Biomedical subjects

S Binet

Publications and source records attributed to S Binet.

At least 19 recordsLinked to original sources

PubMed1999

Evaluation of rat hepatic 2E1 activity in function of age, sex and inducers: choice of an experimental model capable of testing the hepatotoxicity of low molecular weight compounds.

The aim of this work on rat hepatic P450 2E1 activity was to seek the most suitable experimental model to study the role of cytochrome P450 2E1 in the metabolism of industrial chemicals. Two sets of experiments were devoted to selecting the age and sex of animals and to estimating the response of male and female rats to different inducers. In the first set, the effect of three inducers (fasting; ethanol; acetone) was studied in male rats aged 5, 7 and 9 weeks. In the second set, the effect of different inducers, namely beta-naphthoflavone (BNF), phenobarbital (PB), ethanol, acetone and pyridine, on PNP and chlorzoxazone (CLZO) hydroxylase activities was studied in 7 week old male and female rats. The results demonstrate firstly that microsomal p-nitrophenol (PNP) hydroxylase activity significantly decreases in control male rats in inverse function of age, and secondly that induction by ethanol decreases with age. The PNP hydroxylase activity level of controls and the significant increases in PNP hydroxylase activity observed in 7 week old male rats show that this is the most suitable age for the second set of experiments. In this second set, it was shown that P450 1A (induced by BNF) is involved in CLZO hydroxylase activity only. PB increased the hydroxylase activities in male and female rats by about 1.5 and 1.7 times those of the controls, respectively. The effects of P450 2E1 inducers in function of sex show that male rats exhibited more significant increases in PNP and CLZO hydroxylase activities than female. The specificity of these two substrates is discussed. Neither of these two reactions was specifically catalysed by P450 2E1, but PNP may be considered as the most specific and the least sensitive substrate. In addition, the linear relationship observed between the two substrates (PNP and CLZO) showed a good correlation between their activities (r = 0.90, P < 0.001). In conclusion, these results suggest the use of the 7 week old male rat as the experimental model to study the role of cytochrome P450 2E1 in the hepatotoxicity of low molecular weight industrial chemicals.

Age Factors↗

PubMed1999

Occupational cancer in France: epidemiology, toxicology, prevention, and compensation.

This article is a description of the current situation in France with regard to occupational cancer: research, prevention, and occupation. Toxicologic experiments are carried out using (italic)in vitro(/italic) and (italic)in vivo(/italic) tests, particularly using transgenic mice. Several epidemiologic studies have been conducted over the last decades: population-based case-control studies; mortality studies and cancer incidence studies carried out in historical cohorts of workers employed in the industry; and case-control studies nested in occupational cohorts. French ethical aspects of toxicologic and epidemiologic studies are described. The results thus obtained are used to establish regulations for the prevention and the compensation of cancers attributable to occupational exposure. This French regulation for prevention of occupational cancer involves several partners: (italic)a(/italic)) the states authorities, including labor inspectors, responsible for preparing and implementing the labor legislation and for supervising its application, particularly in the fields of occupational health and safety and working conditions; (italic)b(/italic)) the Social Security Organisation for the analysis of present or potential occupational risks based on tests, visits in plants, complaints or requests from various sources, and statistics. These activities are performed within the framework of the general French policy for the prevention of occupational cancer. This organization includes the National Institute for Research and Safety, particularly involved in research in the various fields of occupational risks--animal toxicology, biologic monitoring, exposure measurements epidemiology, psychology, ergonomy, electronic systems and machineries, exposure to chemicals, noise, heat, vibration, and lighting; and (italic)c(/italic)) companies where the regulation defines the role of the plant manager, the occupational physician, and the Health, Safety and Working Conditions Committee (comprising the manager, employees' representatives, the occupational physician, and the safety department) in dealing with any problem regarding safety, occupational hygiene, and working conditions. These organizations along with medical practitioners are involved with the compensation of occupational cancers. The regulation for compensation includes the tables of occupational cancer, the possibility of recognition of a cancer case when the requirements of the tables are not met, and the postprofessional follow-up of workers exposed to a carcinogenic agent.

Animals↗

PubMed1998

Histopathological study in B6C3F1 mice chronically exposed by inhalation to glutaraldehyde.

Glutaraldehyde vapors are irritating for the skin, eyes, nose and lungs; respiratory symptoms and headaches have been described among workers exposed to low concentrations of glutaraldehyde far below to 190 ppb. This study was initiated to determine the chronic effects in mice of inhaled glutaraldehyde vapors. B6C3F1 mice were exposed using whole-body inhalation chambers, 6 h/day, 5 days/week, for 52 and 78 weeks to 100 ppb, or to filtered air (controls). In nasal passages at the level of the vestibule, hyperplasia of the squamous epithelium lining of the dorsal wall and lateral aspect of the atrioturbinate was observed in a greater number of exposed females than in controls. Epidermal erosion and ulceration as well as squamous and inflammatory exfoliation were also seen in the nasal lumens. All these changes were dependent on the length of glutaraldehyde exposure. The present data suggest that glutaraldehyde long term exposure only led to changes in nasal passages of female mice but did not induce mortality and/or tumors in nasal passages, in all mice. These results, along with the previous subchronic inhalation study of Gross et al., 1994, demonstrates that in a long term study, chronic glutaraldehyde exposure close to the current threshold limit values induced lesions at the more anterior part of the nasal passages in mice and that they likely result from an irritation mechanism (antero-posterior gradient).

Animals↗

PubMed1998

Serum-borne factor(s) of 1,1-dichloroethylene and 1,2-dichlorobenzene-treated mice inhibited in vitro antibody forming cell response and natural killer cell activity.

1,1-Dichloroethylene and 1,2-dichlorobenzene administered to mice produced liver and/or kidney damage which was quantified in this study by a histochemical method. The in vitro effect of sera obtained from these mice on antibody forming cell (AFC) response and natural killer (NK) cell activity was investigated in parallel with the assessment of sera tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. 1,1-Dichloroethylene (100, 150 and 200 mg/kg) provoked liver and kidney damage. Peak kidney damage occurred 16 h after the dose was administered and at 24 h in the case of the liver. During the peak level of liver damage, a serum-borne immunosuppressive effect was also at its highest level. With respect to sera cytokine levels, an increase of TNF-alpha and IL-6 was detected earlier, i.e. 6 h after toxic administration, followed by a decrease that tended toward a baseline level. There was a relationship between the tissue damage induced by 1,1-dichloroethylene and the immunosuppressive effect of mice sera on AFC response and NK cell activity. 1,2-Dichlorobenzene (300, 500 and 600 mg/kg) provoked only liver damage. Peak liver damage severity was observed 48 h after toxic administration, whereas the highest serum-borne immunosuppressive effect was observed almost immediately, i.e. 6 h after administration. As regards sera cytokine levels, only TNF-alpha could be detected 6 h after administering 500 and 600 mg/kg doses of 1,2 dichlorobenzene. There was a relationship between the liver damage induced by 1,2-dichlorobenzene and the immunosuppressive effect of mice sera on the AFC response. In view of the above results, this study suggests that the immunosuppressive effect in sera of mice treated with 1,1-dichloroethylene and 1,2-dichlorobenzene may result from tissue damage, and that the increased levels of TNF-alpha and IL-6 in sera may contribute to this effect. Further studies are needed to clarify the factor(s) responsible, including transforming growth factor-beta1 (TGF-beta1) causing immunosuppression.

Animals↗

PubMed1998

Cutaneous sensitization to some polyisocyanate prepolymers in guinea pigs.

Isocyanates are used extensively in the polyurethane industry. Pulmonary and dermal sensitization resulting from exposure to diisocyanates has frequently been reported, but the potential effects of polyisocyanates on health are less well known. Thus, since 1978, occupational exposure limits have been established for diisocyanates only. Nevertheless, respiratory diseases and dermatitis have been reported in the polyurethane industry after accidental isocyanate contact during spills or splashes. The aim of this experimental work was to assess the dermal hypersensitivity of guinea pigs to some polyisocyanate prepolymers by means of a well-conducted standard predictive Buehler test. Our results showed that dicyclohexylmethane 4,4'-diisocyanate (HMDI), toluylene 2,4-diisocyanate (TDI), TDI adduct triol, TDI isocyanurate, 1,6-hexamethylene diisocyanate (HDI), HDI isocyanurate, HDI biuret and isophorone diisocyanate (IPDI) induced dermal sensitization while IPDI isocyanurate did not. In conclusion, the dermal hypersensitivity of guinea pigs to some polyisocyanates was similar to those of their corresponding monomers except for IPDI isocyanurate, suggesting that the results from diisocyanate monomers could not be a valuable approach for the detection of the sensitization potency of the corresponding prepolymers.

Animals↗

PubMed1996

Patch testing with beryllium alloy samples in guinea pigs.

An experimental study was conducted in guinea pigs for the predictive assessment of the beryllium alloy hazard in occupational exposure of the skin to beryllium compounds. Guinea pigs were sensitized to beryllium sulfate according to the maximized Magnusson and Kligman test, and challenged with beryllium alloys and metallic copper, beryllium and aluminum samples. Results showed a delayed skin hypersensitivity reaction in 30 to 60% of pre-sensitized guinea pigs challenged with copper-beryllium alloys and aluminum-beryllium alloy. An inflammatory follicular reaction was induced by copper in both controls and pre-sensitized guinea pigs.

Allergens↗

PubMed1991

Modifications of tubulin heterogeneity during embryonic and postnatal stages in a specific region of mouse brain.

An auditory nucleus (the inferior colliculus of the mouse) was used to study the modifications of the heterogeneity of tubulin which occur at various stages of development and maturation. Both the cold-stable (CS) and cold-labile (CL) fractions of tubulin were analyzed by high-resolution isoelectric focusing. Our results suggest that tubulin heterogeneity is modified at critical stages of development and maturation, with specific variations of the two fractions. Stage E10 corresponding to the appearance of the first young neurons and axonal profiles is marked by the modification of the CS fraction with the emergence of isotypes alpha 5 to alpha 8 and beta 12 and beta 17. Stage E12 is characterized by the modifications of the CL fraction, particularly the beta-group; at this stage the first dendrites become visible. At birth, all isotypes increase in both the CL and CS fractions. At stages P7-P10 transient modifications of a group of both CS and CL fractions and of the beta group of CS fraction occur. These are associated with the emergence of isotypes beta 17 to beta 20 in the CL fraction. This period precludes the initial period of functional maturation of the auditory system which occurs from P10 to P20. During this period, the CL fraction (alpha and beta group) remains unmodified, whereas all isotypes of the CS fraction, except 3-4, display complex variations with an initial decrease until P12, an increase until P17, and a final decrease until P20.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1991

Quantitative analysis of monoclonal immunoglobulins in serum of patients with amyotrophic lateral sclerosis.

In a prospective study, we analysed the presence of monoclonal immunoglobulin (moIg) in the serum from 30 patients with amyotrophic lateral sclerosis (ALS) and 30 matched controls using a sensitive Western blot technique. The incidence of serum moIg was 60% in the ALS group and 13.3% in the control group. Most ALS sera contained 2 or 3 monoclonal components. They were IgG (72.7%) and IgM (27.3%). These results corroborate the concept of a probable association between ALS and serum moIg.

Adolescent↗

PubMed1990

Immunofluorescence study of the action of navelbine, vincristine and vinblastine on mitotic and axonal microtubules.

Among the various non-naturally-occurring Vinca alkaloid compounds, nor-anhydro-vinblastine (Navelbine, NVB) exhibits in preliminary clinical studies broader anti-tumor activity and lower neurotoxicity than vinblastine (VBL) and vincristine (VCR). The action of these 3 Vinca alkaloids on axonal and mitotic microtubules has been studied experimentally in a specific model, the tectal plate anlage of mouse embryos at the earliest stages of neuronal differentiation. Post-implantation embryos were cultured in toto in a medium containing increasing concentrations of drugs. Microtubules were stained using immunofluorescence with a tubulin-specific polyclonal antibody in semi-thin sections after embedding in high-molecular-weight polyethylene glycol. All drugs induced depolymerization of mitotic interpolar microtubules and cell metaphase block at the same concentration. Increasing the concentrations led to progressive depolymerization of kinetochore microtubules. However, NVB was the only drug to induce complete microtubule depolymerization. The activity of the 3 compounds on axonal microtubules was identical: depolymerization of a labile pool of microtubules. This was observed at higher concentrations with NVB than with the 2 other Vinca alkaloids. Our results show that, in this model, NVB is as active on mitotic microtubules as VCR and VBL, and less active on axonal microtubules. None of the 3 drugs modified microtubule length but all appeared to induce disruption of the labile microtubule pool without altering the stable pool.

Animals↗

PubMed1990

Embryotoxic effects of sodium arsenite and sodium arsenate on mouse embryos in culture.

Embryotoxic effects of two inorganic arsenic compounds, sodium arsenite (Asi) and sodium arsenate (Asa), on the development of mouse embryos during early organogenesis were studied using the whole embryo culture technique. Embryos with three to five somites exposed to 1-40 microM Asi or to 10-400 microM Asa were cultured for 48 hours and their development was compared with that of control embryos. Asi proved to be teratogenic between 3 and 4 microM and embryolethal at higher concentrations; Asa had similar activity but at concentrations ten times higher than for Asi. Both compounds produced a growth retardation and a similar pattern of defects. Growth retardation was indicated by a statistically significant reduction in crown-rump length, head length, and yolk sac diameter. Abnormal embryos were characterized by hypoplasia of the prosencephalon with open neural tube, hydropericardium, somite abnormalities, and failure of development of limb buds and sensory placodes. These results confirm that both Asa and Asi are embryotoxic compounds and that the Asi activity occurs at concentrations ten times lower than for Asa. Our results suggest that in humans both of these compounds may be involved in part of "unaccountable" early abortions and malformations claimed to be due to the toxicity of heavy metals.

Animals↗

PubMed1990

In situ response to vinka alkaloids by microtubules in cultured post-implanted mouse embryos.

The response of microtubules to treatment with vinca alkaloids was investigated in vivo and in situ in the embryonic nervous system of mice. For this purpose we used rotatory cultures of post-implanted embryos in a serum medium containing the alkaloid combined with immunofluorescence using a tubulin-specific polyclonal antibody on high molecular weight polyethylene glycol embedded semithin sections. In mitotic cells, kinetochore microtubules were seen to be more resistant to the action of vinca alkaloids than interpolar microtubules. Increasing drug concentrations induced an increasing rate of mitosis together with an increasing rate of disassembly of the cytoplasmic microtubule complex, suggesting a probable relation between these events. In bipolar neuroepithelial cells at interphase, a small pool of microtubules was resistant to the vinca alkaloids. These microtubules were located near the centriolar apparatus associated with the primary cilium; they were short, curly and bent. Disruption of the cytoplasmic microtubule complex did not alter the shape of the bipolar neuroepithelial cells. In the axonal profiles, a drug-stable pool of microtubules were not disrupted by the alkaloids and were also short. They seem to act as microtubule organizing centres. These observations suggest vinca alkaloids seem to act in vivo much more by inducing, at a given concentration, the disruption of a particular group of microtubules without altering the others. The fact that these drugs affect the number, but not the length, of the microtubules raises the hypothesis that these drugs act on microtubules by a mechanism similar to that described as "dynamic instability".

Animals↗

PubMed1989

Characteristics of microtubules at the different stages of neuronal differentiation and maturation.

The developing nervous system has proved to be a very powerful tool to analyze how MT are involved in basic biological processes such as cell proliferation, cell migration, cell shaping, and transport. A better knowledge of the basic events occurring during neurogenesis also affords us the possibility of establishing the basis of experiments and trying to solve unanswered and important questions. Despite the considerable value of cell culture, we need to use more discrete regions of the developing brain in situ in order to analyze the MT and their modifications into cells developing their "natural" environment. One major problem remains the question of the mode of assembly and disassembly, that is, the behavior of MT in living cells. Dynamic instability and/or treadmilling are accurate interpretations of the dynamics of MT at least in vitro or in cell culture, but we do need more information on what happens in situ and in vitro. One of the main tasks of cell biologists is to devise satisfactory tests to approach this fundamental question. In this view, pharmacological manipulation of embryos treated in whole-embryo culture systems might be a possible way. Microtubules are ubiquitous cell components. However, the extensive heterogeneity of MAP and tubulin in the CNS confers on the neurons a wide range of capabilities of assembly of these proteins and suggests that the neuron has a unique potential of a relation between MT composition and cell function. We have seen that each major event during neurogenesis is related to a specific series of modifications of the MT components. It remains to be determined if there is a causal or just a correlative relationship between the appearance of specific isotypes and the occurrence of specific events and/or functions. We have also to determine the exact spatial and temporal relations among the different isotypes of MT proteins, tubulin, and MAP. Is there a close correspondence between a tubulin and a MAP isotype? Can the appearance of one isotype of tubulin influence the appearance and the assembly of a specific MAP, or vice versa? Recent results obtained with the Tyr- and Glu-MT shed light on these questions and suggest a whole series of possibilities for cells to modulate the structure, behavior, and function of MT in specific domains of the neuron or in specific regions of the brain, by only a minute modification of the molecule of tubulin. Microtubule protein heterogeneity raises also a number of questions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Biochemical effects of Navelbine on tubulin and associated proteins.

Navelbine (NVB) or 5' nor-anhydro-vinblastine was shown to present a broader antitumor activity and to induce fewer side effects than vinblastine (VBL) or vincristine (VCR). The possible mechanisms of these differences were analyzed with in vitro methods. At substoichiometric concentrations, the three drugs inhibit microtubule assembly. NVB, in comparison with VCR and VBL, is shown to have a lower inhibitory effect. At stoichiometric concentrations, the three drugs are able to induce tubulin aggregation into spirals and paracrystals. This process involves a microtubule-associated protein (MAPs) family referred to as Tau and is inhibited by another MAPs family referred to as MAP2. However, dramatic quantitative and qualitative differences are observed between NVB and VLB or VCR in TAU-induced aggregation of tubulin. The rate and extent of NVB-induced tubulin aggregation is much lower. With NVB, only certain TAU isoforms are able to induce paracrystals, while all TAU isoforms may contribute to VCR-induced or VBL-induced paracrystals. The TAU isoforms that are not able to induce crystallization with NVB, at least in a certain range of concentrations, are probably involved in mitotic microtubules--the hypothetical antitumoral target of vinca alkaloids (VAS). The present work shows for the first time that an anticancer drug is able to discriminate between the various types of microtubules. A next step will be to investigate whether this property is limited to a modulating effect of the various TAU isoforms on the affinity of VAS for tubulin. These biochemical investigations will be extended to tubulins extracted from tumor cell lines in order to further discriminate NVB from the other VAS.

Animals↗

PubMed1989

In situ analysis of the action of Navelbine on various types of microtubules using immunofluorescence.

Preliminary clinical studies demonstrated that 5' nor-anhydro-vinblastine, Navelbine (NVB) has a broader antitumor activity and fewer neurotoxic effects than vinblastine or vincristine. The tectal plate anlage of mouse embryos at the earliest stages of neuronal differentiation were used to analyze and compare the effect of NVB, vincristine and vinblastine on axonal and mitotic microtubules after culture of post-implantation embryos in a medium containing the agent. All drugs are active on mitotic microtubules at the same concentration (0.1 mumol/L), inducing a depolymerization of microtubules and a blockade of cells at metaphase. At higher concentrations. NVB is the only one of the three drugs that induces a blockade of the cells at prophase. A depolymerization of axonal microtubules occurs at higher concentrations with NVB than with the two other vinca alkaloids. These results demonstrate that NVB is as active on mitotic microtubules and less active on axonal microtubules than vincristine and vinblastine. These findings can be related to the potent antitumor effect of the drug with minor neurotoxicity.

Animals↗

PubMed1988

Biochemical basis of microtubule cold stability in the peripheral and central nervous systems.

Cold-stable, cold-labile and unpolymerized tubulins extracted from thalamic nuclei (soma-enriched fraction) and various nerves (both central and peripheral: axon-enriched fractions) appear different when analyzed by high-resolution isoelectric focusing. Cold-labile tubulin appears identical to unpolymerized tubulin. The axonal fractions contain fewer tubulin isotypes than the soma-enriched fraction; the peripheral axonal fraction has fewer isotypes than the central fraction. Cold-stable tubulin exhibits a specific pattern characterized by the abundance of two isotypes of alpha-tubulin, 7 and 8, and one beta-tubulin, isotype 9, with slightly different patterns of the axon-enriched fractions from the central and peripheral nervous systems. Our results suggest that the cold stability of microtubules is based on biochemical properties of tubulin, and confirm the domain specificity of the heterogeneity of tubulin.

Animals↗

PubMed1988

Modifications of tubulin heterogeneity during axonal growth in the embryonic nervous system.

Tectal plates of mouse embryos were used to analyze the heterogeneity of tubulin with high resolution isoelectric focusing, at time of appearance of the young neurons and axons. In the cold-labile pool of tubulin, isotypes 6 and 7 appear, and isotypes 1, 3, 11, 13 increase their relative quantities. The increase of the prominence of the alpha-group with regard to the beta-group in the cold-stable pool of tubulin raises the question as to the exact role of tubulin in the cold stability. A role of other specific microtubule components also appears probable.

Animals↗

PubMed1988

Spatial organization of microtubules in various types of cells in the embryonic tectal plate of mouse using immunofluorescence after PEG embedding.

The spatial organization of microtubules in mitotic as well as in interphase cells and in axons has been investigated in situ in the embryonic nervous system of mice using high molecular weight polyethylene glycol-embedded semithin sections and immunofluorescence with a tubulin-specific polyclonal antibody. In situ, the overall process of mitosis appears nearly identical to that described in cell culture. All types of mitotic microtubules (kinetochore, interpolar and asterial) can be visualized at the different stages. The slight differences from observations in cell culture are explained by differences in cell interactions. In bipolar neuroepithelial cells, interphasic microtubules appear in the form of a framework surrounding the nucleus during its to-and-fro movements and which follows the modifications in shape of the cell processes. These microtubules seem to play an active role in the mechanism, indicating the modifications in length of the apical process. In the differentiating young neuron, tubulin increases in amount to be involved in the elongation of axonal microtubules. This increase seems to be independent of the presence of axons in the environment. Axonal microtubules are independent of a microtubule-organizing center localized in the perikaryon.

Animals↗

PubMed1988

Modifications of microtubule proteins in ALS nerve precede detectable histologic and ultrastructural changes.

Fast axonal transport is altered in nerves from amyotrophic lateral sclerosis (ALS) patients. Microtubules are involved in axonal transport. We analyzed the possibility of an involvement of microtubule modifications underlying the alterations in transport using biochemical and morphologic analysis of intercostal nerves from ALS and control patients. In intercostal nerves displaying no morphologic signs of acute neuronal degeneration, two-dimensional gels showed modifications of the group of beta tubulins and abnormal spots of proteins, some appearing to be closely related to tau proteins. These results suggest that microtubule proteins are modified in ALS before ultrastructural axonal degeneration, but the significance of these abnormalities remains hypothetical.

Adult↗