Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acrosomal membranes isolated from the caput and cauda epididymal spermatozoa of hamster exhibited protein kinase activity and the endogenous protein substrates that were phosphorylated in the acrosomal membranes of caput and cauda spermatozoa were not all the same. The kinase activity was identified as a cAMP independent type and the use of specific stimulators and inhibitors indicated that the activity was not due to casein kinase, protein kinase A or protein kinase C but due to a tyrosine specific protein kinase that was not inhibited by Genistein. Phosphotyrosine was identified as the predominant phosphorylated residue in the proteins.
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PMID:Acrosome membrane associated protein kinase activity in hamster spermatozoa. 891 71

The effect of genistein on anion secretion via cystic fibrosis transmembrane conductance regulator (CFTR) in cultured rat cauda epididymal epithelia was studied by short-circuit current (Isc) technique. Genistein added apically stimulated a concentration-dependent rise in Isc due to Cl(-) and HCO(3)(-) secretion. The genistein-induced Isc was observed in basolaterally permeabilized monolayers, suggesting that the Isc response was mediated by the apical anion channel. The response could be blocked by the nonspecific Cl(-) channel blocker, diphenylamine-2-carboxylate (DPC), but not by the Ca(2+)-activated Cl(-) channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Genistein did not increase intracellular cAMP, but H-89, a protein kinase A inhibitor, completely abolished the Isc response to genistein. Moreover, pretreatment of the tissues with MDL-12330A, an adenylate cyclase inhibitor, markedly attenuated the Isc response to genistein, but the response was restored upon the addition of exogenous cAMP. Ca(2+), protein kinase C, tyrosine kinase, and protein phosphatase signalling pathways were not involved in the action of genistein. It is speculated that genistein stimulates anion secretion by direct interaction with CFTR. This requires a low level of phosphorylation of CFTR by basal protein kinase A activity. It is suggested that genistein may provide therapeutic benefit to male infertility associated with cystic fibrosis.
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PMID:Activation of cystic fibrosis transmembrane conductance regulator in rat epididymal epithelium by genistein. 1061 Oct 78

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 dose range-finding study was conducted as a prelude to a multigeneration bioassay to assess potential toxicities associated with genistein consumption. Genistein was administered in a soy- and alfalfa-free diet at 0, 5, 25, 100, 250, 625, or 1250 ppm to pregnant dams starting on Gestation day 7 and continuing throughout pregnancy. Dietary exposure of the dams continued through lactation, and pups were maintained on the same dosed feed as their mother after weaning until sacrifice at Postnatal day 50. Body weight and feed consumption of the treated dams prior to parturition showed a decreasing trend with a significant reduction at the highest dose. Litter birth weight was depressed in the 1250 ppm dose group, and pups of both sexes in that dose group had significantly decreased body weights relative to controls at the time of sacrifice. The most pronounced organ weight effects in the pups were decreased ventral prostate weight in males at the 1250 ppm dose 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 250 to 1250 ppm. Ductal/alveolar hyperplasia and hypertrophy also occurred in males, with significant effects seen at 25 ppm and above. Abnormal cellular maturation in the vagina was observed at 625 and 1250 ppm, and abnormal ovarian antral follicles were observed at 1250 ppm. In males, aberrant or delayed spermatogenesis in the seminiferous tubules relative to controls was observed at 1250 ppm. There was a deficit of sperm in the epididymis at 625 and 1250 ppm relative to controls, although testicular spermatid head counts and epididymal spermatozoa counts did not show significant differences from controls at these doses. Both sexes showed an increase in the incidence and/or severity of renal tubal mineralization at doses of 250 ppm and above. Dietary genistein thus produced effects in multiple estrogen-sensitive tissues in males and females that are generally consistent with its estrogenic activity. These effects occurred within exposure ranges achievable in humans.
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PMID:Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. 1173 18

The effects of follicular fluid on the acrosome reaction (AR) and phosphorylation of tyrosine residues of the sperm proteins were examined in mouse epididymal sperm. Human follicular fluid (hFF) increased AR in the capacitated sperm. Genistein, a receptor tyrosine kinase (RTK) inhibitor, inhibited spontaneous AR. When the genistein was primed, hFF-induced AR was attenuated but the A23187-induced AR was not, suggesting that potentiation of AR by hFF attributed to the activation of RTK upstream the mobilization of Ca2+. Phosphotyrosine proteins of Mr 27 to 116 kDa were markedly increased in capacitated sperm but this increase was abrogated by genistein. hFF increased tyrosine phosphorylation of Mr 56 kDa protein with genistein sensitive manner, suggesting that 56 kDa phosphotyrosine protein might be involved in capacitation and AR by follicular fluid.
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PMID:Changes in sperm phosphotyrosine proteins by human follicular fluid in mice. 1461 40

Genistein, a soybean-originated isoflavone, is widely consumed by humans for putative beneficial health effects but its estrogenic activity may affect adversely the development of male reproductive system. Five-week-old ICR mice were purchased and fed with a soybean-based Purina Chow diet until 6 months of age. The animals were exposed by gavage to genistein (2.5 mg/kg/day) or 17beta-estradiol (7.5 microg/kg/day) for five weeks. Corn oil was used for the negative control. The animals were fed the casein-based AIN-76A diet throughout the experimental periods. There were no significant differences in body and organ weights of mice among experimental groups. No significant differences in sperm counts and sperm motile characteristics were found between the control and the genistein groups. Treatment of 17beta-estradiol caused a significant decrease in epididymal sperm counts compared to the control (p<0.05). The level of phospholipid hydroxide glutathione peroxidase in the epididymis of mice exposed to genistein was significantly higher than that of the control mice (p<0.05). 17beta-estradiol treatment caused a reduction of germ cells in the testis and hyperplasia of mucosal fold region in the prostate of mice. Genistein treatment did not cause any lesion in the testis, epididymis, and prostate. These results suggest that dietary uptake of genistein at adult stage of life may not affect male reproductive system and functions.
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PMID:Exposure to genistein does not adversely affect the reproductive system in adult male mice adapted to a soy-based commercial diet. 1536 37

Genistein, a soybean-originated isoflavone, is widely consumed by humans for putative beneficial health effects but its estrogenic activity may adversely affect the development of male reproductive system. Twenty one-day-old ICR mice weaned from dams fed with a soybean-based diet throughout gestation and lactation were exposed by gavage to genistein (2.5 mg/kg b.w./day) or 17beta-estradiol (7.5 microg/kg b.w./day) for five weeks. Corn oil was used as a negative control. The animals were fed with a casein-based AIN-76A diet throughout the experimental periods. There were no significant differences in body and organ weights of mice among experimental groups. No significant differences in sperm counts and sperm motile characteristics were found between control and genistein groups. Treatment of 17beta-estradiol caused a significant decrease in prostate weight and epididymal sperm counts compared to the control (p<0.05). The levels of phospholipid hydroxide glutathione peroxidase in the testis and prostate of mice exposed to genistein or 17beta-estradiol were significantly higher than that of the control mice (p<0.05). 17beta-estradiol treatment caused degeneration and apoptosis of germ cells in the testis, depletion and degeneration in the epididymal epithelium, and hyperplasia of mucosal fold region in the prostate of mice. Genistein treatment did not cause any lesion in the testis, epididymis, and prostate. These results suggest that dietary uptake of genistein during juvenile period may not affect male reproductive development and functions.
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PMID:Effects of exposure to genistein and estradiol on reproductive development in immature male mice weaned from dams adapted to a soy-based commercial diet. 1558 47

Genistein is a phytoestrogen that occurs naturally in the diet, especially in soy based foods. There is wide spread interest in phytoestrogens as chemopreventive agents for a variety of diseases and cancers based on epidemiologic evidence. Although soy, and its constituents such as genistein, have been consumed at high levels in several Asian populations without apparent adverse effects, concern has been raised about potential adverse effects due to the estrogenic and other activities. Safety studies with genistein were conducted in the Wistar rat including two acute studies, two subchronic (4 weeks and 13 weeks) and a chronic 52-week dietary admix study. In the acute studies, genistein had a low order of toxicity. In the three repeated dose safety studies at doses up to 500 mg/kg/day, genistein was well tolerated. In all of the studies, decreased food consumption and body weight gain were observed at 500 mg/kg/day. The main hematological findings were decreased red blood cell parameters at 500 mg/kg/day with a compensatory increase in reticulocytes. For clinical chemistry, with the exception of a slight increase in gamma glutamyl transferase in male and female rats at the high dose, there were a number of other minor changes considered not toxicologically significant. At necropsy, there were relatively few macroscopic changes; in the 52-week study, dilation of the uterus with fluid at the high dose and cysts of the ovaries in treated animals were observed. Organ weight changes in male rats at the high dose of 500 mg/kg/day included increased kidney, spleen, adrenal and testes weights and for females included, increased liver, kidney, spleen, ovary and uterus weights. After 4 and 13 weeks of treatment with genistein, there were no treatment related histopathologic findings. After 26 and 52 weeks of treatment, histological changes were seen in the female reproductive organs (ovaries and uterus), and in males (epididymides and prostate), and bone, kidneys, heart, liver and spleen in both sexes. After 52 weeks of treatment of males, vacuolation of the epididymal epithelium at 500 mg/kg/day and inflammation of the prostate were recorded at a higher incidence at 50 and 500 mg/kg/day. In females, cytological changes in the uterus, squamous metaplasia at 50 and 500 mg/kg/day and hyperplasia at 500 mg/kg/day were observed. Furthermore, hydrometra of the uterus and findings in the vagina consisting of anestric or diestrus vaginal mucosa with vaginal mucification, hyperplastic epithelium and multifocal cystic degeneration were noted at 500 mg/kg/day. Atrophy of the ovaries increased in severity in animals at 50 and 500 mg/kg/day. Osteopetrosis (hyperostosis) was observed in male and female rats at 50 and 500 mg/kg/day along with a compensatory increase in extramedullary hemopoiesis in the spleen; females were more affected than males. Hepatocellular hypertrophy and minimal bile duct proliferation were recorded at a higher incidence in animals at 500 mg/kg/day. It is concluded that almost all of the treatment related findings in these studies are related to the estrogenic properties of genistein as a phytoestrogen and would be expected to occur with a compound with estrogenic activity. The hormonally related changes were considered to be functional in nature and thus not adverse effects. Most of the findings in these studies were limited to the high dose of 500 mg/kg/day and were reversible. The few findings observed at 50 mg/kg/day were relatively minor and in view of the functional (hormonally mediated) nature of the effects, were considered not adverse effects. The increased incidence of minimal bile duct proliferation and slightly increased gamma glutamyl transferase are indicative of a mild hepatic effect at the high dose of 500 mg/kg/day. The no observed adverse effect level (NOAEL) of genistein is considered to be 50 mg/kg/day based on the presence of mild hepatic effects at the high dose of 500 mg/kg/day. The no observed effect level (NOEL) is considered to be 5 mg/kg/day based on the hormonally induced functional changes at higher doses.
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PMID:Acute, subchronic and chronic safety studies with genistein in rats. 1621 46

The soy isoflavone genistein targets adipose tissue and elicits physiological effects that may vary based on dietary intake. We hypothesized that the adipose effects of genistein are dose and gender dependent. Four-week-old C57BL/6 male and female mice received daily oral doses of genistein (50-200,000 microg/kg.d) or 17beta-estradiol (E2) (5 microg/kg.d) for 15 d or a diet containing 800 ppm genistein. Genistein increased epididymal and renal fat pad and adipocyte size at doses up to 50,000 microg/kg.d or at 800 ppm in the diet in males but not in females. The alteration in adipocity correlated with changes in peripheral insulin resistance. These treatments increased genistein serum concentrations from 35+/-6 to 103+/-26 nM 12 h after treatment and lowered plasma triglycerides and cholesterol levels. The 200,000 microg/kg.d genistein dose decreased adipose tissue weight similarly to E2. This genistein dose down-regulated estrogen receptor (beta more than alpha) and progesterone receptor expression and induced estrogen-dependent adipose differentiation factors; it did not change expression of the minimal consensus estrogen-responsive element in ERE-tK-LUC mice, which was positively modulated in other tissues (e.g. the lung). E2 down-regulated almost all examined adipogenic factors. Gene microarray analysis identified factors in fat metabolism and obesity-related phenotypes differentially regulated by low and high doses of genistein, uncovering its adipogenic and antiadipogenic actions. The lower dose induced the phospholipase A2 group 7 and the phospholipid transfer protein genes; the 200,000 microg/kg.d dose inhibited them. The antiadipogenic action of genistein and down-regulation of adipogenic genes required the expression of ERbeta. In conclusion, nutritional doses of genistein are adipogenic in a gender-specific manner, whereas pharmacological doses inhibited adipose deposition.
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PMID:Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner. 1695 45

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