RESUMEN
This study focuses on the fate of chlordecone (CLD) during cooking processes. Neat CLD was subjected to thermogravimetric analysis, which revealed that the vast majority of the compound (79 %) was vaporised at temperatures between 55 and 245 °C. In order to monitor the behaviour of CLD during cooking processes, a QuEChERS extraction protocol was optimised for vegetable cooking oil and a heating kinetics experiment was conducted at 195 °C on CLD-spiked cooking oil. The results showed a strong decrease in CLD over time and, for the first time to our knowledge, transformation of CLD into chlordecol. Finally, a comparison was conducted between the cooking of uncured pork with and without vegetable oil. The use of vegetable oil led to a significant decrease in CLD content, but revealed that a fraction of the CLD transferred into the cooking oil. This study provides data that shed light on the fate of CLD during cooking.
Asunto(s)
Clordecona , Insecticidas , Contaminantes del Suelo , Clordecona/análisis , Insecticidas/análisis , Contaminantes del Suelo/análisis , Culinaria , Aceites de Plantas/análisisRESUMEN
Background: Chlordecone is an endocrine-disrupting chemical with well recognized estrogenic and progestagenic properties. This organochlorine insecticide was extensively used in the French West Indies from 1973 to 1993 to control the banana root borer. Due to its poor degradation in the environment, permanently polluted soil is responsible for the current contamination of the food chain and human beings. We aimed to examine the relationship of in utero exposure to chlordecone and thyroid (thyroid stimulating hormone [TSH], free tri-iodothyronine [FT3], free thyroxine [FT4]), metabolic (insulin growth-factor 1, leptin, adiponectin), and sex-steroid (dehydroepiandrosterone [DHEA], total testosterone [TT], dihydrotestosterone [DHT], estradiol [E2]) hormone levels in children at the age of seven years who participated in TIMOUN, an ongoing birth cohort in Guadeloupe. Methods: Chlordecone concentrations were measured in cord-blood at delivery. Thyroid, metabolic, and sex-steroid hormone levels were determined in the blood of children at seven years of age. Associations between in utero chlordecone exposure and hormone levels at seven years of age were assessed by multiple linear or logistic regression, controlling for confounding factors. Results: Among the study population (210 boys and 228 girls), chlordecone and hormone measurements were available for 124 boys and 161 girls. We found the third quartile of in utero chlordecone exposure relative to the lowest quartile to be associated with elevated TSH levels in girls and elevated DHEA, TT, and DHT levels in both sexes. Complementary non-linear analysis (spline regression) confirmed a significant non-linear trend for TSH in girls and DHEA and DHT in boys. Conclusion: In utero chlordecone exposure was associated with elevated levels of selected thyroid (TSH) and sex-steroid (DHEA, TT, and DHT) hormones at seven years in a non-monotonic dose response (inverted U) relationship. The implications for future health and reproductive function in puberty and adulthood should be determined.
Asunto(s)
Clordecona/toxicidad , Exposición a Riesgos Ambientales , Insecticidas/toxicidad , Efectos Tardíos de la Exposición Prenatal/sangre , Glándula Tiroides/efectos de los fármacos , Adiponectina/sangre , Niño , Deshidroepiandrosterona/sangre , Dihidrotestosterona/sangre , Estradiol/sangre , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/sangre , Masculino , Embarazo , Testosterona/sangre , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
Sixteen weaned male Alpine kids (Capra hircus) were subjected to a 21-day oral daily exposure of 0.05 mg kg-1 BW. d-1 of chlordecone (CLD) and 0.30 µg kg-1 BW. d-1 of each non-dioxin-like polychlorinated biphenyls (NDL-PCBs, congeners 28, 52, 101, 138, 153 and 180). Four kids, identified as the CONTA group, were slaughtered at the end of the exposure, while the remaining animals (n = 12) were fed with specific diets for an additional 21-day decontamination period before slaughtering. Kids from the DECONTA (n = 4) group were fed a control diet, while those from the AC10% and PO8% group received pellets supplemented with 10% activated carbon (AC) and 8% paraffin oil (PO), respectively. CLD and NDL-PCB levels in blood, liver, peri-renal fat and muscles from different groups were analysed to compare the decontamination dynamics of the pollutants and to determine the efficiency of AC and PO to decrease the body levels of pollutants. After the decontamination period, the CLD levels considerably decreased (more than 60%) in blood, liver, muscles and fat. Concerning NDL-PCBs, the decontamination process was much lower. Overall, CLD appeared to be less retained in kids' organism compared with NDL-PCBs, and the decontamination dynamics of these pollutants appeared to be different because of their specific physicochemical properties and lipophilicity. Furthermore, the dietary supplementation with AC or PO did not significantly affect the decontamination dynamics.
Asunto(s)
Carbón Orgánico/metabolismo , Clordecona/metabolismo , Suplementos Dietéticos , Contaminantes Ambientales/metabolismo , Cabras , Aceites/metabolismo , Parafina/metabolismo , Bifenilos Policlorados/metabolismo , Animales , Clordecona/análisis , Descontaminación , Dieta , Contaminantes Ambientales/análisis , Hígado/química , Masculino , Bifenilos Policlorados/análisisRESUMEN
Chlordecone (Kepone) (CLD) is a highly persistent pesticide which was extensively used in the French West Indies; high levels of CLD can still currently be found in large agricultural areas. As CLD transfers from soil to animals mainly via involuntary ingestion, the consumption of foodstuffs derived from animals raised in contaminated areas may significantly contribute to exposure of humans to CLD. The present study was designed to test the efficacy of two different activated carbons (ACs) sources in limiting CLD transfer from soil to animal. Three soils (ASs) were prepared according to the OECD guideline 207. One standard soil (SS) lacking AC, and two modified preparations of SS supplemented with 2% coconut-based activated carbon (ORBO), SSO or with 2% lignite-based one (DARCO), SSD. All three soils were spiked with 10 µg of kepone per g of dry matter and aged for three weeks. This study involved 15 goat kids randomly assigned to the 3 experimental groups (n = 5/group), which were fed the experimental matrices at an exposure dose of 10 µg CLD per kg of body weight per day. After 21 d of oral exposure, CLD in adipose tissue and liver were analysed by LC-MS-MS. A significant decrease of 63.7% and 74.7% of CLD concentrations in adipose tissue and liver, respectively, were obtained from animals exposed using SS containing DARCO as compared to those receiving only SS. Decreases in CLD levels of 98.2% (adipose tissue) and 98.7% (liver) were obtained for animals exposed using SS containing ORBO. This study leads us to conclude that (i) the presence of AC in CLD-contaminated soil strongly reduces CLD bioavailability, and (ii) the efficacy depends on the nature and characteristics of the AC used.
Asunto(s)
Tejido Adiposo/química , Carbón Orgánico , Clordecona/análisis , Hígado/química , Contaminantes del Suelo/análisis , Suelo/química , Adsorción , Animales , Disponibilidad Biológica , Ingestión de Alimentos , CabrasRESUMEN
Chlordecone (CLD), a highly persistent organochlorine pesticide commonly encountered in French West Indies (FWI) agricultural soils, represents a major source of contamination of FWI ecosystems. The potential of chemical reduction for remediation of CLD-contaminated soil has been investigated in laboratory pilot-scale 80 kg mesocosms for andosol, ferralsol, and nitisol from FWI banana plantations. Six cycles consisting of a 3-week reducing phase followed by a 1-week oxidizing phase were applied, with 2 % (dw/dw) Daramend® (organic plant matter fortified with zero valent iron) added at the start of each cycle. Complementary amendments of zero valent iron and zinc (total of 3 % dw/dw) were added at the start of the first three cycles. After the 6-month treatment, the CLD soil concentration was lowered by 74 % in nitisol, 71 % in ferralsol, and 22 % in andosol. Eleven CLD-dechlorinated transformation products, from mono- to penta-dechlorinated, were identified. None of them accumulated over the duration of the experiment. Six of the seven ecotoxicological tests applied showed no difference between the control and treated soils. The treatment applied in this study may offer a means to remediate CLD-contaminated soils, especially nitisol and ferralsol.
Asunto(s)
Clordecona/química , Restauración y Remediación Ambiental , Insecticidas/química , Contaminantes del Suelo/química , Suelo/química , Agricultura , Martinica , Oxidación-ReducciónRESUMEN
Chlordecone is a persistent organochlorine pesticide widely used between 1972 and 1993 in the French West Indies to control the root borer in banana fields. Chlordecone use resulted in long-term pollution of soils, contamination of waters, of aquatic organisms, and of fields. Chlordecone is known to be neurotoxic, to increase prostate cancer, and to have negative effects on cognitive and motor development during infancy. In Guadeloupe, most of the freshwater species living in contaminated rivers exceed the French legal limit of 20 µg·kg(-1) wet weight. In the present study, we chose a transcriptomic approach to study the cellular effects of chlordecone in the giant freshwater prawn Macrobrachium rosenbergii, an important economical species in Guadeloupe. Quantitative PCR revealed an induction of genes involved in defense mechanism against oxidative stress (catalase and selenium-dependent glutathione peroxidase) in prawns exposed to low environmental concentrations of chlordecone after 12 and 24 h of exposure. In prawns reared in a contaminated farm, transcription of genes involved in the biotransformation process (cytochrome P450 and glutathione-S-transferase (GST)) were induced after 8 days of exposure. Our results provide information on the mechanims of defense induced by chlordecone in aquatic crustacean species. This gene expression study of selected genes should be further strengthened by proteomic analyses and enzymatic activity assays to confirm the response of these biomarkers of stress in crustaceans and to give new insights into the mechanism of toxicity by chlordecone.
Asunto(s)
Biotransformación/genética , Clordecona/toxicidad , Contaminantes Ambientales/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Palaemonidae/efectos de los fármacos , Palaemonidae/genética , Animales , Biotransformación/efectos de los fármacos , Clordecona/análisis , Cartilla de ADN/genética , ADN Complementario/genética , Contaminantes Ambientales/análisis , Fluorescencia , Agua Dulce , Regulación de la Expresión Génica/fisiología , Guadalupe , Masculino , Estrés Oxidativo/genética , Reacción en Cadena de la PolimerasaRESUMEN
This study investigated the effects of E2, diethylstilbestrol (DES), antiestrogens, the phytoestrogen resveratrol, and the xenoestrogens octylphenol (OP), nonylphenol (NP), endosulfan, kepone, 2,3,4,5-tetrachlorobiphenyl-4-ol (HO-PCB-Cl(4)), bisphenol-A (BPA), and 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on induction of luciferase activity in breast cancer cells transfected with a construct (pSp1(3)) containing three tandem GC-rich Sp binding sites linked to luciferase and wild-type or variant ERalpha. The results showed that induction of luciferase activity was highly structure-dependent in both MCF-7 and MDA-MB-231 cells. Moreover, RNA interference assays using small inhibitory RNAs for Sp1, Sp3 and Sp4 also demonstrated structure-dependent differences in activation of ERalpha/Sp1, ERalpha/Sp3 and ERalpha/Sp4. These results demonstrate for the first time that various structural classes of ER ligands differentially activate wild-type and variant ERalpha/Sp-dependent transactivation, selectively use different Sp proteins, and exhibit selective ER modulator (SERM)-like activity.
Asunto(s)
Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Estrógenos/farmacología , Factor de Transcripción Sp1/agonistas , Factor de Transcripción Sp1/metabolismo , Compuestos de Bencidrilo , Western Blotting , Línea Celular Tumoral , Clordecona/farmacología , Dietilestilbestrol/farmacología , Estradiol/farmacología , Moduladores de los Receptores de Estrógeno/farmacología , Receptor alfa de Estrógeno/genética , Transferencia Resonante de Energía de Fluorescencia , Humanos , Fenoles/farmacología , Fitoestrógenos/farmacología , Interferencia de ARN , Resveratrol , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción Sp1/genética , Factor de Transcripción Sp3/agonistas , Factor de Transcripción Sp3/genética , Factor de Transcripción Sp3/metabolismo , Factor de Transcripción Sp4/agonistas , Factor de Transcripción Sp4/genética , Factor de Transcripción Sp4/metabolismo , Estilbenos/farmacología , TransfecciónRESUMEN
Chlordecone (CD) and mirex (M) differ by a single carbonyl group in CD in place of two chlorines in M. Although both compounds are lipophilic, their tissue distributions differ markedly: CD concentrations are highest in liver; M concentrations are highest in fat. We used tissue time course data in rats from our laboratory for CD and M and literature data from monkeys to develop PBPK models to study differences in liver and fat partitioning. The PK model for M had partitioning in tissue without specific hepatic binding. The CD model had partitioning similar to M, and also included liver binding: the maximal binding (B(max)) and binding affinity constant (Kd) required to describe the rat data were 370 nmol/g liver and 100 nM, respectively. To see if other ketones with electron withdrawing constituents at the alpha carbon were also preferentially distributed to liver, we developed a PBPK description for tissue distribution of hexafluoroacetone (HFA). Compared to acetone, HFA is known to be preferentially sequestered in liver and more slowly excreted unchanged from the body. Acetone is more equally distributed to tissues. HFA distribution was evaluated with a PBPK model that included hepatic binding. B(max) and Kd were 1.58 micromol/g liver and 301 microM. In summary, liver sequestration of CD and HFA most likely represents relatively high-affinity but reversible binding of activated carbonyls in these compounds (activated by the presence of electron withdrawing substituents on the alpha-carbons) with glutathione and glutathione transferases, that are present at much higher concentrations in liver than in other tissues. Strong, but reversible hemithioketal formation with active sulfhydryls may also be associated with the toxic responses to CD and HFA.
Asunto(s)
Acetona/análogos & derivados , Clordecona/farmacocinética , Fluorocarburos/farmacocinética , Hígado/metabolismo , Modelos Biológicos , Acetona/administración & dosificación , Acetona/química , Acetona/farmacocinética , Administración Oral , Algoritmos , Animales , Clordecona/administración & dosificación , Clordecona/química , Evaluación Preclínica de Medicamentos , Femenino , Fluorocarburos/administración & dosificación , Fluorocarburos/química , Interacciones Hidrofóbicas e Hidrofílicas , Inyecciones Intravenosas , Insecticidas/administración & dosificación , Insecticidas/química , Insecticidas/farmacocinética , Metabolismo de los Lípidos/efectos de los fármacos , Macaca mulatta , Masculino , Mírex/administración & dosificación , Mírex/química , Mírex/farmacocinética , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Fish sexual development is sensitive to exogenous hormone manipulation, and salmonids have been used extensively as environmental sentinels and models for biomedical research. We simulated maternal transfer of contaminants by microinjecting rainbow trout (Oncorhynchus mykiss) and chinook salmon (Oncorhynchus tshawytscha) embryos. Fish were reared for 6 months and sexed, and gonads were removed for histology and measurement of in vitro steroid production. Analysis of fat samples showed that dichlorodiphenylethylene (DDE) levels, o, p'M-DDE and p,o, p'-DDE isomers, were elevated 6 months after treatment. A preliminary study showed an increased ratio of males to females after treatment with 80 mg/kg and 160 mg/kg of the xenoestrogen o,o, p'-DDE. One fish treated with 160 mg/kg o,o, p'-DDE had gonads with cells typical of both males and females. A follow-up study, using more fish and excluding the highly toxic 160 mg/kg o,o, p'-DDE dose, showed no effect on sex ratio or gonadal histology. Embryonic exposure of monosex male trout, monosex female trout, and mixed sex salmon to o, o, p'-DDE, p,o, p'-DDE, mixtures of DDE isomers, and octylphenol failed to alter sexual development. We observed no treatment-dependent changes in in vitro gonadal steroid production in any experiments. Trout exposed in ovo and reared to maturity spawned successfully. These results suggest that mortality attributable to the xenoestrogens o,o, p'-DDE, chlordecone, and octylphenol, and the antiandrogen p,o, p'-DDE, is likely to occur before the appearance of subtle changes in sexual development. Because trout appeared to be sensitive to endocrine disruption, we cannot dismiss the threat of heavily contaminated sites or complex mixtures to normal sexual development of salmonids or other aquatic organisms.
Asunto(s)
Clordecona/efectos adversos , Diclorodifenil Dicloroetileno/efectos adversos , Embrión no Mamífero/efectos de los fármacos , Estrógenos/efectos adversos , Insecticidas/efectos adversos , Exposición Materna/efectos adversos , Microinyecciones , Mitotano/análogos & derivados , Fenoles/efectos adversos , Diferenciación Sexual/efectos de los fármacos , Animales , Trastornos del Desarrollo Sexual , Evaluación Preclínica de Medicamentos , Monitoreo del Ambiente/métodos , Femenino , Gónadas/efectos de los fármacos , Gónadas/ultraestructura , Masculino , Mitotano/efectos adversos , Oncorhynchus mykiss , Residuos de Plaguicidas/efectos adversos , Residuos de Plaguicidas/análisis , SalmónRESUMEN
Several strains of laboratory rats have a high background incidence of mammary tumors and develop a persistent, anovulatory estrus condition at about 12 mo of age. The increased tumor incidence is believed to be associated with elevated estradiol (E2) and prolactin during the period of persistent estrus. A pharmacodynamic estrus cycle (PD-EC) model for the Sprague-Dawley rats has been developed in an attempt to analyze the physiological basis of early-onset persistent estrus and to examine the potential sites of interactions in the hypothalamic-pituitary-ovarian axis for endocrine-modulating xenobiotics that accelerate the onset of persistent estrus. This initial estrus cycle model focused solely on cyclical changes in E2 and luteinizing hormone (LH). An LH surge was scheduled when a hypothetical estrus cycle-related protein (EC-RP) under transcriptional control by the E2 receptor reached a critical concentration. In the model, aging-related cumulative hypothalamic E2 exposure impaired the LH surge by reducing the rate of production of the EC-RP. The progressively decreasing intercycle resynthesis rate leads first to longer, variable-length cycles and finally to persistent estrus at about 12 mo of age. This model construct is consistent with early-onset persistent estrus related to neonatal E2 exposures, with acyclicity associated with high-dose E2 exposure in the adult, and with persistent estrus conditions associated with exposures to xenobiotic endocrine modulators that are either weak E2 antagonists or weak E2 agonists. With further development these pharmacodynamic estrus cycle models should be useful in aiding risk assessments for compounds causing mammary-tissue tumors associated with persistent estrus states.
Asunto(s)
Estradiol/sangre , Estro/efectos de los fármacos , Hormona Luteinizante/sangre , Prolactina/sangre , Receptores de Estradiol/agonistas , Receptores de Estradiol/antagonistas & inhibidores , Envejecimiento/efectos de los fármacos , Animales , Clordecona/toxicidad , Relación Dosis-Respuesta a Droga , Estro/sangre , Estro/fisiología , Femenino , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiología , Insecticidas/toxicidad , Neoplasias Mamarias Animales/etiología , Neoplasias Mamarias Animales/fisiopatología , Ovario/efectos de los fármacos , Ovario/fisiología , Hipófisis/efectos de los fármacos , Hipófisis/fisiología , Ratas , Ratas Sprague-Dawley/genética , Receptores de Estradiol/biosíntesis , Reproducción/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genéticaRESUMEN
It is widely recognized that exposure to combinations or mixtures of chemicals may result in highly exaggerated toxicity even though the individual chemicals might not be toxic. Assessment of risk from exposure to combinations of chemicals requires the knowledge of the underlying mechanism(s). Dietary exposure to a nontoxic dose of chlordecone (CD; 10 ppm, 15 days) results in a 67-fold increase in lethality of an ordinarily inconsequential dose of CCl4 (100 microliters/kg, ip). Toxicity of closely related CHCl3 and BrCCl3 is also enhanced. Phenobarbital (PB, 225 ppm, 15 days) and mirex (10 ppm, 15 days) do not share the propensity of CD in this regard. Exposure to PB + CCl4 results in enhanced liver injury similar to that observed with CD, but the animals recover and survive in contrast to the greatly amplified lethality of CD + CCl4. Investigations have revealed that neither enhanced bioactivation of CCl4 nor increased lipid peroxidation offers a satisfactory explanation of these findings. Additional studies indicate that exposure to a low dose of CCl4 (100 microliters/kg, ip) results in limited injury, which is accompanied by a biphasic response of hepatocellular regeneration (6 and 36 hr) and tissue repair, which enables the animals to recover from injury. Exposure to CD + CCl4 results in suppressed tissue repair owing to an energy deficit in hepatocytes as a consequence of excessive intracellular influx of Ca2+ leading initially to a precipitous decline in glycogen and ultimately to hypoglycemia. Supplementation of cellular energy results in restoration of the tissue repair and complete recovery from the toxicity of CD + CCl4 combination. In contrast, only the early-phase hepatic tissue repair (6 hr) is affected in PB + CCl4 treatment, but this is adequately compensated for by a greater stimulation of tissue repair at 24 and 48 hr resulting in recovery from liver injury and animal survival. A wide variety of additional experimental evidence confirms the central role of stimulated tissue repair as a decisive determinant of the final outcome of liver injury inflicted by CCl4. For instance, a 35-fold greater CCl4 sensitivity of gerbils compared to rats is correlated with the very sluggish tissue repair in gerbils. These findings are consistent with a two-stage model of toxicity, where tissue injury is inflicted by the well described "mechanisms of toxicity," but the outcome of this injury is determined by whether or not sustainable tissue repair response accompanies this injury.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Sustancias Peligrosas/toxicidad , Salud Pública , Animales , Animales Recién Nacidos , Calcio/metabolismo , Tetracloruro de Carbono/toxicidad , División Celular , Clordecona/toxicidad , Colchicina/farmacología , Interacciones Farmacológicas , Sinergismo Farmacológico , Femenino , Gerbillinae , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Necrosis/inducido químicamente , Ratas , Medición de Riesgo , Factores de TiempoRESUMEN
Chlordecone potentiation of the hepatotoxic and lethal effects of CCL4 has been well established. Recent studies have shown that the suppression of hepatocellular regeneration results in an accelerated progression of liver injury leading to complete hepatic failure. Since polyamines are involved in cell division, these studies were designed to investigate the polyamine levels and associated enzymes in the livers of rats treated with a low-dose combination of CD and CCl4. For comparison, a large toxic dose of CCl4 was also employed. The extent of liver toxicity in rats fed 10 parts per million chlordecone (CD) for 15 days and subsequently injected with a single dose of CCl4 (100 microL/kg body weight) or a high dose of CCL4 alone (2.5 mL/kg body weight) was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was significant elevation in liver ornithine decarboxylase, S-adenosylmethionine decarboxylase, and putrescine at 24 hr and spermidine N1-acetyltransferase, N1-acetylputrescine, putreanine, putrescine, and N1-acetylspermidine at 6 hr in rats treated with the high dose of CCl4 alone compared to the combination treatment. Spermidine levels decreased up to 6 hr and then increased up to 24 hr for both treatments. Spermine continuously decreased up to 24 hr for the CD and CCl4 low-dose combination treatment compared to rats treated with a high dose of CCl4 alone. Spermidine levels were lower than in controls and rose towards control value between 6 and 24 hr after the combination treatment and the high dose of CCl4. Results indicate that the CD and CCl4 low-dose combination treatment increased liver toxicity, resulting in compromised polyamine metabolism that is coincidental with suppressed hepatocellular regeneration, which leads to an accelerated progressive phase of liver injury and culminates in complete hepatic failure.
Asunto(s)
Poliaminas Biogénicas/metabolismo , Intoxicación por Tetracloruro de Carbono/metabolismo , Clordecona/toxicidad , Insecticidas/toxicidad , Hígado/metabolismo , Adenosilmetionina Descarboxilasa/metabolismo , Alanina Transaminasa/sangre , Amina Oxidasa (conteniendo Cobre)/metabolismo , Animales , Aspartato Aminotransferasas/sangre , Cromatografía Líquida de Alta Presión , Hígado/enzimología , Masculino , Ornitina Descarboxilasa/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Pretreatment of rats with phenoxybenzamine (5 mg/kg; SC), an alpha adrenergic antagonist, decreased the peak tremor power and startle magnitude of rats subsequently given DDT (75 mg/kg; PO) or chlordecone (60 mg/kg; IP), without having a significant effect on control animals. Pretreatment with an intracerebroventricular injection of calcium (3.75 microM in 5 microliters NaCl) decreased the peak tremor power due to subsequently administered DDT, while increasing the tremor response in rats later dosed with chlordecone. The effects of phenoxybenzamine are postulated to be due to a blockade of an excitatory influence of the adrenergic system. Calcium may decrease DDT-induced tremor by acting as a neuronal stabilizer. Potentiation of the tremorigenic effect of chlordecone by calcium may be due to increased levels of intracellular calcium, resulting in augmented release of neurotransmitters in chlordecone-exposed animals.
Asunto(s)
Clordecona/toxicidad , DDT/toxicidad , Insecticidas/toxicidad , Reflejo de Sobresalto/efectos de los fármacos , Temblor/inducido químicamente , Estimulación Acústica , Animales , Calcio/farmacología , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
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.
Asunto(s)
Glándulas Suprarrenales/enzimología , Clordecona/toxicidad , DDT/toxicidad , Insecticidas/toxicidad , Ornitina Descarboxilasa/metabolismo , Piretrinas/toxicidad , Glándulas Suprarrenales/citología , Glándulas Suprarrenales/efectos de los fármacos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Hipofisectomía , Hipotálamo/efectos de los fármacos , Hipotálamo/enzimología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Permetrina , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
Rats were given 75 mg/kg of 5,5-diphenylhydantoin (phenytoin) or vehicle 30 min prior to 75 mg/kg of 1,1,1-trichloro-bis(p-chlorophenyl)ethane (p,p'-DDT) (p.o.) or chlordecone (i.p.) and tremor was measured 12 h later. Rats were then killed, and regional brain levels of biogenic amines and their acid metabolites and amino acids were determined. Pretreatment with phenytoin significantly attenuated the tremor produced by p,p'-DDT but enhanced that produced by chlordecone. p,p'-DDT had significant effects on the levels of aspartate, glutamate, 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), whereas chlordecone increased glycine, 5-HIAA, and MHPG levels. Pretreatment with phenytoin blocked p,p'-DDT-induced increases of aspartate in the brainstem and spinal cord, 5-HIAA in the hippocampus, and MHPG in the brainstem and hypothalamus. Phenytoin significantly enhanced chlordecone-induced increases of MHPG in the brainstem. These data indicate that organochlorine-induced increases in noradrenergic activity in the brainstem and spinal cord may be directly related to the tremorigenic effects of these chemicals.
Asunto(s)
Química Encefálica/efectos de los fármacos , Clordecona/antagonistas & inhibidores , DDT/antagonistas & inhibidores , Insecticidas/antagonistas & inhibidores , Fenitoína/farmacología , Animales , Tronco Encefálico/análisis , Núcleo Caudado/análisis , Hipocampo/análisis , Ácido Hidroxiindolacético/análisis , Hipotálamo/análisis , Masculino , Metoxihidroxifenilglicol/análisis , Norepinefrina/análisis , Ratas , Ratas Endogámicas F344 , Serotonina/análisis , Médula Espinal/análisis , Temblor/inducido químicamenteRESUMEN
The effects of chlordecone on reproductive function was examined in adult females. Chlordecone was shown to mimic estrogen by producing persistent vaginal estrus in ovariectomized and intact females. In ovariectomized females, chlordecone reduced serum levels of luteinizing hormone (LH) and increased prolactin (PRL). In intact females, chlordecone reduced the preovulatory surges of both LH and PRL but had no effect on serum hormones of diestrous females. Chlordecone failed to mimic estrogen in priming the ovariectomized female for behavioral receptivity, and instead appeared to antagonize the priming action of estrogen. Examination of neurotransmitter changes suggested that chlordecone disrupted the usual sequence of events occurring throughout the female's estrous cycle and that this disturbance of neurotransmitter equilibrium contributed to the reproductive dysfunction. The hypothesis that chlordecone disrupts reproductive function by acting as a weak estrogen received considerable support. However, the results of several studies indicated that the neural effects of chlordecone and estradiol were not identical. We have proposed that chlordecone mimics many of the estrogen-receptor mediated neural events. However, because of the persistence of chlordecone in the organism, chlordecone fails to initiate the sequential changes which characterize estrous cyclicity.
Asunto(s)
Clordecona/toxicidad , Insecticidas/toxicidad , Neurotransmisores/fisiología , Animales , Castración , Catecolaminas/metabolismo , Estrógenos/farmacología , Estro/efectos de los fármacos , Femenino , Ácido Hidroxiindolacético/metabolismo , Hipotálamo/metabolismo , Leucocitos/efectos de los fármacos , Hormona Luteinizante/metabolismo , Neurotransmisores/metabolismo , Embarazo , Prolactina/metabolismo , Ratas , Receptores de Estrógenos/efectos de los fármacos , Reproducción/efectos de los fármacos , Conducta Sexual Animal/efectos de los fármacos , Factores de Tiempo , Vagina/citologíaRESUMEN
3-Methoxy-4-hydroxyphenylglycol (MHPG) is the major metabolite of norepinephrine (NE) in the rat brain. A single injection of tremorigenic doses of chlordecone to adult male Fischer-344 rats resulted in significant increases in MHPG concentrations in hypothalamus, brain stem, cerebellum, and caudate nucleus. The increase in MHPG was accompanied by a decrease in NE in the hypothalamus, suggesting that chlordecone treatment caused an increase in the turnover of NE in the brain. There was a dose- and time-related correlation between the increases in the concentrations of MHPG in hypothalamus, brain stem, and cerebellum and tremor in rats. The increase in MHPG in hypothalamus and brain stem occurred as early as 1 hr postdosing; this preceded the earliest measurable sign of tremor and initial hypothermia. Whether the alterations in the brain NE system are involved in the expression of the tremor and the initial hypothermia induced by chlordecone or whether they are merely associated with these changes is not clear.
Asunto(s)
Tronco Encefálico/efectos de los fármacos , Núcleo Caudado/efectos de los fármacos , Cerebelo/efectos de los fármacos , Clordecona/toxicidad , Glicoles/análisis , Hipotálamo/efectos de los fármacos , Insecticidas/toxicidad , Metoxihidroxifenilglicol/análisis , Norepinefrina/metabolismo , Temblor/inducido químicamente , Animales , Tronco Encefálico/metabolismo , Núcleo Caudado/metabolismo , Cerebelo/metabolismo , Hipotálamo/análisis , Hipotermia/inducido químicamente , Inyecciones Intraperitoneales , Masculino , Norepinefrina/análisis , Ratas , Ratas Endogámicas F344RESUMEN
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.
Asunto(s)
Encefalina Metionina/análogos & derivados , Estrógenos/farmacología , Hipotálamo/efectos de los fármacos , Hipófisis/efectos de los fármacos , Animales , Clordecona/farmacología , Endorfinas/metabolismo , Encefalina Metionina/metabolismo , Estrógenos/metabolismo , Femenino , Hipotálamo/metabolismo , Inyecciones Intraperitoneales , Hormona Luteinizante/sangre , Masculino , Ovario/fisiología , Hipófisis/metabolismo , Prolactina/sangre , Radioinmunoensayo , Ratas , Ratas Endogámicas F344 , Factores Sexuales , betaendorfinaRESUMEN
The purpose of this study was to correlate the chlordecone-elicited tremor activity with alterations of brain neurotransmitters. A single injection of chlordecone (80 mg/kg, ip) significantly increased the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) but did not affect the concentrations of dopamine, dihydroxphenylacetic acid, aspartate, taurine, glutamate, glycine, and gamma-aminobutyric acid (GABA). There was a dose- and time-related correlation between the increases in striatal 5-HIAA levels and tremor after chlordecone treatment. A subsequent study with pargyline indicated that the increase in striatal 5-HIAA level represented an increase in the turnover of serotonin. This study plus the previous finding that pizotifen (BC-105), a serotonin receptor blocker, attenuated chlordecone-elicited tremor strongly suggests a possible involvement of the serotonin system in mediating the tremor elicited by this insecticide.
Asunto(s)
Química Encefálica/efectos de los fármacos , Clordecona/toxicidad , Insecticidas/toxicidad , Neurotransmisores/metabolismo , Serotonina/fisiología , Temblor/inducido químicamente , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Temperatura Corporal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dimetilsulfóxido/farmacología , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Ácido Hidroxiindolacético/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Pargilina/farmacología , Ratas , Ratas Endogámicas F344 , Serotonina/metabolismo , Temblor/metabolismoRESUMEN
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.