Search

Pas de résumé disponible en anglais., Le cytochrome P450 aromatase est l'enzyme responsable de la conversion irréversible des androgènes en estrogènes. Le rôle majeur de ces hormones s'exerce essentiellement sur la reproduction mais aussi sur les fonctions de différents tissus. Les cas de déficience en aromatase et les études de mutagenèse dirigée ont permis de mieux connaître sa structure et son fonctionnement. Nous avons mesuré l'activité de l'aromatase en présence de ses substrats, différents selon leur biodisponibilité tissulaire. En plus de cette diversité tissulaire de l'estrogène formé, le gène CYP19 de l'aromatase présente une régulation tissulaire complexe et différentielle, notamment au niveau des tumeurs mammaires, et nous avons étudié cette régulation par différents facteurs et par mutagenèse dirigée sur des lignées de cellules humaines. Cette approche nous a également conduit à expérimenter la nouvelle stratégie de l'interférence avec les ARNm. Par ailleurs, la contribution des facteurs génétiques dans le cancer du sein notamment pouvant être inférieure à 10%, des facteurs externes pourraient jouer un rôle significatif dans le développement de cette pathologie. Les effets d'un composé industriel, le BPA et de deux pesticides, le lindane, un insecticide, et le Roundup, un herbicide composé de glyphosate et d'adjuvants, modèle intéressant pour étudier les effets combinés des produits chimiques sur la santé, ont été mesurés sur la viabilité, l'activité et l'expres-sion de l'aromatase in vitro. Cette connaissance pourrait permettre d'améliorer la prévention mais aussi de revoir l'homologation des pesticides avant leur mise sur le marché.

The goal of the present review is to collect information concerning membrane effects induced by lindane intoxication, a y isomer of hexachiorocyclohexane (gamma-HCH) that has been largely used as an insecticide and disinfectant in agriculture and entered also in the composition of some lotions, creams and shampoos used against parasites (lice and scabies). Absorbed through respiratory, digestive or transcutaneous pathways, lindane accumulates within lipid rich tissues. Lindane accumulation depends on the duration of the exposure and affects tissues in the following order: adipose tissuesbrainkidneymusclelungsheartliverblood. Whatever the mode of lindane absorption, it accumulates in blood and is distributed throughout the body. It may affect human health by exerting systemic, immunologic, teratogenic, and/or cancerogenic effects. The symptoms of lindane intoxication are different according to the mode of intoxication, acute or chronic. The absorption of high doses of gamma-HCH is particularly toxic for the central nervous system and for the female and male reproduction apparatus in mammals where lindane is considered as an endocrine disruptor. Lindane is highly lipophilic and incorporates into biological membranes according to the following sequence: mitochondriasarcoplasmic reticulummyelinbrain microsomeserythrocytes. Lindane exerts a stimulating action on synaptic transmission and inhibits the chloride current activated by gamma-amino butyric acid (GABA) of many muscular and nervous preparations by interacting with the receptors GABA-chloride channel complex. It seems to affect calcium homeostasis of many tissues. The similarity between lindane and inositol (1, 4, 5) phosphate (IP3) suggested that lindane releases Ca2+ from IP3-sensitive intracellular stores in macrophages and myometrial cells. Ca2+ release from reticulum endoplasmic, mitochondria and other Ca2+ stores has been reported in cat kidney cells. Lindane altered energetic metabolism of hepatic mitochondria and the inositol-phosphate synthesis in neuronal cells. However, lindane does not compete with the IP3 receptor. Lindane produces a Ca2+ influx in mice peritoneal macrophage cells responsible for the Ca2+ induced Ca2+ release produced by phospholipase C via IP3 pathway and resulting in a maintained increase of the free cytosolic Ca2+ concentration. Lindane decreased the membrane erythrocyte and cerebral cell concentration of phosphatidyl inositol PI, PIP and PIP2 in rats repetitively exposed to lindane for 3 or 6 months. Lindane induces oxidative stress; it modifies the activity of the scavenger enzymes. This effect is involved in the inhibition of intercellular gap junctions. Modifications of the electrocardiogram (ECG), sinusal rhythm alteration and negative and dysphasic variations of T wave, similar to those produced by hyperkaliemia, have been reported after lindane absorption. During acute lindane poisoning, the activities of serum transaminases (SGOT, SGTP), and lactate deshydrogenase (LDH) increase. Lindane produces histological alterations of cardiac tissues and a cardio-vascular dystrophy (contracture, degenerescence and necrosis) mainly in the left ventricular wall and a hypertrophy of the left ventricle. Chronic application of residual doses of lindane shortened the action potential duration in rat papillary muscle. These effects were similar to those induced by hyperthyroidism. Lindane increases the triiodothyronine (T3) serum level in hyperthyroid rats. T3 plays an important role in the postnatal development of the rat ventricle by increasing the density of potassium channels which contribute to action potential shortening during the development. Thyroid hormones influence the regulation and the expression of messengers ARN which encode different potassium channels involved in action potential repolarization (Kvl.2; Kvl.4; Kvl.5; Kv2.1; Kv4; HCN2). The thyrotropine-releasing hormone (TRH) modulates the HERG-type rapid delayed potassium channel (IKr) encoded by the human gene ether-a-go-go in rat anterior pituitary cells GH3/B6. This channel is involved in the cardiac long QT syndrome. TRH modifies the current kinetics of human HERG potassium channel co-expressed in Xenopus oocytes with the TRH receptor, whose activity is modulated via the protein kinase C pathway linked to a G protein-coupled receptor and is regulated by changes in the PIP2 concentration in the membrane. IKr channels regulation is also dependent on sexual hormones. In conclusion, lindane affects the excitable membranes and the cardio circulatory system. These alterations (may) represent a potential risk for human health.

The present paper bears on the main effects of lindane (gamma isomer of hexachlorocyclohexane) on endocrine and reproductive functions in mammals. This pesticide, once widely used to kill lice and a variety of pests that attack agricultural products, livestock and trees, has been progressively eliminated from many applications since the mid-1970s in Europe or USA, but is still used in the rest of the world. Lindane is absorbed through respiratory, digestive or cutaneous routes and accumulates in fat tissues. It damages human liver, kidney, neural and immune systems and induces birth defects, cancer and death. Chronic administration results in endocrine disruption in birds as well as in mammals. Treatment with 1-40 mg of lindane/kg b.w. disrupts testicular morphology, decreases spermatogenesis, inhibits testicular steroidogenesis, reduces plasma androgen concentrations and may adversely affect reproductive performances in males. In females, lindane disrupts the estrous cycle, reduces serum estrogen and progesterone levels, decreases sexual receptivity whereas in pregnant dams it decreases whelping rate and litter size. These effects were also observed in some rats exposed to residual environmental doses. In addition, there is concern that irreversible effects may be induced when animals are exposed to endocrine disrupting chemicals during critically susceptible phases of sexual differentiation or development. These effects would results from (i) alterations of gonade or gamete cell membranes (ii) cell metabolism changes including alterations of ionic exchanges (mainly calcium or potassium), direct or free radical-mediated inhibition of steroidogenesis (iii) or neuroendocrine changes leading to a decrease in sexual performance of either parents or their offsprings exposed in utero or through lactation.

A questionnaire survey of head lice treatment was conducted in four schools--each including a nursery and an elementary school--in the Bordeaux area. Two schools were situated in the centre of the city, one in a suburban area and one in a rural area (50 km from the city). Four-page questionnaires were filled in anonymously by the parents in April 1991; 840 answers were obtained (80 p. 100 response rate). Between January 1990 and March 1991, 48.7 p. 100 of children had at least one episode of head lice infestation (infestation rates varied from 38.8 to 62.6 p. 100 depending on the schools); 30.5 p. 100 of children were contaminated for the first time during that period. Lice were detected by the parents in 95 p. 100 of the cases. The prevalence of lice was higher in females (60 p. 100) than in males (40 p. 100). The highest prevalence was noted in the suburban school where 17 p. 100 of the parents were unemployed at the time of the survey. The peak age for head lice was 7, but 19.4 p. 100 of nursery school children aged 2-4 years had been contaminated at least once. Impetigo was rare (1.2 p. 100), and pruritus was noted in only 14.2 p. 100 of the cases. Most children had been contaminated at school. Curative treatment was counselled by a chemist in 87 p. 100 of the cases. Pyrethrins were used in 81 p. 100, and the shampoo (Hegor) plus spray (Paraspecial Poux) association was the most frequent, totalling two-thirds of prescriptions.(ABSTRACT TRUNCATED AT 250 WORDS)

The monthly analysis of milk mixtures from ten French human milk banks, over a period of two years, showed that there was marked pollution by organochlorine insecticide residues. The following averages were noted: hexachlorocyclohexane + hexachlorobenzene 2,75 mg/kg of pure fat, DDT and derivatives 3,24 mg/kg fat, heptachlor epoxide 0,28, dieldrin 0,23. The main insecticides were, with average values, beta hexachlorocyclohexane (1,67), hexachlorobenzene (0,98), and dichlorodiphenyldichloroethylene (2,40). All these milks were invariably very polluted throughout the year, but there were however noted some qualitative differences according to the geographic position of the milk banks: South of the Loire river, the main polluting factor was hexachlorocyclohexane, whilst North of the Seine, fairly high values were found for heptachlor epoxide and dieldrin. The special study of human milk from Lille showed a 50% reduction in pollution between 1970 and 1973. The probable routes of contamination are human food and the ill-advised domestic use of pesticides.

Chemical substances added for various purposes to the feeds of farm-reared animals may enter the body of these animals. This may lead to the persistence, in food offered for human consumption, of residues which may be potentially toxic under conditions of repeated absorption over the greater part of the life span. The evaluation of the safety of these residues for man poses complex problems. Their ideal solution demands very often a number of careful experiments. The methodology called "toxicity by relay" consists essentially of the submission of the animal feed itself, which is likely to contain a mosaic of residues, to long-term testing in laboratory animals. Provided a satisfactory safety factor can be applied, this methodology can contribute information permittinga conclusion regarding the acceptablity, even provisionally, of the feed additive for the use which is envisaged. In addition this methodology enables the provision of results constituting a criterion for the rejection of the additive under test. For these reasons it appears to us an appropriate procedure, taking its place among the tests to be undertaken for the toxicological evaluation of additves to the feeds of farm-reared animals.

Acute intoxication of adult female rats by an injection of 15 mg of Lindane or 25 mg of 2-4-5 T induces, in one hour, as decrease in the adrenal epinephrine level and an increase in the urinary excretion of this hormone. These modifications are absent after chronic intoxication by these pesticides added in the food (60 and 100 ppm respectively), under normal, hypo- and hyperlipidic diet.

The olfactory bulb responses induced by nasal infusion of three pesticides (Atrazine, Lindane, Ethyl Parathion) were studied in the rainbow Trout, Salmo gairdneri. Amplitude and frequency changes were characteristic for each solution tested at concentrations ranging between 10 ng/l and 1 mg/l.

The risks of incidents and accidents--especially systemic ones--complicating topical scabies treatment in infants are reviewed. After a short review concerning insecticides (sulphur, benzyl-benzoate, DDT, Lindane, Crotamiton) and the use of several drugs proposed for infants, the authors insist on the choice of the drug and the therapeutic protocol, that are as important as the drug itself. Directions for use should be strict, in order to avoid automedication and overdosage. There is no study concerning the comparative evaluation of risks and efficacy of each drug.

Lindane neurotoxicity is studied in vitro on Rat brain synaptosomes. Calcium uptake of isolated synaptosomes increases in the presence of pesticide; lindane action is observed on both normal and depolarized preparations.

Young male rats, Wistar CF strain, about 70 g body weight, were fed a well-balanced diet containing 0 (control), 60 or 240 ppm lindane. The day before the experiment, all the animals were fasted, and some of them placed in a restraint wheel forcing them to walk on during 18 hrs; another group was given an i.p. injection of 2.6 g/kg glucose 30 minutes before their sacrifice. The redox and energy potentials of liver and muscle tissues were estimated after the determination of the following compounds: lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, ATP, ADP, AMP, inorganic phosphate, NADP and NADPH. No effect of lindane was observed on muscle metabolism and the 60 ppm dose was without significant effect on liver metabolism. At the 240 ppm dosage: a. Lindane ingestion increased the liver betaHOB/AcAc ratio and decreased the Lac/pyr ratio. The ATP/ADP ratio was not significantly lowered, although the ATP concentration was diminished and, conversely, the AMP and inorganic P ones were elevated; b. Whereas lindane lowered the glucose effect on the mitochondrial redox potential, it had no influence on the increasing of the ATP/ADP ratio by glucose, or on the antiketogenic effect of this sugar; c. In the animals fed the lindane-contaminated diet, muscular exercise increased the liver betaHOB/AcAc and NADPH/NADP ratios, while the lac/pyr and ATP/ADP ratios were unaltered. But blood pyruvate was increased. The following interpretation has been given. Lindane ingestion inhibits liver mitochondrial activity and increases ketogenesis. The glucose treatment results in a poor glucose utilization for energy needs in the contaminated animals and the forced muscular exercise shows that gluconeogenesis proceeds at a slower rate than in the controls. It is suggested that an increased demand in NADPH, as resulting from the induction of the microsomal enzymes by lindane, is one of the mechanisms by which the pesticide inhibits the activity of the tricarboxylic acid cycle.

Effects of assocation of lindane ingestion and sulfur depletion on pregnancy in the rat. Sulfoconjugation stands as one of the main processes of foreign compound detoxication in mammals. When feeding conditions are adequate, sulfate ions necessary to form sulfoconjugates are provided by the sulfur aminoacids of the diet. The feeding to pregnant rats of a diet containing lindane, when sulfur aminoacids are limiting factors, should lead to competition between their utilisation for anabolic or detoxifying processes. The balance between stimulation of glucuroconjugation and sulfoconjugation seems to depend on which of the 2 compounds necessary for detoxification is the most limiting factor. Glucuroconjugation spares sulfur aminoacids for foetal growth; sulfoconjugation spares glucose for foetal utilisation. The foetal needs appear to modulate the orientation of the maternal detoxication processes; foetal anabolism is predominent over detoxication.

The pulverization of Japanese Quail eggs with a solution of commercial Lindane has a repercussion on fertility, embryonic mortality, hatchability, egg production, eggs and Quail-Chickens weight (Studies in for generations).

14C-Lindane retentions in Rat tissues were studied until 24 hrs after a single dose pesticide administration. Each organ shows particular kinetics. Adipose tissue is the most active in pesticide fixation but the lungs retain retain momentarily a large fraction of Lindane after intravenous injection.

Lindane or HCH is gamma-hexachlorocyclohexane, still used as an agricultural insecticide. Tests were carried out using primary cultures of chicken embryo hepatocytes at the 11th day of incubation, for a fixed period of 40 hours, using different concentrations of the substance. From 0.5 to 10 mumol/l, acid phosphatase fell significantly, without any other consequences being observed. From 25 to 50 mumol/l, there was a tendency to hypertrophy of the mitochondria, to hyperplasia of the granular and smooth endoplasmic reticulum, and of the Golgi system. Growth was unchanged and acid phosphatase decreased. From 75 to 125 mumol/l, these changes were accompanied by signs of cellular damage and there was marked autophagia. Growth was reduced and acid phosphatase greatly decreased. From 150 to 175 mumol/l, the lesions were markedly polymorphous and some indicative of impending cytolysis, in particular spiral tearing of the hyaloplasm. Growth was markedly impaired, whilst there was a paradoxal increase in acid phosphatase. In increasing concentration, L first had the effect of a metabolisable foreign substance, of the "phenobarbital" type, then a definite toxic action. Sensitivity of the individual hepatocytes differed.

The effects of 0.5 ppm of lindane were studied on the morphogenesis and the initial functioning of the thyroid gland. Some disturbances were observed: the formation of the first follicles were delayed and ultrastructural changes were noted: increase in the number of mitochondria, reduction of the endoplasmic reticulum. This demonstrates a noxious effect of lindane at the beginning of the functional maturation of the thyroid gland.

Residual radioactivity in Rat brain structures is studied after single dose 14C Lindane administration. Short time after injection, at the onset of convulsions, white matter and myelinated structures show important retention, nucleated cells do not. This heterogeneous distribution agrees with the lipophilic behaviour of the pesticide.

Any topical treatment may lead to systemic side-effects through epidermal penetration. In children the ratio surface treated/weight is usually high, implying greater risk. Factors which determine percutaneous absorption in childhood are reviewed as well as the main drugs which are toxic when applied to the skin.

Lindane, in contact with cultured foetal chicken liver cells over a period of 40 hours, has a biphasic action on the lysosomal system of the cells. For the concentrations between 1 micronM and 25 micronM not affecting the cellular growth, the decrease of the acid phosphatase activity and the absence of any reaction in the Golgi saccules might indicate a reduction in the synthesis of the lysosomal enzyme. For the concentrations above 25 micronM slowing down cellular growth, acid phosphatase activity is partialrogeneous content and an increase in the relative acid phosphatase activity in the soluble extralysosomal fraction, for doses over 150 micronM, might indicate the development of the phenomenon of autophagocytosis.

The action of the ingestion of balanced diets containing pesticides [lindane (125 ppm) or/and zineb (5200 ppm)] on aflatoxin B1-induced toxic effects (inhibition of RNA and protein syntheses in liver) has been determined in two animal species. In the rat, the ingestion of these diets for 4 weeks before aflatoxin B1 treatment (0,7 mg/kg for 3 h), strongly decreased the toxic effects on both transcription and translation. By contrast, in the mouse, the above-mentioned diets did not modify the extent of the inhibition produced by aflatoxin B1 (60 mg/kg for 3 hr) on RNA and protein syntheses. These results were discussed.

The effect of lindane commercial solution spraying on quail eggs is studied in four generations running issued from a single parental strain. Observations have been made on fourteen-day embryos, one-day chicken and also two-or eight-month adults quail. The results lead to conclude that pathogenous effects of lindane on gonads and müllerian tract are slowly annuled through successive generations when the experimental procedure consists in treating only the parental eggs. Conversely, following pesticide administration repeated at every generation, the action becomes cumulative and the ratio of aberrations increases. In ovarian and testicular tissues there are cyto-histopathological modifications. Many gonocytes are abnormal and cannot divide. Some of these cells degenerate at the meiotic prophase. Egg production and fertility in adults depend on these phenomenons.

Indoor spraying with residual insecticides is at present the most effective method of malaria control. Following the failures observed during the campaigns of malaria control using D.D.T., B.H.C. and dieldrin, the W.H.O. has undertaken a wide programme for evaluating and testing new insecticides. The principal compounds tested are discussed. Only four insecticides have been held back: malathion, propoxur, fenitrothion and dichlorvos. However this compounds are very expensive and less remanent than D.D.T.