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PubMed1986

Serotonin receptors in striatum after chlordecone treatment of adult female rats.

Serotonin receptors were examined in various brain regions of female rats 24 hours after treatment with 25, 50 or 75 mg/kg chlordecone. With each dose of chlordecone, there was a significant reduction in the specific binding of 3H-5-HT to striatum. Binding to cortex, hippocampus, hypothalamus, midbrain or brainstem did not systematically vary as a function of treatment conditions. Tremor developed in chlordecone treated female rats in a dose dependent manner with 25 mg/kg producing only slight tremor. Moderate to severe tremor was evident in rats given 75 mg/kg chlordecone. These findings support previous indications that chlordecone's action on the striatal serotoninergic system in an important component in its induction of tremor. Most such studies, however, have used relatively high doses of chlordecone so it has been difficult to determine if the serotoninergic change preceded or resulted from the tremor. The significant decrease in serotonin receptors at a dose of chlordecone which led to only slight tremor suggest that the serotoninergic change may be causally related to the production of the tremor.

Animals↗
PubMed1987

Modulation of adrenal ornithine decarboxylase by chlordecone, p,p'DDT and permethrin.

Adrenal ornithine decarboxylase (ODC) is greatly elevated in rats dosed once with one of several insecticides; chlordecone, p,p'DDT or permethrin. An abrupt rise in the dose-response curve was apparent between 25 and 50 mg chlordecone/kg body wt, corresponding to the range where major behavioral changes occur. The latter dose of chlordecone resulted in a persistent elevation of adrenal ODC for at least 4 days, longer than that caused by the other insecticides examined. No equivalent changes were found in levels of hypothalamic or hippocampal ODC after chlordecone treatment. Hypophysectomy did not reduce the response of adrenal ODC to chlordecone, after the diminished size of the adrenal gland in operated animals was taken into account. Isolated adrenal cortical cells of a mouse tumor line (Y-1), when incubated in media containing 10(-5) M chlordecone, responded with increased ODC activity. These data suggest that the mechanism of adrenal activation by chlordecone may possess a direct component, in addition to the well-characterized stimulation of pituitary ACTH secretion caused by chlordecone acting on the hypothalamo-hypophyseal system.

Adrenal Glands↗
PubMed1993

Hepatic failure leads to lethality of chlordecone-amplified hepatotoxicity of carbon tetrachloride.

Chlordecone (Kepone) amplification of CCl4 toxicity occurs at small, nontoxic levels of chlordecone and CCl4 and results in highly increased irreversible hepatotoxicity culminating in lethality. Although it is generally assumed that CCl4 lethality is due to hepatic failure, no definitive studies are available in the literature bridging massive liver failure and death. The present studies were designed to evaluate whether hepatic failure is the cause of the lethality during chlordecone-amplified CCl4 toxicity. Male Sprague-Dawley rats were maintained on control or a chlordecone (10 ppm) diet for 15 days and injected with CCl4 (100 microliters/kg, ip) on Day 16. Rats were killed at 0, 6, 12, 24, 36, and 48 hr after CCl4 challenge. Hepatic failure was evaluated by measuring plasma glucose, ammonia, bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), sorbitol dehydrogenase (SDH), hepatic ATP, glycogen, and by histological and histomorphometric analyses. Plasma creatinine, urea, and kidney histopathology were also assessed for possible renal injury. As expected CCl4 administration to chlordecone-pretreated rats resulted in 20% lethality by 36 hr, which progressed with time, and all rats died within 72 hr. A significant and progressive hypoglycemia was observed with a 60% reduction in plasma glucose at 48 hr. Hepatic glycogen content dropped precipitously. Similarly, hepatic ATP levels remained suppressed (80% of control) at all the time points studied. Plasma ammonia levels were significantly elevated, and by 48 hr, a threefold increase was observed. Plasma ALT, AST, SDH, and bilirubin increased progressively until the death of rats receiving the chlordecone + CCl4 combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Changes in synaptosomal pH and rates of oxygen radical formation induced by chlordecone.

The resting pH of 7.14 +/- 0.02 within rat cortical synaptosomes is elevated in vitro by the insecticide chlordecone, in a dose-dependent manner. Chlordecone also reduces the rate of oxygen radical formation within synaptosomes. Both of these changes can also be demonstrated following in vivo treatment of rats with chlordecone (75 mg/kg body wt). Although chlordecone increases the permeability of the plasma membrane, the increase in pH observed is unlikely to be caused by this, since in vivo administration of chlordecone does not appreciably alter membrane order as evaluated by both a lipophilic probe, and a probe with an ionic segment. Another xenobiotic agent, methyl mercuric chloride, and a free radical generating system, an ascorbic acid-ferrous sulfate mixture, did not modulate synaptosomal pH, although membrane permeability was increased. Other evidence of the ability of synaptosomes to maintain homeostasis was the failure of mitochondrial inhibitors to significantly reduce pH. The drop in synaptosomal pH effected by amiloride, an inhibitor of Na+/H+ exchange, and the transient rise in pH caused by ammonium chloride further suggested that synaptosomes may be a good model in the study of the regulation of intracellular pH. The elevation of cytosolic pH, and depression of oxygen radical formation by chlordecone, may result from both the attenuation of respiratory metabolism and an impaired capacity of the plasma membrane to maintain ionic gradients.

Amiloride↗
PubMed1983

Chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity: a light and electron microscopic study.

Previous studies have shown that a chlorinated pesticide, chlordecone (Kepone), greatly potentiates carbon tetrachloride (CCl4) hepatotoxicity and lethality (Curtis, L.R., Williams, W.L., and Mehendale, H.M. (1979). Toxicol. Appl. Pharmacol. 51, 283-293; Curtis, L.R., and Mehendale, H.M. (1980). Drug Metab. Dispos. 8, 23-27). The present study describes sequential morphologic changes which occurred in livers of rats given a "nontoxic" level of chlordecone (10 ppm for 15 days) followed by a single injection of CCl4 (0.1 ml/kg). The hepatic alterations were examined 1 to 36 hr after exposure of the rats to CCl4. Those changes were compared to hepatic alterations which occurred in rats that received the same dose of chlordecone (10 ppm for 15 days) or a single injection of CClr (0.1 ml/kg) alone. The only change noted in livers from rats that received chlordecone alone was focal increase in smooth endoplasmic reticulum (SER) of hepatocytes at 24 hr and continuing throughout the time course of the experiment. Livers from animals that received CCl4 alone showed morphologic changes at 6 hr consisting of glycogen loss, increase in SER, and dilatation of rough endoplasmic reticulum (RER) in pericentral hepatocytes. Accumulation of small lipid droplets was also noted in midzonal hepatocytes. After 6 hr, there was no further increase in severity of injury. At 12 hr recovery was noticeable and, by 36 hr, livers from the CCl4 group appeared normal. Prior administration of chlordecone greatly potentiated pathologic changes in livers of animals that received CCl4. By 4 hr, there was total loss of glycogen in hepatocytes throughout the entire lobule. Small lipid droplets were present in pericentral, midzonal and periportal hepatocytes. Hepatocytes with extremely dilated RER were randomly scattered throughout the entire lobule. At 6 hr, there was further accumulation of lipid in the form of large droplets in hepatocytes. Focal, necrotic cells surrounded by polymorphonuclear leukocytes were randomly distributed throughout the lobule. The number of necrotic foci had progressively increased at the 12- and 24-hr intervals. By 36 hr, confluent areas of necrosis in pericentral and midzonal areas were observed in livers of some animals. This study indicates that although the combination of chlordecone and CCl4 produces much greater hepatic injury resembling damage due to a massive dose of CCl4, histologically, some differences in the progression and distribution of hepatocellular damage within the lobular architecture of the liver are evident.

Animals↗
PubMed1988

Pharmacological evaluation of central adrenergic involvement in chlordecone-induced hypothermia.

Adrenergic involvement in the hypothermia produced by systemically administered chlordecone (CLD) was evaluated in the rat using intracisternal pretreatment with 6-hydroxydopamine (6-OHDA), alpha-adrenergic receptor antagonists (phenoxybenzamine and phentolamine) and beta-adrenergic antagonists (propranolol and atenolol). The effect of intraperitoneal administration of 75 mg/kg of chlordecone on colonic temperature (Tcol) in male Fischer-344 rats was measured 7 days after administration of 6-OHDA and 30 min following pretreatment with the receptor antagonists. Prior depletion of catecholamines in brain with 250 micrograms of 6-OHDA administered intracerebrally attenuated hypothermia induced by chlordecone, without affecting basal Tcol. Phenoxybenzamine (10 or 20 micrograms) and phentolamine (5 or 10 micrograms) also reduced the hypothermic response to chlordecone. The beta-adrenergic receptor antagonists propranolol (50 or 100 micrograms) and atenolol (10 or 20 micrograms) did not attenuate chlordecone-induced hypothermia. These data suggest that the hypothermia induced by chlordecone is a result of alterations in central alpha-adrenergic functions, possibly involved with the sympathetic control of vasomotor tone.

Animals↗
PubMed1983

Studies on the possible sites of chlordecone-induced tremor in rats.

A series of psychopharmacological agents were administered to adult male Fischer-344 rats pretreated with a tremorigenic dose of chlordecone in an attempt to elucidate the involvement of spinal and supraspinal processes in the mediation and/or expression of chlordecone-induced tremor. Agents effective in attenuating the frequency of tremor were chlordiazepoxide, muscimol, and mecamylamine; quipazine exacerbated the tremor. Catecholaminergic agents including yohimbine, clonidine, propranolol, and haloperidol did not affect the frequency of chlordecone-induced tremor. Disinhibition of postsynaptic inhibitory sites in the spinal cord with strychnine and antagonism of spinal and supraspinal polysynaptic pathways with mephenesin exacerbated and attenuated the effects of chlordecone, respectively. Destruction of the climbing fibers with 3-acetylpyridine effectively blocked harmine, but not chlordecone-induced tremor, suggesting that chlordecone does not act through this pathway.

Animals↗
PubMed1983

Effects of chlordecone and its alteration products on isolated rat liver mitochondria.

Partitioning of chlordecone, chlordecone alcohol, monohydrochlordecone, and dihydrochlordecone (2 to 100 microM) into isolated rat liver mitochondria altered the permeability properties of the inner membrane as evidenced by: inhibition of valinomycin-induced swelling, induction of passive swelling, oxidation of exogenous NADH, and induction of lysis. Associated with the increase in permeability were stimulation of state 4 and inhibition of state 3 respiration for the oxidation of both succinate and glutamate. Except for the inhibition of valinomycin-induced swelling, the following order of potency for all assays was obtained: chlordecone alcohol greater than or equal to chlordecone greater than monohydrochlordecone much greater than dihydrochlordecone. Mirex, a 12-chlorine analog of chlordecone, and a dioxolane-chlordecone adduct did not affect any of the reactions at saturating concentrations of 40 and 100 microM, respectively. The hydrated ketone, or a hydroxyl moiety, and a high chlorine content appear to be responsible for lytic and inhibitory activity. Lysis resulted in the leakage of water-soluble matrix enzymes from the mitochondria, but not in the solubilization of integral proteins.

Animals↗
PubMed1986

Dominant lethal assay of chlordecone and its distribution in the male reproductive tissues of the rat.

Male rats received 3.6 or 11.4 mg/kg/day of chlordecone orally for 5 days. Some statistically significant events were seen in the reproductive data of females mated to males receiving chlordecone. However, these events did not follow a consistent pattern and do not suggest the conclusion that chlordecone causes dominant lethal effects. Male rats received a single oral dose (40 mg/kg) of chlordecone and were killed at 1, 2, 3, 5, 7, 14 or 21 days. Chlordecone was distributed throughout the reproductive tract. The descending order of concentration was seminal vesicular fluid greater than prostate greater than vas deferens greater than seminal vesicle greater than unwashed sperm greater than washed sperm. It is concluded that chlordecone is well distributed throughout the reproductive tract of the male rat, appears in the ejaculate, and does not appear to produce dominant lethal effects.

Animals↗
PubMed1989

Chlordecone-induced follicular toxicity in mouse ovaries.

The effect of the pesticide, chlordecone, on murine follicular development was examined. Female CD-1 mice were exposed to chlordecone for 5 consecutive days for each of 4 consecutive weeks (0.25 mg/day). Controls received sesame oil vehicle or estradiol-17 beta (E-17 beta; 0.1 mg/day) since chlordecone has been ascribed estrogenic activity. Animals were sacrificed 24 h following the final exposure. Ovaries were removed, serially sectioned, and stained. Follicles were classified as small, medium, or large and were tabulated. Twice as many medium-sized follicles were found in the E-17 beta-treated mice as in both the chlordecone-exposed and sesame oil control groups. Both pesticide- and E-17 beta-exposed mice displayed a much higher percent of atresia in the large follicles; however, there were more actual healthy, large follicles in the E-17 beta group. Thus, both chlordecone and E-17 beta induced increased atresia among large follicles, which could be due to the estrogenicity of these agents. However, a decreased pool of healthy large- and medium-sized follicles occurred in chlordecone-treated mice, a condition not seen in E-17 beta-treated mice. Thus, the pool of potentially ovulatory follicles is reduced in the pesticide-treated animals.

Animals↗
PubMed1994

Adenosine triphosphate protection of chlordecone-amplified CCl4 hepatotoxicity and lethality.

Dietary exposure to a nontoxic level of chlordecone (10 ppm for 15 days) followed by a single exposure to a subtoxic dose of CCl4 (100 microliters/kg, ip) is known to result in a 67-fold amplification of CCl4 toxicity. The hypothesis that the underlying mechanism is due to incapacitation of hepatocytes leading to an ablation of the early-phase hormetic response of tissue repair as a consequence of precipitous decline in hepatic glycogen and ATP, received experimental support from Mehendale in 1990. The present study was designed to investigate if direct administration of ATP to rats maintained on the chlordecone diet would result in protection from the hepatotoxic and lethal effects of the chlordecone+CCl4 combination. Male Sprague-Dawley rats (125-150 g) were maintained either on a diet containing no added contaminants (control) or on a diet containing 10 ppm chlordecone for 15 days, and were challenged with CCl4 (100 microliters/kg, ip) on day 16. Without ATP administration all rats died within 72 h, while administration of ATP (100 mg/rat, sc) to chlordecone-pretreated rats at -1, +1, 3, 5, 12, 24 and 36 h of CCl4 injection resulted in 100% survival. Injection of ATP, at -1, +1, 3 and 5 h of CCl4 administration to chlordecone pretreated rats decreased plasma enzyme elevations (alanine and aspartate aminotransferase, sorbitol dehydrogenase) as well as substantially preventing elevation of plasma bilirubin levels at 6, 12 and 24 h. Hepatic ATP levels were also elevated at 6 and 12 h, but not at 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMedDate not supplied

Neurochemical evaluation of chlordecone toxicity in the mouse.

Plasma and brain levels of chlordecone in chlordecone-induced motor impairment, lethal levels of chlordecone, and cumulative LD50 of chlordecone in the mouse are presented. In terms of biochemical events, the possible contributory role of neurotransmitters in chlordecone-induced neurotoxicity is also discussed. On the basis of the data obtained so far, it is suggested that the dopaminergic pathway and its interaction with other neurotransmitter systems in the basal ganglia may be primarily involved in chlordecone-induced neurotoxicity.

Animals↗
PubMed1985

Chlordecone inhibition of calmodulin activated calcium ATPase in rat brain synaptosomes.

The effect of chlordecone on Ca2+-ATPase of rat brain synaptosomes in the absence and presence of calmodulin was determined in vitro and in vivo. A 50% activation of Ca2+-ATPase was obtained at 5 micrograms calmodulin per 1.5 ml reaction mixture containing 50 micrograms synaptosomal protein. Chlordecone inhibited Ca2+-ATPase in the absence of calmodulin with an IC50 of 10 microM, whereas chlordecone at 1.0 microM, which had no effect on the basal enzyme activity, completely inhibited the calmodulin activated Ca2+-ATPase. Chlordecone-treated rats showed a significant reduction in calmodulin levels in brain P2 fraction. Brain synaptosomal Ca2+-ATPase in chlordecone-treated rats showed a 50% reduction, which was restored by exogenously added calmodulin. These results suggest that chlordecone may be altering calmodulin-regulated synaptic processes in the brain.

Animals↗
PubMed1988

Biotransformation of chlordecone by Pseudomonas species.

1. Six-month chlordecone enrichment cultures with added chlordecone yielded several Gram-negative micro-organisms that were resistant to and/or degraded chlordecone. 2. Three Pseudomonas spp. were further characterized for their chlordecone degrading ability. 3. Chlordecone and two derivatives, Mirex and Kelevan, supported growth of these strains. 4. All three Pseudomonas spp. decreased the concentration of chlordecone in the medium after 14 days incubation, as determined by h.p.l.c. analysis when it was added either as sole carbon source or in the presence of medium supplements.

Biotransformation↗
PubMed1990

Initiation of embryo implantation and maintenance of early pregnancy in the rat by chlordecone (Kepone).

The effect of chlordecone (Kepone), an insecticide/fungicide with reproductive toxicity, on the early stages of pregnancy in the rat was studied. Intraperitoneal injection of chlordecone into adult virgin female Holtzman strain rats before mating, in doses as high as 80 mg/kg, did not prevent fertilization, early development of the embryo to the blastocyst stage, transport of the embryo through the oviduct, or its implantation into the uterus. However, a single dose of 60 or 80 mg/kg, but not 20 or 40 mg/kg, before mating significantly reduced the concentration of progesterone in the serum of rats undergoing normal embryo implantation 5 days later. A dose of 80 mg/kg of chlordecone reduced progesterone levels in the serum by more than 50% within 48 hr in ovariectomized rats with Silastic tubing implants containing crystalline progesterone. This dose of chlordecone induced deciduomata formation in progesterone-primed ovariectomized rats to the same extent as 1 microgram of estradiol benzoate. The minimal effective single dose of chlordecone to initiate implantation of blastocysts in the uteri of hypophysectomized progesterone-primed rats, and to maintain embryo development for at least 5 days, was 50 mg/kg. Daily doses of 20 mg/kg for 3 or 5 days were effective at initiating implantation but did not maintain pregnancy. The latter treatment, however, did not prevent initiation of implantation or embryo development induced by subsequent administration of estrone. The results are consistent with the view that chlordecone is a weak estrogen that has both nongenomic and genomic estrogenic actions.

Animals↗
PubMed1986

Long-term consequences of neonatal exposure to chlordecone.

Neonate, female rats pups were injected with varying doses of chlordecone in cotton seed oil or with 1 mg chlordecone in dimethylsulfoxide. The effects of these neonatal treatments on vaginal opening, persistent vaginal estrus and adult sexual behavior were examined. Females treated with chlordecone showed earlier onset of vaginal opening and developed persistent vaginal estrus in adulthood. Sexual behavior of intact adult females was irregular but after ovariectomy and estrogen plus progesterone hormonal priming, chlordecone treated females showed normal lordosis responding. Females did not appear to have been defeminized by the neonatal chlordecone. After treatment with testosterone in adulthood, chlordecone treated females exhibited high levels of mounting behavior indicating that the neonatal treatments may have masculinized the developing hypothalamus. No significant effects of the vehicle were detected.

Animals↗
PubMed1988

Proestrous effects of chlordecone on the serotonin system.

This study concentrates on the role of the serotonin system in mediating the proestrous effects of chlordecone on female rodent sexual behavior. The pesticide was examined within the context of serotonin changes taking place on proestrous. Between morning and evening on the day of proestrus there was an increase in 3H-5-HT binding, an increase in serotonin (5-HT) and an increase in 5-hydroxyindoleacetic acid (5-HIAA). Proestrous treatment with chlordecone attenuated the increase in 5-HT and in 3H-5-HT binding but had no effect on 5-HIAA. These findings suggest that the pesticide blocked proestrous changes essential for the female's development of sexual receptivity. The 5-HT1A agonist, 8-OH-DPAT, was an inefficient competitor for 3H-5-HT binding in frontal cortex of females treated with chlordecone. It is speculated that the pesticide disrupts a balance between serotonin sites which facilitate and those which inhibit sexual behavior. Consistent with this speculation, the 5-HT agonist, quipazine, partially attenuated chlordecone's reduction of sexual behavior. Finally, the rapid effects of estradiol and chlordecone on 3H-5-HT binding sites were compared in ovariectomized female rats. These results showed no resemblance between the effects of chlordecone and those of estradiol.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Chlordecone interaction with catecholamine binding and uptake in rat brain synaptosomes.

The in vitro and in vivo effects of chlordecone on rat brain synaptosomal binding and uptake of 3H-dopamine and 3H-norepinephrine were determined. The data show that chlordecone decreases both binding and uptake of the 3H-catecholamines in vitro and in vivo. The uptake of 3H-dopamine was more sensitive to chlordecone than binding. 3H-norepinephrine binding and uptake was decreased to a lesser degree as compared to dopamine. In general, chlordecone at about 25-50 microM concentration produced a 50% decrease of the ligands binding and uptake. Mirex, a non-neurotoxic compound and a structural analog of chlordecone altered neither binding nor uptake of the ligands tested. These studies suggest that chlordecone may be modulating the pre and post synaptic function.

Animals↗