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At least 19 recordsLinked to original sources
PubMed1991

Chlordecone (Kepone) on the night of proestrus inhibits female sexual behavior in CDF-344 rats.

The effect of the estrogen-like chlorinated pesticide chlordecone (Kepone) on sexual behavior was examined in proestrous rats following treatment with 25, 50, or 75 mg/kg chlordecone. In most animals, sexual behavior, both receptivity and proceptivity, was reduced within 60 min following the higher dosage of chlordecone. Reduced sexual receptivity occurred more slowly with 50 mg/kg chlordecone (usually within 180 min) and no reduction was seen following 25 mg/kg chlordecone. The reduced sexual behavior after chlordecone treatment preceded the onset of marked chlordecone-induced tremor. A group of rats treated with 75 mg/kg chlordecone was euthanized at the time that behavioral inhibition began to develop. The content of serotonin, norepinephrine, and their principal metabolites was determined by high-performance liquid chromatography of extracts of brain tissue of these animals. In hypothalamus, increases in serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content, and a decrease in the level of norepinephrine (NE), were detected in chlordecone-treated rats relative to matched controls which received vehicle. The content of 5-HT was also increased in preoptic area of chlordecone-treated females. The content of the catecholamine metabolite, 3,4-dihydroxy-phenylacetic acid, was unaffected by chlordecone in either part of brain. These are the first observations of the parallel effects of chlordecone on receptive and proceptive behaviors, and on neurochemistry, in female rats; the results demonstrate short-latency effects of the pesticide treatment on the CNS events that mediate female reproductive behavior. Results of previous studies had led to the suggestion that chlordecone's inhibition of sexual behaviors resulted from its interaction with the intracellular estrogen receptor. However, the rapidity of the inhibition during the period of ongoing sexual behavior makes it unlikely that the inhibition is mediated by the pesticide's action at the intracellular estrogen receptor. Because of the importance of sexual behaviors to reproductive fitness, the current results indicate that nonsteroidal, behavioral mechanisms could contribute to chlordecone's neuroreproductive toxicity.

Analysis of Variance↗
PubMed1979

Excretion of chlordecone by the gastrointestinal tract: evidence for a nonbiliary mechanism.

Workers exposed to chlordecone (Kepone), a toxic organochlorine pesticide, excreted larger amounts of chlordecone in bile than in stool, suggesting that it may undergo enterohepatic recirculation. We found in a single subject that equal amounts of chlordecone and of its reduced metabolite, chlordecone alcohol, were excreted in bile at a rate four times as great as in stool. When biliary contents were diverted from the intestine through a T tube, fecal excretion of chlordecone alcohol was abolished, presumably due to interruption of its passage via bile to intestine. This change was not accompanied by disappearance of chlordecone from the stool. The amount of chlordecone in stool when bile was diverted was increased six- to tenfold over that when diverted bile was continuously infused into the duodenum. Analogous experiments with [14C]-chlordecone-treated rats in which bile flow was exteriorized through a plastic cannula showed that the excretion of radioactivity in feces was in the same range when bile was reinfused in the duodenum or was totally diverted. Moreover, in rats with bile diverted, cholestyramine, an anion-exchange resin which binds chlordecone in vitro, doubled the excretion of radioactivity in stool. A similar effect was observed in intact animals. We conclude that chlordecone enters the intestinal lumen from a nonbiliary source, probably the gut, and that net excretion of chlordecone from this source can be augmented by cholestyramine.

Bile↗
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↗
PubMed1992

Effects of chlordecone on food intake and body weight in the male rat.

The effects of the chlorinated pesticide chlordecone on food intake, body weight, and water intake were examined in adult male rats. Chlordecone treatment produced a dose dependent suppression of food intake. Loss of body weight accompanied the reduced food intake. However, chlordecone did not suppress water intake. Chlordecone treated animals maintained on a liquid diet also demonstrated reduced food intake, suggesting that chlordecone has a specific effect on feeding behavior and not a general effect on ingestive behaviors. The potential contribution of chlordecone-induced tremor to the suppressed food intake and the loss of body weight was considered. When treatment occurred immediately before a 24 hr fast, controls and animals given 75 mg/kg showed no differences in the body weight decline, even though tremor occurred in the pesticide-treated rats. Thus, it is unlikely that tremor alone produced the body weight loss observed in the present experiment. Similarly, animals were capable of initiating eating behavior even though tremor was present. In addition, chlordecone treatment inhibited food intake within 2 hr. Consequently, these results suggest that chlordecone suppresses food intake which in turn produces the decline in body weight.

Animals↗
PubMed1978

Treatment of chlordecone (Kepone) toxicity with cholestyramine. Results of a controlled clinical trial.

Industrial workers exposed to the organochlorine pesticide, chlordecone (Kepone), had signs of toxicity in several organs. The extent of toxicity was proportional to the levels of this chemical in the tissues. In 22 patients, chlordecone was eliminated slowly from blood (half time of 165 +/- 27 days--mean +/- S.E.M.) and fat (half time of 125 days, with a range of 97 to 177), chiefly in the stool. Output of chlordecone in bile was 10 to 20 times greater than in stool, suggesting that chlordecone is reabsorbed in the "ntestine. Cholestyramine, an anion-exchange resin that binds chlordecone, increased its fecal excretion by seven times. In a five-month trial, cholestyramine significantly accelerated elimination of chlordecone from blood, with a half life of 80 +/- 4 days (S.E.M.) (P less than 0.005) and fat (half life of 64 days, with a range of 52 to 85) (P less than 0.05). Cholestyramine offers a practical means for detoxification of persons exposed to chlordecone and possibly to other lipophilic toxins.

Adolescent↗
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↗
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↗
PubMed1990

Chlordecone interaction of calmodulin binding with phosphodiesterase.

The effects of organochlorine (O.C.) compounds, such as aldrin, dieldrin, endrin, isodrin, chlordecone and mirex, on calmodulin (CaM) activity were investigated. Changes induced by O.C. compounds on biological and physical properties of CaM were monitored in terms of phosphodiesterase stimulation and tyrosine fluorescence, respectively. None of the O.C. compounds altered tyrosine fluorescence of CaM in the presence of Ca2+. Except for chlordecone, none of the O.C. compounds inhibited CaM-activated phosphodiesterase (PDE). Chlordecone significantly decreased (P less than 0.05) CaM-activated PDE in a concentration-dependent manner without affecting the basal enzyme. Combination of chlordecone with W-7 (CaM antagonist) increased the inhibitory effect of W-7 on CaM activity. These results suggest that O.C. compounds may not be changing the tyrosine fluorescence of CaM. Among the O.C. compounds tested, chlordecone is a specific inhibitor of CaM-activated PDE.

Binding, Competitive↗
PubMed1992

The clinical toxicology of chlordecone as an example of toxicological risk assessment for man.

Safety assessment procedures still rely heavily if not exclusively on the results of tests carried out in laboratory animals, then extrapolated to man. There are few examples of environmental compounds examined extensively enough in both man and animals to permit a critical comparison of the accuracy of such risk assessment procedures. Chlordecone (Kepone) is a lipophilic, rodent liver carcinogen which now stands among the most extensively studied environmental agents in humans. More than five years of clinical investigations of workers heavily exposed to organochlorine pesticide have established the spectrum of human toxicity of Chlordecone, its dose-response relationships, tissue distribution, metabolic pathways, half-time for elimination, and the concentration at which its major toxic manifestations involving the central nervous system, the liver, and the testes are not observed (no observable effect level, NOEL). Taking advantage of this unique opportunity to proximately compare humans with experimental animals for a single compound administered at comparable doses, we find that none of the toxic effects produced in humans were unrepresented in animal testing. However, the animal testing produced numerous "false positive" results. Hence, accurately predicting the qualitative toxicity of chlordecone in man based on studies in rats would have been impossible. Indeed, proteinuria observed in rats fed small amounts of chlordecone for two years was chosen as a sensitive endpoint by the United States Environmental Protection Agency as the basis for establishing acceptable levels of human exposure. However, we never observed proteinuria even in humans whose dose of chlordecone was hundreds of times higher than that given to the rats. We conclude that greater emphasis should be placed on clinical investigation of humans exposed to environmental agents. A better understanding of the strength and also of the limitations of animal toxicity testing will improve the reliability of extrapolating results of animal testing to human exposure conditions.

Animals↗
PubMed1978

Chlordecone intoxication in man. I. Clinical observations.

Industrial overexposure to chlordecone, an organochlorine insecticide, caused tremor in 76 of 148 exposed workers. Chlordecone was absorbed through oral, respiratory, and dermal routes, the last possibly the most significant. Epidemiology of this incident disclosed low-level, widespread environmental exposure of man to chlordecone. In 23 workers with chronic chlordecone intoxication, tremor was associated with opsoclonus, pleuritic pain and arthralgia. No seizures were reported. The site of action of chlordecone on the central nervous system is unknown. It concentrates in human adipose and hepatic tissue but is not biodegradable, either in humans or elsewhere in nature.

Chemical Phenomena↗
PubMed1991

Carbon tetrachloride-induced alterations of hepatic calmodulin and free calcium levels in rats pretreated with chlordecone.

Calmodulin, a low molecular weight Ca2+ binding protein, regulates a large number of cell activities including cell division. Previous studies from our laboratory indicated excessive accumulation of Ca2+ in hepatocytes succeeded by rapid glycogen breakdown and suppressed cell division in rats receiving CCl4 after previous dietary exposure to 10 ppm chlordecone. Since calmodulin plays a major role in Ca2(+)-regulated events and has been reported to be localized in mitotic apparatus during cell division, we have assessed subcellular distribution of calmodulin and estimated cytosolic phosphorylase a to indicate cytosolic free Ca2+ levels in livers of rats fed 0 ppm or 10 ppm (chlordecone) in the diet for 15 days before CCl4 (100 microliters/kg) administration to understand the role of Ca2(+)-calmodulin in chlordecone + CCl4 toxicity. Hepatotoxicity was assessed by determining serum AST and ALT succeeded by histopathological observations of liver sections. Serum aminotransferases were significantly elevated 6 hr after CCl4 administration to normal rats and returned to control level by 24 hr. However, serum AST and ALT elevations were severalfold higher, and progressive increase was observed starting 4 hr after CCl4 administration to chlordecone rats. Histopathological observations of liver sections for necrotic, swollen and lipid-laden cells provided findings commensurate with the serum enzyme data. These data indicate that normal rats do recover from CCl4 hepatotoxicity. However, the CCl4 hepatotoxicity is progressive in chlordecone rats without recovery. In normal rats, CCl4 administration resulted in a slight increase in phosphorylase a starting at 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1991

Biochemical assessment of the genotoxicity of the in vitro interaction between chlordecone and carbon tetrachloride in rat hepatocytes.

The genotoxic potential of the administration of carbon tetrachloride alone or carbon tetrachloride to chlordecone-pretreated rats was investigated using an in vivo-in vitro animal model and a battery of biochemical assays to measure DNA repair in rat hepatocytes. Whereas carbon tetrachloride alone was not genotoxic, chlordecone or chlordecone in combination with carbon tetrachloride was genotoxic. The need for further investigation into the mechanism underlying the interaction between chlordecone and carbon tetrachloride is indicated strongly by the results of the present study.

Animals↗
PubMed1990

Potentiation of halomethane hepatotoxicity by chlordecone: a hypothesis for the mechanism.

A major toxicological issue today is the possibility of unusual toxicity due to interaction of toxic chemicals upon environmental or occupational exposures to two or more chemicals, at ordinarily harmless levels individually. While some laboratory models exist for such interactions for the simplest case of only two chemicals, progress in this area has suffered for want of a model where the two interactants are individually nontoxic. One such model is available, where prior exposure to nontoxic levels of the pesticide Kepone (chlordecone) results in a 67-fold amplication of CCl4 lethality in rats. Extensive hepatotoxicity observed in this interaction is characterized by histopathological alterations, perturbation of related biochemical parameters and is followed by complete hepatic failure. This propensity for chlordecone to potentiate hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study to unravel the underlying mechanism. Mechanisms such as induction of microsomal cytochrome P-450 by chlordecone and greater lipid peroxidation are inadequate to explain the remarkably powerful potentiation of halomethane toxicity. Compelling experimental evidence supports the hypothesis that hepatocellular division during early time points after the administration of CCl4 is an important determinant of the progression (or repair of it) of the liver injury and consequent destruction (or restoration) of the hepatolobular architecture and function. This paper advances a hypothesis for the mechanism of hepatotoxic and lethal effect of CCl4 as being primarily related to the accelerated progression of liver injury due to suppressed hepatocellular regeneration and hepatolobular restoration. This is in contrast to the widely accepted putative mechanism, one which invokes only bioactivation followed by runaway lipid peroxidation as the events determining the course of the progressive phase of liver injury. The concept being advanced in this paper accepts bioactivation (and perhaps lipid peroxidation) as the primary initiating events of cell injury, but maintains that they are not the determinants of the progressive phase of liver injury. The biological issue of whether the cells are incapacitated from regenerating is the determinant of the progression of liver injury, and therefore, the ultimate outcome of hepatotoxicity and lethality.

Animals↗
PubMed1990

Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase.

Chlordecone (Kepone), a toxic organochlorine pesticide, undergoes bioreduction to chlordecone alcohol in human liver. This reaction is controlled by a cytosolic enzyme, chlordecone reductase (CDR), which may be of the aldo-keto reductase family of xenobiotic metabolizing enzymes [Molowa et al. (1986) J. Biol. Chem. 261, 12624-12627]. To further investigate the primary structure and expression of CDR, we screened a library of human liver cDNAs cloned in the expression vector lambda gt11 and isolated an 800 bp cDNA that directed synthesis of a fusion protein recognized by polyclonal anti-CDR antibodies. Using this cDNA as a probe, we screened two human liver cDNA libraries and found several 1.2-kb cDNAs which would code for a polypeptide with 308 residues (35.8 kDa). However, a similar full-length cDNA, possibly the transcript of a pseudogene, contained an in-frame nonsense codon. The deduced protein sequence of CDR showed 65% similarity to the primary structure of human liver aldehyde reductase and 66% similarity to the inferred protein sequence of rat lens aldose reductase. A search of GenBank revealed significant nucleotide similarity to a cDNA coding for bovine lung prostaglandin f synthase and to a partial cDNA coding for frog lens rho-crystallin. Southern blot analysis of human genomic DNA displayed between 45 and 65 kilobases of DNA hybridizable to CDR cDNA and demonstrated several restriction fragment length polymorphisms among 26 individuals. Northern blot analysis of RNA from human, gerbil, rabbit, hamster, mouse, and rat livers disclosed hybridization with CDR cDNA only for the first three species.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Oxidoreductases↗
PubMed1976

[The effect of chlordecone (Kepone) on the laboratory colonies of the Pharaoh's ant Monomorium pharanois].

The control of the Pharaoh's ant Monomorium pharaonis is very difficult because of the social way of life in this insect pest. In regard to the reported good suppressing results of Chlordecone we analyzed the mode of action in this compound at laboratory colonies of the pharaoh's ant. Commercial gel and granular formulations as well as selfmade baits have been tested. The best results showed the granular bait on the basis of ground nut butter, while the effects of all of the others was much weaker. The pure gel, developed for cockroach control, was like the application in drinking water without success. The treatment of the colonies after a starvation period of 60 hours improved all of the effects. Sterility (fertility, fecundity) in the surviving queens was not measurable. For practical control measures the often recommended prebaiting is not at all desirable. The action on the worker ants is good, but the special mode of action based on the selective mortality in the queens and its detailed effects are unknown. Through the early absence of queens in the colonies will be induced in many cases a production of new sexuals, which compensate the success of the poison and allow the colonies to recover. The treatment leads faster to an eradiction if the ET90 to workers mortality reached earlier than that in the queens. Successful control of pharaoh's ant will Chlordecone should be considered with reserve. Nethertheless Chlordecone is in the present situation of pharaoh's ant control one of the best so far known organic-synthetically insecticides.

Animals↗
PubMed1990

Perturbations in polyamines and related enzymes following chlordecone-potentiated bromotrichloromethane hepatotoxicity.

The mechanism by which chlordecone (CD) amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. Recent work has shown that suppression of hepatocellular regeneration leads to accelerated progression of liver injury leading to complete hepatic failure due to an unusual interaction between individually nontoxic low-dose combination of CD and CCl4. Since polyamines are involved in cell division, their levels reflect the extent to which there is suppression of hepatocellular regeneration during CD and CCl4 interaction. The present studies were designed to investigate the polyamine levels and associated enzymes in livers of rats treated with BrCCl3 alone or CD and BrCCl3 low-dose combination in order to confirm whether the sequence of events of hepatotoxicity is similar to that seen in CCl4 toxicity or that seen during CD and CCl4 interaction. The extent of liver toxicity in rats fed 10 ppm chlordecone (CD) for 15 days prior to the injection of a single low dose of BrCCl3 (15 microL/kg body weight) or after exposure to a high dose of BrCCl3 (80 microL/kg body weight) without CD pretreatment, was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was also an increase in transaminase levels, in rats exposed to a single low dose of BrCCl3 alone (15 microL/kg body weight) but this increase was far below the high-dose exposure alone or the combination treatment. Hepatic levels of ornithine decarboxylase, S-adenosylmethionine decarboxylase, N1-acetylputrescine, N1-acetylspermidine, putrescine, spermidine, and spermine at the end of 24 hr increased after exposure to a low dose of BrCCl3 alone as compared to exposure to a high dose alone or the low-dose combination of CD and BrCCl3. Liver spermidine N1-acetyltransferase was elevated at 2, 6, and 24 hr after exposure to a high dose of BrCCl3 alone as compared to treatment with a low-dose combination of CD and BrCCl3 suggesting decreased synthesis of this enzyme, in spite of a greater need as seen from liver transaminase levels. In general, it was observed that there is significant elevation in some polyamines and related enzymes during toxicity of a low dose of BrCCl3 which seemed to stabilize within 24 hr. This was not observed with the other two groups of rats exposed either to BrCCl3 high dose alone or the low-dose combination of CD and BrCCl3.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetyltransferases↗
PubMed1979

Estrogenic activity of the insecticide chlordecone (Kepone) and interaction with uterine estrogen receptors.

The chlorinated insecticide chlordecone (Kepone) interacts with the estrogen receptor system in the rat uterus in vitro and in vivo. It competes with estradiol for binding to the cytoplasmic receptor in vitro and also induces nuclear accumulation of estrogen receptor sites in uteri in vitro. When injected into immature rats, chlordecone translocates estrogen receptor sites to the uterine nucleus, increases uterine weight, and stimulates the synthesis of the progesterone receptor, an estrogen receptor-mediated process. Its slow onset of action but prolonged duration of interaction with estrogen receptor and stimulation of uterine weight gain and progesterone receptor synthesis indicates that, although it has an affinity for receptor only 0.01-0.04% that of estradiol, its considerable estrogenic activity may likely be derived from its long half-life and bioaccumulative character.

Animals↗
PubMed1978

Cholestyramine: use as a new therapeutic approach for chlordecone (kepone) poisoning.

In rats, as reported in humans, chlordecone (Kepone) is excreted predominantly in the feces. Cholestyramine, an anion exchange resin, binds chlordecone in rat intestine, increases its excretion into the feces, and decreases its content in the tissues. The resin appears to offer a practical method for treating chronic poisoning with this and possibly with other lipophilic toxins.

Animals↗