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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a quantitative cytochemical study on cytochrome oxidase and lactate dehydrogenase activities on rabbit epididymal spermatozoa during spontaneous lipid peroxidation. Our data show that during aerobic incubation both in NTP and KTP media the sperm cytochrome oxidase activity undergoes a significant decrease. The lactate dehydrogenase activity shows different cytochemical patterns in comparison between the two media considered. Such activity significantly increases in rabbit spermatozoa suspended in NTP medium from the first until the sixteenth hour of incubation time. At the following times the lactate dehydrogenase activity significantly declines showing yet until the later times of incubation integrated optical density values fairly high. During the whole period of the aerobic incubation, the spermatozoa suspended in medium KTP show lactate dehydrogenase integrated optical density values which not significantly differ from those of the control in spite of an initial enhancement from the first until the thirteenth hour of the experimental treatment.
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PMID:Cytochrome oxidase and lactate dehydrogenase activities in peroxidized rabbit epididymal spermatozoa. 254 15

Damage to the plasma membrane of rabbit epididymal spermatozoa during spontaneous lipid peroxidation was examined by means of trypan blue uptake and expression of activity of the intracellular enzymes, lactate dehydrogenase and pyruvate kinase. Both the dye uptake and the expression of enzyme activity probe cell damage from lipid peroxidation as loss of integrity of the plasma membrane. A linear correlation was obtained between trypan blue staining of the cells and malondialdehyde production, a quantifiable measure of the extent of lipid peroxidation. At the point of trypan blue staining of all cells, 0.5 nmol malondialdehyde/10(8) cells was produced. This is the same amount produced at the point of complete loss of motility and superoxide dismutase activity. We have defined this as the "lipoperoxidative lethal end point." Expression of lactate dehydrogenase and pyruvate kinase activities increased with time of aerobic incubation. In the high Na+ medium, NTP, in which lipid peroxidation is slow, there is a linear correlation between increase in expressed enzyme activities and malondialdehyde production. But in the high K+ medium, KTP, in which lipid peroxidation is rapid, there is an initial rapid rise in expressed enzyme activity over 3 h, followed by a slower increase. Activities of rabbit sperm lactate dehydrogenase, pyruvate kinase, and flagellar ATPase were unaffected by aerobic incubations for up to 48 h, double the incubation period used for the assay of enzymatic activities for the first two. The activity of glyceraldehyde-3-phosphate dehydrogenase decreased during aerobic incubation, the time course matching the loss of motility. The subcellular distribution of lactate dehydrogenase in rabbit spermatozoa was determined: 4% in the mitochondrial matrix, 10% in the plasma membrane and 85% in the cytosolic compartment.
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PMID:Assessment of cell damage caused by spontaneous lipid peroxidation in rabbit spermatozoa. 623 Oct 58

Butyl benzyl phthalate is a plasticizer added to polymers to give flexibility and softness. It is used extensively in polyvinyl chloride and in cellulose plastics, polyvinyl acetate, polysulfides, and polyurethane. Butyl benzyl phthalate was nominated as part of a class study of phthalates. Previous studies of butyl benzyl phthalate by the NTP (1982a) resulted in chemical-related mortality in male rats beginning at about 14 weeks of exposure and, thus, were inadequate for evaluating carcinogenicity in male rats. The companion studies revealed a marginal increase in leukemia in female rats and no evidence of carcinogenicity in B6C3F1 mice. Consequently, the present evaluations were conducted only in F344/N rats. Male and female F344/N rats were given butyl benzyl phthalate (at least 97% pure) in feed for 10 weeks, 26 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, mouse bone marrow cells, and Drosophila melanogaster. 10-WEEK MODIFIED MATING STUDY IN RATS: Groups of 15 male F344/N rats were given 0, 300, 2,800, or 25,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 20, 200, or 2,200 mg butyl benzyl phthalate/kg body weight) in feed for 10 weeks. All rats survived to the end of the study. The final mean body weight and body weight gain of the 25,000 ppm group were significantly less than those of the controls. Feed consumption by the 25,000 ppm group was less than that by the controls at the end of the study. A few minimal hematology changes occurred in the 25,000 ppm male rats. There was some evidence of a minimal anemia characterized by a decreased erythrocyte count and increases in mean cell hemoglobin and platelet count. The absolute and relative prostate gland weights of the 25,000 ppm males were significantly less than those of the controls. Degeneration of the seminiferous tubule germinal epithelium was observed in all males from the 25,000 ppm group. The absolute right cauda, right epididymis, and right testis weights of the 25,000 ppm males were significantly less than those of the controls. The epididymal spermatozoal concentrations in 2,800 and 25,000 ppm males were significantly less than that in the controls. Although 10 females mated to 25,000 ppm males were initially found to be sperm positive, none of these females were pregnant at necropsy. The fertility indices of males and females in the 25,000 ppm group were significantly lower than those of the controls. The maternal body weights of females mated to 300 and 2,800 ppm males were similar to those of females mated to control males. There were no significant differences in litter data between the controls and the 300 and 2,800 ppm groups. 26-WEEK STUDY IN RATS: Groups of 15 male F344/N rats were given 0, 300, 900, 2,800, 8,300, or 25,000 ppm butyl benzyl phthalate in feed for 26 weeks. Dietary levels of 300, 900, 2,800, and 8,300 ppm delivered average daily doses of approximately 30, 60, 180, and 550 mg butyl benzyl phthalate/kg body weight. The final mean body weight and body weight gain of the 25,000 ppm males were significantly less than those of the controls. Except for the 25,000 ppm males, feed consumption by all exposed groups was similar to that by the controls. An exposure-related macrocytic responsive anemia was present in the 25,000 ppm group at all time points. Additionally, minimal erythrocyte count decreases occurred sporadically in the 2,800 and 8,300 ppm groups at various time points. Reticulocyte counts were increased on days 60 and 90. Increases in mean cell hemoglobin and mean cell hemoglobin concentrations occurred in the 8,300 and 25,000 ppm rats. The absolute right cauda, right epididymis, and right testis weights and the sperm concentration of 25,000 ppm males were significantly less than those of the controls. The incidences of hypospermia and of atrophy of the seminiferous tubule in the testis and of hypospermia in the epididymis in 25,000 ppm males were significantly greater than those in the in the controls. Degenerative changes of the testis and epididymis in the 25,000 ppm males were qualitatively and quantitatively similar to those observed in males in the 10-week modified mating study. 2-YEAR STUDY IN RATS: Groups of 60 male F344/N rats were given 0, 3,000, 6,000, or 12,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 120, 240, or 500 mg butyl benzyl phthalate/kg body weight), and groups of 60 female F344/N rats were given 0, 6,000, 12,000, or 24,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 300, 600, or 1,200 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption: Survival of all exposed groups of male and female rats was similar to that of the controls. Mean body weights of the 12,000 ppm males and 24,000 ppm females were less than those of the controls throughout most of the study. Feed consumption by the females exposed to 24,000 ppm was less than that by the controls at the beginning of the study, but was similar to that by the controls by week 6. Hematology and Hormone Assays: In general, hematology changes were sporadic and minor. At 6 months, a minimal decrease in erythrocyte count and an increase in mean cell hemoglobin, similar to that which occurred in the 26-week study, occurred in male rats in the 12,000 ppm group. In female rats, a decreased hematocrit value occurred at 15 months in the 24,000 ppm group. There was also a mild decrease in triiodothyronine concentrations in the 24,000 ppm females at 6 and 15 months and at the end of the study. Pathology Findings: of pancreatic acinar cell adenoma and adenoma or carcinoma (combined) in 12,000 ppm males were significantly greater than those in the controls. The incidences of adenoma and of adenoma or carcinoma (combined) in 12,000 ppm males exceeded the ranges of historical controls from NTP 2-year feed studies. One carcinoma was observed in one 12,000 ppm male, and two adenomas were observed in 24,000 ppm females. At 2 years, the incidence of focal hyperplasia of the pancreatic acinar cell in 12,000 ppm males was significantly greater than that in the controls. At 2 years, transitional epithelial papillomas in the urinary bladder were observed in one control female and in two 24,000 ppm females. The incidence of this neoplasm exceeded the range of historical controls from NTP 2-year feed studies. The incidence of transitional epithelial hyperplasia in 24,000 ppm females was significantly greater than that in the controls. The absolute right kidney weight of 12,000 ppm females and the relative right kidney weights of all exposed groups of males and of 24,000 ppm females were significantly greater than those of the controls at the 15-month interim evaluation. The severities of renal tubule pigmentation in 12,000 ppm males and in 24,000 ppm females were greater than those in the controls at 15 months and 2 years. At 2 years, the incidences of kidney mineralization in 6,000 and 24,000 ppm females were significantly less than that in the controls, and the severity was decreased in exposed females. The incidence of preputial gland adenoma or carcinoma (combined) in 12,000 ppm male rats was significantly less than in the controls, and the incidences occurred with a negative trend. GENETIC TOXICOLOGY: Results from in vitro mutagenicity tests with butyl benzyl phthalate were uniformly negative. No mutagenic response was obtained in any of several strains of Salmonella typhimurium treated with up to 11,550 mg/plate butyl benzyl phthalate, with or without S9 metabolic activation enzymes. Negative results were also obtained in in vitro studies of mammalian cell systems with and without S9. No induction of trifluorothymidine resistance in L5178Y mouse lymphoma cells or sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells were observed. These assays also were conducted with and without S9. No significant increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster after administration of butyl benzyl phthalate either in feed or by injection. In contrast to the negative results obtained in vitro and in Drosophila, butyl benzyl phthalate gave positive responses in two in vivo studies with mice. Results of a mouse bone marrow sister chromatid exchange test were positive at sample times of 23 and 42 hours, but no confirmatory test was conducted. Chromosomal aberrations were induced in bone marrow cells of male mice sampled 17 hours after intraperitoneal injection of 5,000 mg/kg butyl benzyl phthalate. CONCLUSIONS: Under the conditions of this 2-year feed study, there was some evidence of carcinogenic activity of butyl benzyl phthalate in male F344/N rats based on the increased incidences of pancreatic acinar cell adenoma and of acinar cell adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of butyl benzyl phthalate in female 344/N rats based on the marginally increased incidences of pancreatic acinar cell adenoma and of transitional epithelial papilloma of the urinary bladder. Exposure of rats to butyl benzyl phthalate in feed for 2 years resulted in focal hyperplasia in the pancreas in male rats and in transitional epithelial hyperplasia in the urinary bladder of female rats. Synonyms: A13-14777; BBP; 1,2-benzenedicarboxylic acid butyl phenylmethyl ester (9CI); benzyl n-butyl phthalate; n-butyl benzyl phthalate; butyl phenylmethyl 1,2-benzenedicarboxylate; NCI-C54375; phthalic acid benzyl butyl ester (8CI) Trade names: Palatinol BB; Santicizer 160; Sicol 160; Unimoll BB
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PMID:NTP Toxicology and Carcinogenesis Studies of Butyl Benzyl Phthalate (CAS No. 85-68-7) in F344/N Rats (Feed Studies). 1258 18

Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that resurvival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that received 50 mg/kg was lower than that of vehicle controls after week 101 (final survival--male: 33/50; 25/50; 27/50; female: 29/50; 27/50; 17/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Chemical-related nonneoplastic lesions in both rats and mice included hyperkeratosis and epithelial dysplasia of the forestomach. Fibrosis of the spleen was also present in rats of each sex, and cysts of the preputial gland and kidney were present in male mice. Exposure to glycidol induced dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice (see summary table on page 5 of the Technical Report). In male rats, mesotheliomas arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with the presence of mammary gland neoplasms. Genetic Toxicology: Glycidol was mutagenic in a variety of in vitro and in vivo short-term tests. Mutagenic activity was observed in S. typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 exposed to glycidol with and without exogenous metabolic activation. Glycidol was positive in the absence of exogenous metabolic activation in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells; it was not tested with activation. In cytogenetic tests with CHO cells, glycidol induced both sister chromatid exchanges and chromosomal aberrations in the presence and absence of exogenous metabolic activation. Glycidol induced sex-linked recessive lethal mutations and reciprocal translocations in the germ cells of male D. melanogaster exposed by feeding. The incidence of micronucleated polychromatic erythrocytes was increased in the bone marrow of male B6C3F1 mice administered glycidol by intraperitoneal injection. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. Synonym: 2,3-epoxy-1-propanol
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PMID:NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 47

Genistein is a naturally occurring isoflavone that interacts with estrogen receptors and multiple other molecular targets. Human exposure to genistein is predominantly through consumption of soy products, including soy-based infant formula and dietary supplements. A series of short-term studies with genistein was conducted with two goals: 1) to obtain data necessary to establish dose levels for subsequent multigeneration reproductive and chronic toxicity studies and 2) to evaluate the effects of genistein on endpoints outside the reproductive tract. The data generated from these studies have been reported previously in the peer-reviewed literature or in technical reports (Appendix C). In addition, selected data from these studies were analyzed and discussed in the National Toxicology Program's Report of the Endocrine Disruptors Low-Dose Peer Review (NTP, 2001). The present report focuses on the reproductive and general toxicology endpoints evaluated. Data obtained in separate evaluations of behavioral, neuroanatomical, neurochemical, and immunological endpoints, as well as the assessment of serum genistein levels, are also discussed to put in better perspective the selection of doses for the multigenerational and chronic studies. Genistein was administered in an irradiated soy- and alfalfa-free diet (Purina 5K96) at exposure concentrations of 0, 5, 25, 100, 250, 625, or 1,250 ppm to 10 vaginal plug-positive, female Sprague-Dawley rats starting on gestation day 7 and continuing throughout pregnancy. These dietary exposure concentrations resulted in ingested doses of approximately 0.3, 1.7, 6.4, 16, 38, and 72 mg genistein/kg body weight to dams in the 5, 25, 100, 250, 625, and 1,250 ppm groups, respectively. Dietary exposure of the dams continued through lactation, during which time ingested doses were approximately 0.6, 3.5, 14, 37, 84, and 167 mg/kg per day. Pups from five litters, culled to eight per litter with an equal sex distribution on postnatal day (PND) 2, were maintained on the same dosed feed as their mothers after weaning until sacrifice at PND 50. Ingested doses were approximately 0.6, 3, 11, 29, 69, and 166 mg/kg per day for male pups and 0.6, 3, 12, 31, 73, and 166 mg/kg per day for female pups. Body weight and feed consumption of the treated dams prior to parturition showed decreasing trends with increasing dose, and both parameters were significantly less than those of the controls in the 1,250 ppm group. A significant exposure concentration-related effect on litter birth weight was observed, but no exposed group differed significantly from the control group in pairwise comparisons. Pups in the 1,250 ppm group had significantly decreased body weights relative to controls at the time of sacrifice (males, 9% decrease; females, 12% decrease). The most pronounced organ weight effects in the pups were decreased ventral prostate weight (absolute weight, 28% decrease; relative weight, 20% decrease) in males at 1,250 ppm and a trend toward higher pituitary gland to body weight ratios in both sexes. Histopathologic examination of female pups revealed ductal/alveolar hyperplasia of the mammary glands at exposure concentrations greater than 250 ppm. Ductal/alveolar hyperplasia and hypertrophy also occurred in males, with significant effects seen at exposure concentrations of 25 ppm or greater for hypertrophy and 250 ppm or greater for hyperplasia. Abnormal cellular maturation (mucocyte metaplasia) in the vagina was observed at 625 and 1,250 ppm, and abnormal ovarian antral follicles were observed at 1,250 ppm. In males, aberrant or delayed spermatogenesis in the seminiferous tubules relative to controls was observed at 1,250 ppm. Histologic evaluation indicated a deficit of sperm in the epididymis at 625 and 1,250 ppm relative to controls, although testicular spermatid head counts and epididymal spermatozoa counts did not show significant differences from controls at these exposure concentrations. Control females showed a high incidence of renal tubule mineralization, and the severity of this lesion was significantly increased at exposure concentrations of 250 ppm or greater. Males showed no renal tubule mineralization below 250 ppm, but incidence and severity increased with increasing exposure concentration at 250 ppm and greater. The primary goal of the current study was to provide information for the selection of exposure concentrations to be used in subsequent multigenerational and chronic studies. These long-term studies were designed to address multiple aspects of the endocrine disruptor hypothesis, that is, the hypothesis that exposures of human and wildlife populations to endocrine-active compounds contribute to adverse reproductive tract effects and cancers of hormone-sensitive organs. In particular, the long-term consequences of low dose exposures that may produce subtle initial effects, the magnification of those effects across generations, and the reversibility of those effects were to be investigated. The goal was to select a high exposure concentration that would not induce overt toxicity in the dams or pups but would induce observable effects in the reproductive organs of the pups without severely impairing fertility in the F1 generation. The 1,250 ppm exposure concentration was clearly ruled out for further testing based on the effects on body weights, histopathologic observations in males and females, and a reduction in the proportion of mated dams producing litters. While the effects observed at 625 ppm would not be predicted to significantly impair reproduction, the observation of significant effects at 250 ppm (hyperplasia in the mammary gland of both sexes), together with the suggestion of subtle effects at this exposure concentration and less in the parallel immunotoxicity and neuroanatomical surveys, a high exposure concentration between 250 and 625 ppm was deemed appropriate for the purposes of the multigenerational reproductive toxicology study and the chronic study of genistein. A high exposure concentration for the multigenerational and chronic studies was thus set at 500 ppm. A low exposure concentration of 5 ppm, where no significant effects were observed in the reproductive dose range-finding, and an intermediate exposure concentration of 100 ppm were also selected. Synonyms: 4',5,7-Trihydroxyisoflavone.
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PMID:NTP toxicity report of reproductive dose range-finding study of Genistein (CAS No. 446-72-0) administered in feed to Sprague-Dawley rats. 1868 12