RESUMEN
Planarians (Dugesia dorotocephala) were evaluated as bioassay organisms to detect inhibition of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. Thirty planaria per dose were exposed to 0 (control), 0.001, 0.01, 0.1, or 1 mM 3-iodo-L-tyrosine (monoiodotyrosine or MIT) in standard test media beginning 24 hr before decapitation and continuing for 13 days. Complete regeneration of normal heads occurred over the first 6 days in all dose groups, a response reported to be partially dependent on catecholamines. Beginning on Day 7, the black eye pigments began fading in the 0.1 and 1 mM dose groups and were completely absent macroscopically and histologically by Day 11. The 0, 0.001, and 0.01 mM dose groups did not lose visible eye pigments. On Day 13, 3 planaria/dose were harvested for histopathology; 15 planaria/dose were decapitated a second time and remained in MIT solutions; and 12 planaria/dose were left intact, placed in fresh control media, and evaluated for eye repigmentation. Normal head regeneration (including eyes) was detected grossly in all groups, even in those animals devoid of eye pigments at the time of decapitation. As before, eye pigments began fading 7 days after decapitation (Day 20 of experiment) and were completely absent in 73 and 33% of the animals in the 0.1 and 1 mM groups, respectively, on Day 25. All animals moved to control media reformed eye pigments, beginning within 48 hr. Analysis of the decapitated heads by HPLC-ECD on Day 13 revealed a significant decrease in dopamine and 5-hydroxytryptamine (serotonin) concentrations in MIT-exposed animals. Tyrosine hydroxylase activity (and possibly tyrosinase activity) was shown to be inhibited by the highest two concentrations for whole planaria homogenates in vitro.
Asunto(s)
Color del Ojo/efectos de los fármacos , Monoyodotirosina/farmacología , Planarias/efectos de los fármacos , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , Animales , Dopamina/análisis , Relación Dosis-Respuesta a Droga , Planarias/fisiología , Putamen/efectos de los fármacos , Ratas , Regeneración/efectos de los fármacos , Serotonina/análisisRESUMEN
Spatial learning and memory was assessed in rats following gestational and lactational exposure to specific ortho-substituted PCBs. Time-mated Sprague-Dawley rats were exposed to PCB 28 (2,4,4'-trichlorobiphenyl), 8 or 32 mg/kg/day, PCB 118 (2,3',4,4',5-pentachlorobiphenyl), 4 or 16 mg/kg/day, PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl), 16 or 64 mg/kg/day, or corn oil vehicle via gavage on Gestation Days 10-16. Litters were culled to eight on Day 2 and weaned on Day 21. Beginning on Day 90, one male and one female from each litter were tested on a working/reference memory task on an eight-arm maze. For each rat, the same four arms were baited throughout training. Animals were tested Monday-Friday, for seven consecutive weeks. No differences in working or reference memory errors were observed. The same animals were later tested on a T-maze delayed spatial alternation task. On each trial, the reinforcer was placed in the arm opposite that chosen by the rat on the previous trial. Intertrial delays of 15, 25, or 40 sec appeared in counterbalanced order. Rats were tested Monday-Friday for three consecutive weeks. The higher doses of all three congeners resulted in slower acquisition by female rats. Males were not affected. PCB-exposed females were impaired at all delays and were not differentially more impaired at longer delays, suggesting a learning or attentional deficit, rather than a mnemonic deficit. These findings demonstrate that perinatal exposure to ortho-substituted PCBs can result in long-lasting deficits in learning and suggest that the effects of PCBs on learning may be sex specific.
Asunto(s)
Lactancia , Aprendizaje/efectos de los fármacos , Exposición Materna/efectos adversos , Memoria/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Efectos Tardíos de la Exposición Prenatal , Animales , Peso Corporal/efectos de los fármacos , Femenino , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Caracteres SexualesRESUMEN
Perturbations in the developing nervous system have been associated with perinatal exposures to polychlorinated biphenyls (PCBs). It remains unclear whether these neurotoxic effects are direct or secondary to other toxic processes. This study was designed to determine which PCB congeners accumulate in the brain as a result of perinatal exposure and if this accumulation is regionally specific. Sprague-Dawley rat dams were dosed by gavage with corn oil or Aroclor 1242 in corn oil (4 or 16 mg/kg/d) on d 10-16 of gestation. At weaning (d 21), one male and one female pup from each litter were euthanatized and three specific regions of the brain (frontal cortex, hippocampus, and caudate putamen) were collected for PCB analysis by gas chromatography. Ten peaks, which represent 10-14 PCB congeners, were detected in all samples. There were no differences in PCB concentration between sexes or among brain regions, but the different congeners differed from each other in degree of bioaccumulation. Brain PCB concentrations increased with increased dose for all congeners except PCB 28 (2,4,4'), which was present at a higher concentration in the lower dose-group. To characterize regionalization of PCBs in the brain further, weanling rats were dosed intravenously with [14C]-PCB 77 (3,3',4,4'-tetrachlorobiphenyl; 0.25 microCi/g; 2.0 micrograms/g) or [14C]-PCB 47 (2,2',4,4'-tetrachhlorobiphenyl; 0.25 microCi/g; 5.3 micrograms/g) in dimethyl sulfoxide (DMSO). Rats were killed after 72 h and the brains were quickly removed and frozen on dry ice. The brains were serially sectioned on a cryostat and the sections (16 microns) subjected to autoradiography (3-5 mo of exposure). The radioactivity was homogeneously distributed in the brain tissue for both PCBs. PCB 77-treated, but not PCB 47-treated, pups showed increased activity in areas with blood vessels present. This was consistent with differences in the blood-brain ratios for PCB 47 and PCB 77, which were determined to be 0.44 and 16.8, respectively.
Asunto(s)
Encéfalo/metabolismo , Bifenilos Policlorados/farmacocinética , Animales , Arocloros/farmacocinética , Autorradiografía , Proteínas Sanguíneas/metabolismo , Cromatografía de Gases , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Intercambio Materno-Fetal , Bifenilos Policlorados/análisis , Embarazo , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Distribución TisularRESUMEN
Fumonisin B1 (FB1), a mycotoxin produced by Fusarium moniliforme and F. proliferatum, induces liver damage and pulmonary edema in swine. We examined the temporal and dose-response features of FB1 toxicosis in male weanling crossbred pigs fed nutritionally balanced diets, containing corn screenings naturally contaminated with fumonisins, for 14 days. Total fumonisins (FB1 and FB2) in diets 1 through 6 were assayed at 175, 101, 39, 23, 5, and < 1 ppm (below detectable concentrations), respectively. Clinical signs, serum biochemical alterations, and morphologic changes were evaluated. Pigs were weighed, and bled for hematologic and clinical chemistry evaluation on days 5 and 14. They were euthanized on day 14, or earlier if respiratory distress was observed. Respiratory distress developed in 3/5 pigs fed diet 1 between days 4 and 6 due to severe pulmonary edema and pleural effusion. Histologic evidence of hepatic injury was present in all pigs fed diets 1 and 2, 3/5 on diet 3, and 1/5 on diet 4. Serum bilirubin and cholesterol concentrations, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and arginase (ARG) activities were elevated in pigs fed diets 1 and 2. Based on liver histopathology, the no observed adverse effect level (NOAEL) for fumonisin toxicity in swine was < 23 ppm total fumosins for the 14-day period. Based on regression analyses of the clinical chemistry profiles at 14 days, the NOAEL was < 12 ppm, with ALP being the most sensitive parameter. In conclusion, pulmonary edema occurred only at the highest fumonisin concentration (175 ppm), while liver damage occurred at much lower concentrations with a NOAEL of < 12 ppm.
Asunto(s)
Alimentación Animal/toxicidad , Fumonisinas , Micotoxicosis/veterinaria , Micotoxinas/toxicidad , Animales , Dieta , Relación Dosis-Respuesta a Droga , Microbiología de Alimentos , Hígado/patología , Pulmón/patología , Masculino , Micotoxicosis/patología , Micotoxinas/análisis , Organismos Libres de Patógenos Específicos , Porcinos , Factores de Tiempo , Zea maysRESUMEN
Time-mated Sprague-Dawley rats were exposed to PCB 28 (2,4,4'-trichlorobiphenyl), 8 or 32 mg/kg/day; PCB 118 (2,3',4,4',5-pentachlorobiphenyl), 4 or 16 mg/kg/day; or PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl), 16 or 64 mg/kg/day. At weaning, serum thyroxine (T4) was markedly depressed in pups, but not dams, exposed to PCB 118 or 153. Triiodothyronine (T3) was unchanged in pups and dams. In a histological evaluation of thyroids, the PCB 118 pups revealed changes suggestive of sustained TSH stimulation, including increased follicular cell vacuolization and height, increased nuclear vesiculation, and decreased colloid area. Decreases in body and brain weights and increases in liver weights were observed in some groups, with the high dose PCB 118 pups showing the greatest effect.
Asunto(s)
Bifenilos Policlorados/toxicidad , Efectos Tardíos de la Exposición Prenatal , Glándula Tiroides/efectos de los fármacos , Hormonas Tiroideas/sangre , Animales , Peso al Nacer/efectos de los fármacos , Encéfalo/efectos de los fármacos , Femenino , Hígado/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Glándula Tiroides/patología , Aumento de Peso/efectos de los fármacosRESUMEN
Fumonisin B1 (FB1), a recently identified mycotoxin produced by Fusarium moniliforme in corn, has been shown to cause death in swine due to pulmonary edema, an apparently species specific effect, and to interfere with sphingolipid metabolism in vitro. Here we characterize the toxicity of fumonisins, using female cross-bred swine weighing 6 to 13 kg, and present a hypothesis regarding the mechanism of fumonisin-induced pulmonary edema in swine. FB1 was given daily intravenously (IV) to pig 1 for 9 days for a total of 72 mg (7.9 mg/kg) and to pig 2 for 4 days for a total of 67 mg (4.6 mg/kg). Pig 3 (control) was given saline IV for 9 days. Corn screenings naturally contaminated with FB1 (166 ppm) and FB2 (48 ppm) were fed to pigs 4, 5, and 6, and ground corn was fed to pigs 7 and 8 (controls). Pigs 4 and 7 were killed on day 5; pig 5 was found dead on day 6; and pigs 6 and 8 were killed on day 15. Pigs 4 and 5 had ingested 187 and 176 mg total fumonisins, respectively, while pig 6 had ingested 645 mg. Feed consumption had decreased in pigs fed corn screenings, with an additional sharp decrease prior to onset of clinical signs. Increases in serum liver enzymes, total bilirubin, and cholesterol were present, but electrocardiograms, heart rate, and body temperature were unaffected. Pigs dosed IV with FB1, developed mild intermittent respiratory abnormalities, while those fed screenings developed respiratory distress within 5 days. Mild interstitial pulmonary edema was observed in pig 1. Severe interstitial pulmonary edema, pleural effusion, and increased lung wet/dry weight ratio were observed in pigs 4 and 5. All pigs given fumonisin (either IV or orally) had hepatic changes characterized by hepatocyte disorganization and necrosis; pancreatic acinar cell degeneration was also observed. Ultrastructural changes in orally dosed swine included loss of sinusoidal hepatocyte microvilli; membranous material in hepatic sinusoids; and multilamellar bodies in hepatocytes, Kupffer cells, pancreatic acinar cells and pulmonary macrophages. Pulmonary intravascular macrophages (PIMs) contained large amounts of membranous material. Thus, the target organs of fumonisin in the pig are the lung, liver, and pancreas. At lower doses, slowly progressive hepatic disease is the most prominent feature, while at higher doses, acute pulmonary edema is superimposed on hepatic injury and may cause death. We hypothesize that altered sphingolipid metabolism causes hepatocellular damage resulting in release of membranous material into the circulation.(ABSTRACT TRUNCATED AT 400 WORDS)