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)

This study determined the effects of feed restriction (FR) during in utero and postnatal life on standard reproductive toxicity and developmental immunotoxicity end points. Groups of 26 time-mated CD rats were fed various amounts of Purina 5002 diet from gestation day 7 through lactation. Control rats were fed once per day in amounts based on historical control feed consumption data, while the amounts fed to the FR groups were reduced by 10% (10% FR), 30% (30% FR), or 50% (50% FR) relative to controls. Selected F1 weanlings were necropsied on postnatal day (PND) 22, assessed for immunotoxicity end points between PND 22 and 27 or PND 52 and 56, or maintained on FR through PND 70. Thereafter, half the remaining F1 rats in each group were fed ad lib (recovery subgroup), while the rest continued on FR. Both subgroups were necropsied at 21 weeks of age. In the 10% FR group, slight decreases in maternal body weight had no effect on F1 offspring body weights, but did decrease F1 liver weights. FR at the 30% level reduced maternal body weights by 10-20%, reduced F1 offspring body weights by as much as 21%, caused changes in numerous weanling organ weights, but did not affect reproductive or immune system function. Dams in the 50% FR group were 17-32% lighter than controls, resulting in F1 body weights that were 12-47% lower than controls. F1 estrous cycle length was increased, puberty was delayed by 6 days (males and females), and anogenital distance, epididymal sperm counts, and all organ weights were decreased in this group. Antibody responses were unaffected despite decreased spleen and thymus weights. Essentially all effects of feed restriction showed evidence of reversibility.
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PMID:The effects of feed restriction during in utero and postnatal development in rats. 1531 Aug 60

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