of the expected size for both OX(1)R and OX(2)R was shown in human pituitary by RT-PCR. The cellular localization of OX(1)R and OX(2)R was carried out using histological techniques. By consecutive sections we demonstrated that OX(1)R was present in acidophil, diffusely distributed cells, which represent the half of the total adenohypophysis cell population. As was expected, these cells were shown to coexpress GH. OX(2)R was found in the pars intermedia and in clusters of basophil cells of the anterior pituitary, which coexpress ACTH. These results were confirmed by double immunofluorescence techniques. We also found focal positivity in axon terminals of neurohypophysis, more intense for OX(2)R than for OX(1)R. In conclusion, these results demonstrated for the first time that OX(1)R and OX(2)R were expressed by somatotrope and corticotrope cells, respectively.

Aged↗

PubMed2001

Cellular localization of orexin receptors in human pituitary.

Aged↗

PubMed2000

HCaRG, a novel calcium-regulated gene coding for a nuclear protein, is potentially involved in the regulation of cell proliferation.

Since a negative calcium balance is present in spontaneously hypertensive rats, we searched for the gene(s) involved in this dysregulation. A cDNA library was constructed from the spontaneously hypertensive rat parathyroid gland, which is a key regulator of serum-ionized calcium. From seven overlapping DNA fragments, a 1100-base pair novel cDNA containing an open reading frame of 224 codons was reconstituted. This novel gene, named HCaRG (hypertension-related, calcium-regulated gene), was negatively regulated by extracellular calcium concentration, and its basal mRNA levels were higher in hypertensive animals. The deduced protein showed no transmembrane domain, 67% alpha-helix content, a mutated calcium-binding site (EF-hand motif), four putative "leucine zipper" motifs, and a nuclear receptor-binding domain. At the subcellular level, HCaRG had a nuclear localization. We cloned the human homolog of this gene. Sequence comparison revealed 80% homology between rats and humans at the nucleotide and amino acid sequences. Tissue distribution showed a preponderance in the heart, stomach, jejunum, kidney (tubular fraction), liver, and adrenal gland (mainly in the medulla). HCaRG mRNA was significantly more expressed in adult than in fetal organs, and its levels were decreased in tumors and cancerous cell lines. We observed that after 60-min ischemia followed by reperfusion, HCaRG mRNA declined rapidly in contrast with an increase in c-myc mRNA. Its levels then rose steadily to exceed base line at 48 h of reperfusion. HEK293 cells stably transfected with HCaRG exhibited much lower proliferation, as shown by cell count and [(3)H]thymidine incorporation. Taken together, our results suggest that HCaRG is a nuclear protein potentially involved in the control of cell proliferation.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Internalization and nuclear translocation of IFN-gamma and IFN-gammaR: an ultrastructural approach.

IFN-gamma signalling involves the Jak-STAT pathway. However, several hypothesis have been proposed where the receptor and its ligand itself took an active role within the cell. Using a quantitative immunogold approach, we found that both IFN-gamma and its receptor are rapidly internalized and translocated in the nucleus. We found that cell surface heparan sulfate, which binds IFN-gamma, delayed the nuclear accumulation of IFN-gamma suggesting that these molecules serve as storage depot around the cell for local delivery of the cytokine.

Cell Nucleus↗