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PubMed1986

Purification and characterization of chlordecone reductase from human liver.

The toxic organochlorine pesticide, chlordecone (Kepone), is excreted in human bile primarily as a stable, reduced monoalcohol metabolite. This bioreduction is catalyzed by a hepatic cytosolic enzyme activity termed chlordecone reductase. We purified this enzyme from human liver and found that chlordecone reductase resembles the family of xenobiotic metabolizing enzymes referred to as the aldo-keto reductases based on its biochemical characteristics, including its ability to catalyze the reduction of a carbonyl-containing substrate. However, analyses of liver cytosolic samples on immunoblots developed with anti-chlordecone reductase antibodies revealed that immunoreactive proteins were present only in those mammalian species that convert chlordecone to chlordecone alcohol in vivo (man, gerbil, and rabbit) and not in those species unable to reduce chlordecone (rat, mouse, and hamster). Hence, chlordecone reductase is unique among aldo-keto reductases in being species-specific. Quantitative immunoblot analyses of seven human liver specimens disclosed two immunoreactive proteins whose total concentration varied over a 6-fold range. Moreover, the amount of immunoreactive protein was directly proportional to chlordecone reductase activity in each sample. We conclude that chlordecone reductase is a unique aldo-keto reductase of potential clinical importance whose expression varies markedly among individuals.

Alcohol Oxidoreductases↗
PubMed1984

New approaches for treatment of humans exposed to a slowly excreted environmental chemical (chlordecone).

Workers in a small factory that manufactured the organochlorine pesticide chlordecone were exposed to large amounts of this toxic material for many months. Toxic manifestations prominently involved the nervous system, liver and testes. Chlordecone was present in high concentrations in samples of blood, liver, and fat from these workers. A plasmaphoresis experiment indicated that chlordecone is rapidly transferred from tissues to blood. However, hemoperfusion was unsuccessful for removing chlordecone from the body because chlordecone is avidly bound by plasma proteins. Based on the observation that stool contains only a small fraction of the substantial amounts of chlordecone excreted in bile, we administered orally cholestyramine, a nonabsorbable resin that binds chlordecone in vitro. Cholestyramine increased fecal excretion of chlordecone and accelerated the rate of disappearance of the pesticide from the body. This was accompanied by amelioration of the clinical manifestations of toxicity, indicating that the subacute toxic effects of chlordecone are reversible. We conclude that therapy with binding agents taken orally provide a safe and effective means for treatment of humans poisoned with chlordecone and, possibly with other organochlorine pesticides.

Adipose Tissue↗
PubMedDate not supplied

Evaluation of neonatal chlordecone neurotoxicity during early development: initial characterization.

The effects of neonatal exposure of rats to chlordecone were assessed in the preweaning period of development. On day 4 postpartum, pups received a SC injection (20 microliter) of either dimethylsulfoxide (DMSO) or 1 mg/pup of chlordecone dissolved in DMSO. Body weights on days 14 and 21 were slightly (9-14%), but significantly, depressed in both sexes by the neonatal chlordecone exposure. Whole body movements, monitored via a spectral analyzer, indicated a significant high frequency tremor in the chlordecone-exposed pups on postnatal days 10, 14, and 18. The auditory startle response to a 4 kHz, 110 dB (SPL) tone was examined on days 12, 16, and 20. A significant enhancement of startle responsiveness was noted in chlordecone-exposed pups relative to vehicle-injected littermates; this effect was localized primarily at 16 days of age and in the female pups. Evaluation of undifferentiated motor activity, as assessed by testing individual pups in the presence of homecage shavings, indicated significant chlordecone-induced hypoactivity in both sexes on postnatal day 15. Hypoactivity persisted through 21 days of age in the female, but not male, chlordecone-exposed pups. This neurotoxic profile of tremor, depressed body weight, and altered responsiveness to novel/stressful environments is detectable in early life and is similar to that observed when adult rats are exposed to chlordecone. The profile also bears similarity to the primary signs and symptoms of chlordecone exposure in adult humans. Collectively, the present observations offer a tentative working model for the further investigation of the developmental neurotoxicity of chlordecone.

Acoustic Stimulation↗
PubMed1988

Possible brainstem involvement in the modification of thermoregulatory processes by chlordecone in rats.

The involvement of the central nervous system in the hypothermia induced by chlordecone was studied by evaluating the effects of infusions of chlordecone injected into the lateral and third ventricles and the cisterna magna on colonic temperature (Tcol). Compared to rats given vehicle, infusions of 40, 320 or 800 micrograms of chlordecone into the lateral ventricle or 320 or 800 micrograms of chlordecone into the third ventricle, through chronic indwelling cannulae, did not change significantly Tcol. However, intracisternal infusions of 80, 160, 320 or 800 micrograms of chlordecone produced significant hypothermia (maximally 2.2 degrees C) which persisted for as long as 6 hr. Intracisternal infusions of chlordecone also produced a rapid increase in the temperature of the tail skin (Tsk) which persisted throughout the period of hypothermia. This suggests that the hypothermia produced by central administration of chlordecone is related to peripheral vasodilation. Since chlordecone has been reported to induce release of NE in the brainstem, and NE is known to modulate tonic vasomotor control in the medulla, the effects of NE infused intracisternally were studied. Intracisternal infusions of NE (16 micrograms) significantly decreased Tcol and increased Tsk, supporting the hypothesis that hypothermia induced by chlordecone is associated with vasodilatory effects, mediated by an adrenergic mechanism in the brainstem.

Animals↗
PubMed1989

Estradiol and chlordecone interactions with the estradiol receptor.

The in vivo and in vitro effects of the chlorinated pesticide, chlordecone, on the estradiol receptor of adult ovariectomized CDF-344 rats were examined. Chlordecone's competition with [3H]estradiol for binding to the estradiol receptor in vitro was similar whether receptors were derived from neural or uterine tissue. In vivo, chlordecone led to nuclear retention of estradiol receptors in both tissues, but in comparison to estradiol, the latency for such retention was slower following chlordecone. Nevertheless, chlordecone- and estradiol-treated animals eventually achieved the same degree of nuclear retention in uterine tissue. In brain, estradiol-like levels of nuclear retention were never found in chlordecone-treated females. Estradiol receptor replenishment following chlordecone or estradiol was similar in uterine tissue but not in brain. Chlordecone's lesser ability to mimic estradiol's receptor dynamics in the brain may contribute to the apparent tissue differences in chlordecone's estrogenicity.

Animals↗
PubMed1980

Functional and biochemical correlates of chlordecone exposure and its enhancement of CCl4 hepatotoxicity.

Animals pretreated with chlordecone exhibit a greatly increased hepatotoxic response to CCl4 challenge. Possible mechanisms underlying this interaction were examined. A single p.o. administration of chlordecone (5 mg/kg) was followed by CCl4 (200 microliter/kg) administered i.p. 48 h later. Twenty-four hours later, animals treated with chlordecone mccl4 had decreased hepatic excretory function (20% of controls) and elevated plasma transaminase activities and bilirubin. Hepatic mixed function oxidase activity was assessed as pentobarbital sleeping time and was not affected by chlordecone pretreatment. Irreversible binding of label from 14CCl4 to hepatic protein or lipid was not different in the chlordecone group compared to vehicle controls. Hepatic and renal glutathione concentrations were not affected by chlordecone alone (at 6 h, 1, 2, 3, 5 and 7 days) or by a combination of chlordecone (48 h) and CCl4 (24 h). CCl4-induced lipid peroxidation of liver tissue, measured in vitro or in vivo, was not increased by chlordecone treatment. Thus, while the mechanism for the enhanced toxicity remains to be elucidated, these results suggest that the interaction between chlordecone and CCl4 is a subtle one, not causally involving increased covalent binding of the toxin, increased susceptibility of tissue lipids to peroxidative damage or decreased hepatic GSH.

Animals↗
PubMed1984

Excessive hepatic accumulation of intracellular Ca2+ in chlordecone potentiated CCl4 toxicity.

The possible role of Ca2+ in chlordecone potentiation of CCl4 hepatotoxicity was examined in male Sprague-Dawley rats. The rats were maintained on a diet containing either 0, 10, 25, 50 or 100 ppm chlordecone for 15 days. On day 15, they received a single i.p. injection of corn oil (1 ml/kg) or CCl4 (100 microliter/kg) in corn oil vehicle. The animals were killed at 1, 6, or 12 h after the oil or CCl4 challenge for hepatic Ca2+ determinations. Ca2+ in whole liver, mitochondria, microsomes or in cytosolic fraction was unaltered in any group of animals receiving chlordecone + oil treatments, indicating that chlordecone alone does not alter whole liver content or hepatic subcellular distribution of Ca2+, even after exposure to toxic levels (50 or 100 ppm). Administration of CCl4 at an otherwise non-toxic dose to chlordecone treated animals resulted in significant increases of whole liver and subcellular Ca2+ as compared to chlordecone alone and CCl4 alone with a characteristic biphasic response. These increases were significant at all 3 time points in whole liver, cytosolic and mitochondrial fractions. Microsomal Ca2+ increased only at 12 h after CCl4. The increases were all progressive with increases in dietary levels of chlordecone, indicating that chlordecone-induced sensitivity is responsible for CCl4 elicited perturbations in whole liver and intracellular Ca2+ levels. This study suggests that chlordecone modifies the liver plasma membrane to amplify the CCl4 elicited perturbations in hepatocellular Ca2+ homeostasis especially during 6-12 h after CCl4 administration. This perturbation of Ca2+ homeostasis may be related to the arrested repair and regeneration of damaged liver tissue leading to progressive deterioration observed in previous histomorphometric studies.

Animals↗
PubMed1989

Mechanism of the lethal interaction of chlordecone and CCl4 at non-toxic doses.

There is significant interest in the possibility of unusual toxicity due to interaction of toxic chemicals upon environmental or occupational exposures even though such exposures may involve levels ordinarily considered harmless individually. While many laboratory and experimental models exist for such interactions, progress in this area of toxicology has suffered for want of a model where the interactants are individually non-toxic. We developed such a model where prior exposure to non-toxic levels of the pesticide Kepone (chlordecone) results in a 67-fold amplification of CCl4 lethality in experimental animals. The mechanism(s) by which chlordecone amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. The biological effects of this interaction include extensive hepatotoxicity characterized by histopathological alterations, hepatic dysfunction, and perturbation of related biochemical parameters. Close structural analogs of chlordecone such as mirex and photomirex do not share the propensity of chlordecone to potentiate halomethane toxicity. Mechanisms such as induction of microsomal cytochrome P-450 by chlordecone and greater lipid peroxidation are inadequate to explain the remarkably powerful potentiation of toxicity and lethality. Time-course studies in which liver tissue was examined 1-36 h after CCl4 administration were conducted. While animals receiving a normally nontoxic dose of CCl4 alone show limited hepatocellular necrosis by 6 h, proceeding to greater injury after 12 h, recovery phase ensues as revealed by greatly increased number of mitotic figures. Such regeneration and hepatic tissue repair processes are totally suppressed in animals exposed to chlordecone prior to CCl4. Thus, the arrested hepatocellular repair and renovation play a key role in the potentiation of CCl4 liver injury by chlordecone. These findings have allowed us to propose a novel hypothesis for the mechanism of chlordecone amplification of halomethane toxicity and lethality. While limited injury is initiated by the low dose of CCl4 by bioactivation followed by lipid peroxidation, this normally recoverable injury permissively progresses due to arrested hepatocellular regeneration and tissue repair processes. Recent studies designed to test this hypothesis have provided additional supporting evidence. Hepatocellular regeneration stimulated by partial hepatectomy was unaffected by 10 ppm dietary chlordecone, while these animals were protected from the hepatotoxic and lethal actions of CCl4 if administered at the time of maximal hepatocellular regeneration. The protection was abolished when CCl4 was administered upon cessation of hepatocellular regeneration.

Animals↗
PubMed1991

Vaginal cyclicity, sexual receptivity, and eating behavior of the female rat following treatment with chlordecone.

The effects of 25, 50, or 75 mg/kg chlordecone on vaginal and behavioral estrus were examined following treatment of intact rats during estrus, diestrus 1, or diestrus 2. Chlordecone accelerated vaginal estrus, but sexual behavior was eliminated, delayed, or reduced. Chlordecone treatment led to the presence of vaginal estrus within 2 days, but reduced or eliminated sexual behavior on the evening of predicted proestrus. Of the females that received chlordecone, 20% to 50% showed some behavior on the day after the evening of predicted proestrus and 20% to 35% never showed behavior during the 8-day observation period. Although the lordosis to mount ratio was still reduced, the occurrence of behavior a day late suggested that the pesticide had delayed behavioral estrus. Chlordecone also rapidly suppressed food intake and led to a significant decline in body weight; these nutritional factors could have contributed to the disrupted estrous cycle. Some support for this possibility was derived from a reduced sexual receptivity on the evening of proestrus when the caloric intake of untreated female rats was matched to that of the chlordecone treated animals. However, the effects of caloric reduction on proestrous lordosis behavior were less robust than seen following chlordecone. Chlordecone treatment on diestrus 2 reduced the number of progesterone receptors in uterine tissue of females on the predicted day of proestrus. This suggested that the tissue sensitivity to circulating levels of progesterone would be reduced within 2 days after chlordecone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Evaluation of chlordecone in a two-stage model of hepatocarcinogenesis: a significant sex difference in the hepatocellular carcinoma incidence.

Chlordecone (Kepone) has been extensively studied for its toxicity in male production workers who were exposed to large quantities of this organochlorine pesticide. Concern that these workers might be at an increased risk of developing liver cancer prompted us to test chlordecone in a two-stage rat model of hepatocarcinogenesis. Chlordecone acted largely as a liver tumor promoter rather than as a complete hepatic carcinogen in both male and female Sprague-Dawley rats. Dose-response experiments showed that the hepatocarcinogenic effects of long-term chlordecone administration became undetectable at concentrations in non-initiated rat liver in the same range as those measured in human biopsies taken from exposed workers who exhibited no liver effects. Although the toxicity of chlordecone in women has never been studied, we found a dramatic sex difference in the incidence of malignant liver tumors caused by chlordecone promotion in rats. Frank hepatocellular carcinomas were observed in up to 63% of female rats whose livers were previously 'initiated' with a subcarcinogenic dose of diethylnitrosamine given 24 h after partial hepatectomy, and then 'promoted' by 27 weeks of chlordecone administration. In contrast, none of comparably treated males had malignant liver tumors, even after 44 weeks of 'promotion' with chlordecone. Females in the diethylnitrosamine-initiated/chlordecone-promotion groups also contained gamma-glutamyltranspeptidase-positive 'preneoplastic' hepatocellular foci that were more abundant and larger than those observed in comparably-treated males. Moreover, because similar levels of chlordecone were measured in the livers of both sexes at the end of the experimental period, the development of hepatocellular carcinomas in the diethylnitrosamine-initiated female rats appeared to be due to their increased sensitivity to the promotion treatment.

Animals↗
PubMed1993

Resiliency to amplification of carbon tetrachloride hepatotoxicity by chlordecone during postnatal development in rats.

The interactive hepatotoxicity of CCl4 and chlordecone, at an individually nontoxic dosage, was studied in neonatal and young developing rats. The well-documented amplification of CCl4 (100 microL/kg) hepatotoxicity and lethality by prior dietary exposure to chlordecone (10 ppm, for 15 d) was absent in neonatal and developing rats through 35 d of age. The chlordecone-potentiated hepatotoxicity and lethality of CCl4 was partially expressed in 45-d-old rats and fully expressed in 60-d-old rats. Although hepatic microsomal cytochrome P-450 content in 2- or 5-d-old rats was significantly lower than that in older age groups, the cytochrome P-450 content was not significantly different between 35-, 45-, and 60-d-old chlordecone-treated rats. During postnatal development, the ongoing hepatocellular proliferation declined in a biphasic manner, more rapidly up to 20 d and slowly thereafter, as indicated by 3H-thymidine incorporation in hepatic nuclear DNA. This pattern of postnatal liver proliferation and growth was not altered by exposure to chlordecone. In vivo metabolism of CCl4, in terms of 14CO2 production derived from 14CCl4 and 14CCl4 metabolites bound to hepatic tissue, was not significantly different between 35-, 45-, and 60-d-old chlordecone-treated rats, whereas CCl4-stimulated hepatocellular regeneration in 35-d-old chlordecone-treated rats was significantly higher than in 45- or 60-d-old chlordecone-treated rats, as indicated by 3H-thymidine incorporation into hepatic DNA and histomorphometric analysis. These data suggest that the absence of potentiation of CCl4 toxicity by chlordecone in postnatally developing rats is well correlated with the presence of ongoing and stimulatable hepatocellular regenerative activity.

Age Factors↗
PubMed1981

Assessment of neurotoxicity induced by oral administration of chlordecone (Kepone) in the mouse.

Neurotoxicity in the mouse was produced following oral administration of chlordecone at 10, 25 and 50 mg/kg/day in corn oil vehicle. Hyperexcitability and tremors were observed on the 1st, 4th and 9th day after the administration of chlordecone at 50, 25 and 10 mg/kg/day, respectively, and mortality occurred on the 5th, 7th and 13th day after daily administration of the respective doses. In all cases, the cumulative LD 50 for chlordecone was estimated between 180 and 200 mg/kg. Daily oral administration of chlordecone caused loss of body weight, and the loss of body weight was greatest at the onset of tremor. The effect of chlordecone on food and water consumption varied depending on the dose. A recovery in body weight, and food and water consumption were observed upon the termination of chlordecone treatment. In terms of neurotoxic responses, the effect of chlordecone on motor coordination in the mouse was dose-dependent, both during treatment and during recovery after terminating treatment. The threshold for pentylenetetrazol-induced seizures was significantly reduced in chlordecone treated animals. This study may provide essential basic information for studying the biochemical mechanisms of chlordecone-induced neurotoxicity in the mouse.

Animals↗
PubMed1987

Direct administration of chlordecone into Japanese quail eggs has persistent effects on conditioned behavior of adults.

Chlordecone (0.1 to 10 mg) or corn oil vehicle was injected into Japanese quail eggs on day 1 of incubation. Higher doses (0.5-10 mg per egg) produced tremor and ataxia at hatching and dose-related decreases in hatchability and survivability. Doses lower than 0.25 mg per egg had no effects. Gonad weights were not affected at 12 weeks of age. A second study examined the effect of injecting 0.5 mg of chlordecone into the egg on day 1, 3, 7 or 14 of incubation. Chlordecone-induced tremor was present at hatching regardless of the day of injection. Significant decreases in hatchability and increases in embryonic mortality were seen when chlordecone was injected on day 1 of incubation. Survivability to 5 weeks of age was decreased in birds receiving chlordecone on day 1 or 3 of incubation. At 75 to 84 days of age, egg production was decreased only in birds injected on day 1 of incubation. The offspring from these studies were mated and the hatchability and reproductive capability of these birds was studied at 75 to 84 days of age and found to be not significantly affected. In a third study, birds exposed to 0.5 mg of chlordecone or vehicle on day 1 of incubation were trained as adults in a food reinforced operant task. Exposure to chlordecone affected performance during the first 3 of 15 days of a match-to-sample task. The baseline response rate of these animals on a food reinforced random interval 60 sec schedule was then determined. During the last two weeks of asymptotic performance, chlordecone-exposed birds had a significantly lower rate of responding than controls. These data indicate that in ovo exposure to chlordecone can have significant long-term effects on conditioned behavior and egg production, particularly if exposure occurs on day 1 of incubation.

Animals↗
PubMed1985

Effects of chlordecone administration on brain and pituitary peptide systems.

It has been clearly demonstrated that chlordecone exerts estrogen-like effects on the reproductive system. However, the extent to which the estrogenic activity of this neurotoxicant may contribute to its central nervous system effects is not clear. The purpose of this study was to compare the estrogenic activity of chlordecone and estrogen on the rat hypothalamo-pituitary axis (HPA) by using the pituitary enkephalin system as a model. It was found that the enkephalin system of the anterior pituitary is regulated by circulating estrogen. Ovariectomy caused an increase in the pituitary content of enkephalin and this increase was prevented by estrogen treatment. Administration of estrogen reduced the pituitary content of this peptide in intact male rats. Similarly, chlordecone treatment reduced the pituitary content of enkephalin in a manner identical to that of estrogen. A single injection of chlordecone (75 mg/kg; i.p.) caused a delayed decrease in the enkephalin level of the anterior lobe (but not the posterior lobe) of the pituitary. This effect of chlordecone was selective to male rats since the pituitary enkephalin level of females was not altered by such treatment. Levels of other pituitary hormones such as beta-endorphin, vasopressin, etc., were not decreased. Further studies revealed that the similarities between chlordecone and estrogen could be extended to other pituitary hormones. For example, implantation of estrogen or of chlordecone in ovariectomized rats caused similar changes in serum prolactin and luteinizing hormone levels. Thus, this study demonstrates a clear estrogen-like action of chlordecone on the HPA. Moreover, due to the similarity of both estrogen and chlordecone to anti-dopaminergic agents in altering [Met5]-enkephalin levels in both the pituitary and caudate nucleus it is speculated that a dopaminergic mechanism is responsible for their actions on the enkephalin system.

Aging↗
PubMed1981

Correlation between neurotoxicity and chlordecone (Kepone) levels in brain and plasma in the mouse.

The brain and plasma levels of chlordecone were monitored after daily oral administration of chlordecone at 10 to 50 mg/kg/day. At a low dose, the plasma level of chlordecone increased steadily and the brain level showed a steady increase and then a plateau. However, at the higher dose the brain and plasma concentrations of chlordecone decayed biphasically. The data also revealed that chlordecone-induced neurotoxicity correlated closely with both brain and plasma concentration of chlordecone. Brain and plasma concentrations required for low and high dose for induction of the loss of motor coordination were estimated to be 10 to 65 ug/g and 10 to 25 microgram/ml, respectively. In addition, the chlordecone levels in the brain at time of death were 0.10 and 0.41 mg/g in groups receiving 10 and 50 mg/kg/day, respectively. However, the cumulative lethal dose of chlordecone in animals treated with different doses was about the same. This study established the threshold levels of chlordecone in plasma and brain for motor incoordination and mortality in the mouse.

Animals↗
PubMedDate not supplied

Neonatal chlordecone exposure impairs early learning and retention of active avoidance in the rat.

The effect of neonatal exposure of rats to chlordecone on the acquisition and retention of active avoidance was investigated. Pups were trained and tested on one-way (preweaning) and/or two-way (post-weaning) active avoidance tasks. Offspring of Fischer-344 rats were administered 1 mg/pup of chlordecone (SC) dissolved in DMSO on postnatal day 4. Body weights were slightly, but significantly, depressed for chlordecone-exposed males (10-11%) and females (7-8%) during preweaning development. Post-weaning body weights were also slightly depressed by the chlordecone treatment (8% for the males, 7% for the females). For pups trained (day 18) on one-way (small to large compartment) active avoidance (OWA), chlordecone treatment increased the number of trials needed to attain the acquisition criterion; the effect was most pronounced in the males. A 72-hr retention test revealed a sex-dependent effect of chlordecone on response latency during the initial test trials. Acquisition of two-way avoidance (TWA) (days 28-30) was superior in female pups relative to males; chlordecone treatment significantly reduced this sex difference in pups which had prior or no prior OWA training. Perhaps most importantly, however, following prior OWA training, vehicle control pups demonstrated a directional bias to make an avoidance response from a small to a large compartment, whereas chlordecone-treated pups executed their avoidance responses in both directions at comparable rates. Similar evidence indicative of a selective retention deficit also characterized TWA performance when a "reversal" procedure was used. A final retention (extinction) session indicated that the chlordecone-treated pups made fewer responses than vehicle-treated controls during the test trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Effect of chlordecone on pH and temperature dependent substrate activation kinetics of rat brain synaptosomal ATPases.

Chlordecone, a polycyclic chlorinated insecticide known as Kepone, inhibited the activities of (Na+-K+)ATPase and Mg2+-ATPase in rat brain synaptosomes. Altered pH and specific activity curves for both enzymes demonstrated significant inhibition by chlordecone in buffered acidic, neutral and alkaline pH ranges. Noncompetitive inhibition with respect to activation by ATP in the case of (Na+-K+)ATPase was indicated by altered Vmax values with no significant change in Km values at any pH studied, except at pH 9.5. Mg2+-ATPase was inhibited uncompetitively as evidenced by altered Vmax and Km values. The activities of both ATPase were decreased in the presence of chlordecone at higher temperatures. Activation energy (delta E) values were found to be decreased significantly in the presence of chlordecone at 37 degrees. Arrhenius plots of both ATPases preincubated with chlordecone were found to be nonlinear. In the presence of chlordecone, Vmax was decreased without significant change in Km values for (Na+-K+)ATPase at all temperatures, suggesting a noncompetitive type of inhibition. In the case of Mg2+-ATPase, similar noncompetitive type inhibition was obtained at 27 degrees but not at 32 and 37 degrees. The kinetic data in general suggest that the chlordecone inhibited (Na+-K+)ATPase noncompetitively and Mg2+-ATPase uncompetitively at all pHs and temperatures studied. The present data suggest that inhibition of (Na+-K+)ATPase and Mg2+-ATPase, the two membrane-bound enzymes in synaptosomes, by chlordecone is temperature dependent and pH independent.

Adenosine Triphosphatases↗
PubMed1984

Estrogen-like activity of chlordecone (kepone) on the hypothalamo-pituitary axis: effects on the pituitary enkephalin system.

Similarities between the activity of chlordecone and estrogen on the hypothalamo-pituitary axis (HPA) were examined by using the pituitary enkephalin system as a model. A single injection (25 to 75 mg/kg, ip) or repeated injections (2.5 to 10 mg/kg/day for 10 days, ip) of chlordecone caused a time- and dose-related decrease in pituitary [Met5]-enkephalin-like immunoreactivity (ME-LI) in adult rats. Similar to the reported effects of estrogen, chlordecone treatment decreased the levels of ME-LI in the anterior lobe but not in the neurointermediate lobe of male pituitaries. Furthermore, chlordecone failed to alter the pituitary levels of ME-LI in female rats. The level of another pituitary peptide hormone, beta-endorphin, was increased in male rats after chlordecone treatment, indicating some degree of selectivity of this effect. Similarities between chlordecone and estrogen were found with other pituitary hormones, i.e., implantation of diethylstilbestrol or of chlordecone in ovariectomized rats caused qualitatively similar changes in serum prolactin and luteinizing hormone levels. These results suggest that chlordecone qualitatively resembles estrogen in its effect on some HPA peptide systems.

Animals↗