Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single oral doses of ferbam, thiram, zineb, or maneb produced central nervous system stimulation followed by depression and alopecia. Ferbam and thiram were more toxic on the basis of weight than zineb; maneb was relatively nontoxic. There was no species difference in acute toxicity between rats and mice. In 13- and 80-wk feeding studies, the toxic effects of ferbam and thiram in rats were similar; however, thiram was more toxic on the basis of weight than ferbam. During the 80-wk feeding study, weight gain was reduced in ferbam-treated rats starting at daily doses of 8 mg/kg in males and 37 mg/kg in females and in thiram-treated rats staring at daily doses of 5 mg/kg in males and 26 mg/kg in females. Food consumption was reduced in proportion to the reduced weight gain. Death occurred in males fed 109 or 331 mg/kg.d ferbam and in males fed 58 or 132 mg/kg.d thiram. Female rats fed 96 mg/kg.d ferbam or 67 mg/kg.d thiram developed alopecia and ataxia, which led to paralysis of the hind limbs. Male rats fed ferbam or thiram had a more severe incidence of squamous metaplasia in the thyroid and fatty infiltration in the pancreas than control males. Ferbam or thiram reduced the incidence of spontaneous nephritis in both males and females. The male rats that were fed 109 or 331 mg/kg.d ferbam and died betweeen 1 and 5 wk had golden pigment in the reticuloendothelial cells of the spleen and in the enlarged mesenteric lymph nodes, associated with hemosiderosis. Moderate tubular degeneration of the testes with atypical spermatids in the epididymis occured in some rats fed 132 mg/kg.d thiram for 13 wk but not in rats fed up to 52 mg/kg.d for 80 wk. Periodic hematologic examination and terminal clinical blood tests did not reveal any severe changes. Ferbam and thiram did not alter the occurrence or latent period of the spontaneous tumors seen in control rats.
 ...
PMID:Oral toxicity of ferric dimethyl-dithiocarbamate (ferbam) and tetramethylthiuram disulfide (thiram) in rodents. 63 15

EDB significantly depressed GSH in caput and cauda epididymis, but not in testis, 2 hours following injection. This depression was dose-related. EDB enhanced EMS-induced dominant lethal mutations at mating weeks 2 and 3 (of 6). At mating week 2 the fetal death rate was increased two-fold, while at week 3, the fetal death rate had increased to nearly three-fold greater than the EMS-only controls. Enhancement of fetal death rate was confined to postimplantation loss. As with EMS alone, the EDB potentiation of EMS-induced mutations was limited to postmeiotic stages of spermatogenesis. EDB also enhanced alkylation of rat spermatozoa by labeled EMS. Depression of GSH in reproductive tissues is correlated with a potentiation of dominant lethal mutations, as well as an increase in the binding of EMS to sperm heads.
 ...
PMID:Potentiation of ethyl methanesulfonate-induced germ cell mutagenesis and depression of glutathione in male reproductive tissues by 1,2-dibromoethane. 198 7

The objective of this investigation was to characterize the acute and short- and long-term toxic potency of orally administered 1,2-dichloropropane (DCP). In the acute and short-term studies, male rats of 250-300 g were gavaged with 0, 100, 250, 500, or 1000 mg DCP/kg in corn oil once daily for up to 10 consecutive days. Although ingestion of DCP caused body weight loss and CNS depression, few other toxic effects were manifest 24 hr after a single dose of the chemical. Morphological changes were limited to liver centrilobular cells in 500 and 1000 mg/kg rats. Similarly, elevated activity of some serum enzymes occurred only at these two highest dose levels. Hepatic nonprotein sulfhydryl (NPS) levels were decreased and renal NPS levels increased at 24 hr. In the short-term study resistance developed to DCP hepatotoxicity over the 10 consecutive days of exposure, as reflected by progressively lower serum enzyme levels and by decreases in the severity and incidence of toxic hepatitis and periportal vacuolization. Nucleolar enlargement in hepatocytes, however, was observed at all dosage levels at 5 and 10 days. There were a number of manifestations of hemolytic anemia, including erythrophagocytosis in the liver, splenic hemosiderosis and hyperplasia of erythropoietic elements of the red pulp, renal tubular cell hemosiderosis, and hyperbilirubinemia. Urinalyses and histopathology revealed no evidence of nephrotoxicity. In the long-term study, male rats initially weighing 180-200 g were gavaged five times weekly for up to 13 weeks with 0, 100, 250, 500, or 750 mg DCP/kg. As over one-half the 750 mg/kg group died within 10 days, the survivors were sacrificed. Histopathological changes in the 750 mg/kg animals included mild hepatitis and splenic hemosiderosis, as well as adrenal medullary vacuolization and cortical lipidosis, testicular degeneration and a reduction in sperm, and increased number of degenerate spermatogonia in the epididymis in some members of the group. Similar testicular and epididymal degenerative change also were observed in some 500 mg/kg animals after 13 weeks of dosing. There was a progressive increase in the number of deaths in the 500 mg/kg group, such that more than 50% were dead by 13 weeks. No deaths occurred in the 100 or 250 mg/kg groups. The DCP dosage regimen also produced a dose-dependent decrease in body weight gain. DCP exhibited very limited hepatotoxic potential and no apparent nephrotoxic potential in the long-term study. Slight elevations in serum ornithine-carbamyltransferase activity, periportal vacuolization, and active fibroplasia in the liver were seen in the 500 mg/kg animals.
 ...
PMID:Oral toxicity of 1,2-dichloropropane: acute, short-term, and long-term studies in rats. 274 74

The reproductive system effects of cocaine were studied in male rats. The analysis included measurements of circulating levels of luteinizing hormone (LH) and testosterone (T) by radioimmunoassay (RIA). The weights of the testes and sex accessory organs were also assessed and compared with control animals. Dosage level, duration of treatment, and interval between injection and sacrifice were the parameters examined. Following a single intraperitoneal (IP) injection, LH levels decreased over a 3-hour period. At a high dosage (40 mg/kg), cocaine caused a significant elevation in serum T followed by a significant depression of T for at least 2 hours. When administered chronically for 15 days, the low dose group (10 mg/kg) did not vary significantly from the vehicle controls. However, the high dose group had lower LH and T levels, as well as correspondingly lighter weight seminal vesicles and epididymis. No changes were noted in the weights of the ventral prostate or testes. This research suggests that cocaine acts primarily at the hypothalamic-hypophyseal axis with a possible secondary action at the gonadal level.
 ...
PMID:Effects of cocaine hydrochloride on the male reproductive system. 274 20

Modern research in male contraception is focusing on 4 areas: 1) hormonal control of spermatogenesis, the complex processes of spermiogenesis in the testis where the spermatogonia stem cells mitotically divide into spermatocytes, which meiotically divide into nondividing spermatids, which become the spermatozoa; 2) direct (nonhormonal) inhibition of spermatogenesis; 3) the suppression of sperm maturation in the epididymis; and 4) the immunological suppression of fertility through the identification of an antisperm antibody. Hormonal suppression of spermatogenesis requires depression of testosterone levels in the testis, either by direct inhibition of the Leydig cells or by inhibition of the hypothalamic production of luteinizing hormone-releasing hormone, which induces the pituitary secretion of luteinizing hormone, which induces the secretion of testosterone. Testosterone suppression in the testis must be accompanied by exogenous androgen supplements or there will be loss of libido and potency. Preparations under investigation in the hormonal suppression of spermatogenesis include monthly injections of 200 mg depot medroxyprogesterone acetate with 200 mg testosterone enanthate; danazol with testosterone enanthate; anabolic steroids, such as 19-NT-hydroxyphenylpropionate; cyproterone acetate, an antiandrogen with progestational effects; and luteinizing hormone-releasing hormone agonists, which down-regulate pituitary receptors, or luteinizing hormone-releasing hormone antagonists, which competitively block receptor activation. None of these preparations have yet struck a balance where they can completely but reversibly block spermatogenesis at doses which do not have toxic or feminizing effects. 3 nonhormonal agents which suppress sperm production are gossypol, extract of Trypterigium wilfordii, and tolnidamine. Gossypol, an extract of cottonseed oil, has been widely studied in China and has been found 99% effective in producing azoospermia or severe oligospermia. However, it is extremely toxic, damages cells in the seminiferous epithelium, and causes hypokalemia. Over time, its effects become irreversible, and its mutagenicity and teratogenicity are not known. Agents which suppress sperm maturation in the epididymis act after cell division is complete and hence are not mutagenic, but they are extremely toxic. Alpha-chlorohydrin and 6-chloro-6 deoxysugars act by inhibiting the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase with the result that sperm cannot metabolize sugar. The sulfonamide compound, sulfasalazine, disrupts sperm motility by a mechanism not yet known. The development of a contraceptive vaccine relies on the identification of the antigenic determinants on sperm surface. Even if such a vaccine could be developed, there remains the problem of reversibility. None of the methods now being studied have demonstrated that they can reliably prevent unwanted pregnancy, and none have been around long enough for their longterm side effects to be known.
 ...
PMID:Male contraception: current status and future prospects. 307 64

Arotinoids, which are analogs of retinoic acid (RA) and retinol (RO) with the carbon skeleton in a rigid conformation, have more favorable therapeutic indices relative to all-trans-RA and all-trans-RO. The purpose of this investigation was to obtain preliminary in vivo toxicity data on SMR-2(analog of RO) and SMR-6 (analog of RA), arotinoids with promising activity (ED50's of 20 X 10(-11) and 5 X 10(-11) M, respectively; ED50 of RA = 1 X 10(-11) M) for reversal of keratinization in tracheal organ culture. A preliminary toxicity study was conducted in male B6D2F1 mice with gavage of retinoids in corn oil (0.01, 0.05, and 0.1 mg/kg/day of SMR-2 or SMR-6; 1, 5, and 10 mg/kg/day of RA as reference control). Due to lack of toxicity, each dose level for SMR-2 and SMR-6 was increased by 4-fold on Day 29 of dosing. The study was terminated on Day 57. Hypervitaminosis A (weight loss, alopecia, skin scaling, and bone thinning) was induced in the mid- and high-dose SMR groups; weight-gain depression was predominant in the high-dose RA group. The SMR compounds were approximately 100-fold more toxic, based on weight loss, than RA. In the SMR dose groups with hypervitaminosis A, white blood cell counts were elevated 2- to 4-fold; and there were microscopic lesions in skin, testes, epididymis, bone, thymus, bone marrow, peripheral lymph nodes, spleen, stomach, adrenal, and pituitary. The leukocytosis was attributed to leukopoiesis in spleen and bone marrow, which may be due to either a direct effect and/or a secondary response to a subacute inflammatory reaction in skin. Only peripheral lymph node hyperplasia was observed in SMR-2 and RA low-dose groups. Enlarged thymus, lymph node hyperplasia, leukopoiesis in spleen and bone marrow, elevated alkaline phosphatase with bone hypertrophy, and testicular degeneration were observed in the mid-dose RA group. The results indicate that immune stimulation may be a primary early response to retinoids and that skin, leukopoietic tissues, reproductive organs, stomach, and bone are primary targets for retinoid toxicity.
 ...
PMID:Preliminary toxicity profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. 360 38

A method has been developed for isolation of cells from the efferent ductules of the rat epididymis to obtain a population of epithelial cells. The technique depends on a transfer of segments of the ductules into a new isolation medium and gradual purification from fat cells, fibroblasts, collagen fibres and smooth muscle cells. Segments of the ductules so isolated were further separated into single cells or their aggregates. The mode of isolation applied allowed to obtain morphologically unchanged and functionally fully efficient cells. When transferred to culture they rapidly formed a single layer and further developed into a multi-layer culture. The cells divide and preserve their ability of producing secretion. They react to the absence of androgenous hormones by a considerable depression of the number of mitotic divisions and reduction of their secretion.
 ...
PMID:Isolation technique and identification of epithelial cells from efferent ductules of the rat epididymis. 384 20

Male and female Fischer-344 rats were exposed to methyl chloride by inhalation (0, 150, 475, or 1500 ppm, 6 hr/day, 5 days/week, 40 males and 80 females per group). The only treatment-related clinical signs were a 10 to 20% body weight gain depression (BWGD) in both males and females exposed to 1500 ppm at all weekly weighings after 2 weeks of exposure and a 5-7% BWGD in 475-ppm exposed animals after Day 57. After 10 weeks the exposure schedule was changed to 6 hr/day, 7 days/week and each male was mated to two exposed females. The mating period was ended after 2 weeks, at which point 10 males/group were necropsied. The only treatment-related lesions found were severe bilateral testicular degeneration (10/10) and granulomas in the epididymis (3/10) in the 1500-ppm males. The remaining 30 males per group were then removed from exposure and mated during a 2-week period with 60 unexposed females. The exposed females were continued on exposure from the start of mating to Postnatal Day 28 (6 hr/day, 7 days/week). The females were not exposed from Gestation Day 18 to Postnatal Day 4, and the pups were never directly exposed prior to weaning. There were no significant differences between groups in the number of exposed or unexposed females that mated, as evidenced by copulation plugs. No litters were born to exposed or unexposed females mated to the 1500-ppm males. There was no significant difference in the number of litters produced by the 150-ppm groups when compared to the control groups. Fewer litters were born in the 475-ppm groups than in the control groups. No differences in litter size, sex ratio, pup viability, or pup growth were found among the 475-ppm, 150-ppm, or control F0 groups. When bred 10 weeks after the cessation of exposures, 5 to 20 1500-ppm F0 males had regained the ability to sire normal litters. The same number of 475-ppm F0 males proved as fertile (15/20) as control F0 males (13/20). After weaning, F1 pups from the 475-, 150-, and 0-ppm groups were exposed to the same concentrations of methyl chloride for 10 weeks and then mated. A trend toward decreased fertility was found in the 475-ppm F1 group.
 ...
PMID:Reproduction in Fischer-344 rats exposed to methyl chloride by inhalation for two generations. 400 11

Sensitivity of male F-344 rats to the dominant lethal (DL) mutagenic effect of ethyl methanesulfonate (EMS) was studied in conjunction with an evaluation of EMS-induced depression of glutathione (GSH) in testis, epididymis and vas deferens. At the maximal effect, during week 3 (days 15-19 post-EMS), a dosage of 50 mg/kg caused 13.3% fetal death (FD) vs. 3.3% in controls, while 100 mg/kg caused 56.6% FD in the same interval. EMS maximally depressed GSH to 33%, 54% and 77% of control in vas, epididymis and testis respectively. The slope of the DL dose-response curve for EMS in rats shows a 3-4-fold greater sensitivity than that reported for mice. The steepness of this curve suggests that small perturbations in endogenous protective mechanisms, such as GSH depression, may exert a greater proportional effect on germ-cell mutagenesis in rats which should be more readily observable than in mice. EMS and other electrophilic toxicants may thus influence their own primary reproductive toxicity and/or that of other agents by depression of GSH in male reproductive tissue.
 ...
PMID:Germ-cell mutagenesis and GSH depression in reproductive tissue of the F-344 rat induced by ethyl methanesulfonate. 404 76

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the male reproductive system were investigated. Sexually mature (290 g) Sprague-Dawley rats were given single oral doses of TCDD sufficient to cause varying degrees of hypophagia and impaired body weight gain. The largest doses decreased plasma testosterone and dihydrotestosterone concentrations by 90 and 75%, respectively, from ad libitum-fed control values, while decreasing seminal vesicle and ventral prostate weights by 68 and 48%. On Day 7, the approximate ED50 for these responses was 15 micrograms TCDD/kg, a nonlethal dose. Reductions in caput epididymis and testis weights were also observed. The androgenic deficiency was seen as early as 2 days after dosing and persisted for at least 12 days. Based on data from pair-fed control rats, only about half the decreases in accessory sex organ weights and in plasma androgen concentrations could be accounted for by TCDD-induced hypophagia or body weight loss. These signs of androgenic deficiency were not the result of stress (based in part on plasma corticosterone assays), nor could they be accounted for by the known effects of TCDD on steroid metabolism. While the TCDD-induced depression in plasma testosterone concentrations appears to be the primary event observed, the mechanism by which testosterone concentrations were decreased remains unknown. The androgenic deficiency may account for the male reproductive pathology and dysfunction in animals treated with overtly toxic doses of TCDD.
 ...
PMID:Androgenic deficiency in male rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. 404 10


1 2 3 Next >>