ascorbic-acid and Abnormalities--Drug-Induced

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Extremities; Female; Humans; Immune System Diseases; Infant, Newborn; Pregnancy; Species Specificity; Teratogens; Thalidomide

Vitamins contain reactive functional groups necessary to their established roles as coenzymes and reducing agents. Their reactive potential may produce injury if vitamin concentration, distribution, or metabolism is altered. However, identification of vitamin toxicity has been difficult. The only well-established human vitamin neurotoxic effects are those due to hypervitaminosis A (pseudotumor cerebri) and pyridoxine (sensory neuropathy). In each case, the neurological effects of vitamin deficiency and vitamin excess are similar. Closely related to the neurological symptoms of hypervitaminosis A are symptoms including headache, pseudotumor cerebri, and embryotoxic effects reported in patients given vitamin A analogs or retinoids. Most tissues contain retinoic acid (RA) and vitamin D receptors, members of a steroid receptor superfamily known to regulate development and gene expression. Vitamin D3 effects on central nervous system (CNS) gene expression are predictable, in addition to the indirect effects owing to its influence on calcium and phosphorus homeostasis. Folates and thiamine cause seizures and excitation when administered in high dosage directly into the brain or cerebrospinal fluid (CSF) of experimental animals but have rarely been reported to cause human neurotoxicity, although fatal reactions to i.v. thiamine are well known. Ascorbic acid influences CNS function after peripheral administration and influences brain cell differentiation and 2-deoxyglucose accumulation by cultured glial cells. Biotin influences gene expression in animals that are not vitamin-deficient and alters astrocyte glucose utilization. The multiple enzymes and binding proteins involved in regeneration of retinal vitamin A illustrate the complexity of vitamin processing in the body. Vitamin A toxicity is also a good general model of vitamin neurotoxicity, because it shows the importance of the ratio of vitamin and vitamin-binding proteins in producing vitamin toxicity and of CNS permeability barriers. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than that of most, perhaps all other vitamins. Megadose vitamin therapy may cause injury that is confused with disease symptoms. High vitamin intake is more hazardous to peripheral organs than to the nervous system, because CNS vitamin entry is restricted. Vitamin administration into the br

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Avitaminosis; Blood-Brain Barrier; Carrier Proteins; Coenzymes; Drug Interactions; Folic Acid; Humans; Injections, Spinal; Liver; Methotrexate; Nervous System Diseases; Oxidation-Reduction; Pseudotumor Cerebri; Pyridoxine; Self Medication; Vitamin A; Vitamins

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Child; Chloroquine; Enzymes; Eye Diseases; Female; Humans; Lysosomes; Pigmentation; Porphyrias; Pregnancy; Protein Biosynthesis; Psoriasis; Pyridoxine; Rabbits; Retina; Ultraviolet Rays

Due to the risks of disease progression and transmission to the newborn, treatment of tuberculosis is often pursued during pregnancy and fixed-dose combined antituberculous agents have been found to be beneficial. Unfortunately, there is paucity of data on the safety of the fixed-dose combined antituberculous drugs during pregnancy. This study intends to assess the teratogenic effect of fixed-dose combined antituberculous drugs on the organogenesis stage of fetal development and also investigate the possible roles of vitamin C in modulating the teratogenic effects of these agents on the fetus using animal model. Pregnant rats were divided into 3 groups with 12 animals per group: group 1 received distilled water (10 mL/kg) orally; group 2 received 51.4 mg/kg/day of fixed-dose combined antituberculous agents orally; group 3 received 51.4 mg/kg/day of fixed-dose combined antituberculous agents plus vitamin C (10 mg/kg/day) orally. Six rats in each group were randomly selected and sacrificed on day 20 by cervical dislocation prior to day 21 of gestation, and the foetuses were harvested through abdominal incision for physical examination. Blood samples were collected from the 1st filial rats of the remaining six animals for biochemical and hematological examination. The liver, kidney, heart, and brain of all the sacrificed animals were used for histopathological examination. There were significant (P ≤ 0.05) low birth weights of the foetuses of the animals that were treated with fixed-dose combined antituberculous agents. The haematological parameters also revealed a reduction in the platelets counts and neutrophiles at the first filial generation. Significant (P ≤ 0.05) elevations in the levels of aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the foetuses of the animals treated with fixed-dose combined antituberculous agents were also observed. However, the combination of vitamin C with fixed-dose combined antituberculous agents significantly (P ≤ 0.05) reduced the level of AST. Fixed-dose combined antituberculous agents have teratogenic potential as shown in low birth weight and mild liver damage in the first filial of the treated animals. As much as it is imminent to treat TB patients in pregnancy, there is need to always exercise caution and clinically weigh the risk-benefit ratio.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Antioxidants; Antitubercular Agents; Ascorbic Acid; Drug Combinations; Female; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Risk Assessment; Treatment Outcome

Exposure of male (55.1 mg/kg b.wt. orally for 60 days) and/or pregnant female Wistar rats (55.1 mg/kg b.wt. orally at days 6-15 of gestation), to the insecticide cypermethrin (CYP); resulted in the development of a lot of external morphological deformities and visceral malformations in their offspring pubs, which signify the potential of such insecticide to induce reproductive toxicity and teratogenesis. Data cleared that CYP treatment induced significant increase in the percentages of post-implantation deaths, dwarf foeti and subcutaneous oedema beside significant decrease in percentages of live borne foeti and uterine implants. CYP also caused many visceral malformations among different treated groups including nasal, ophthalmic, cerebral, pulmonary, cardiac and renal malformations. Concomitant oral administration of garlic extract or vitamin C (5 days/week) to treated fathers and/or pregnant mothers with CYP provided significant reduction in the percentage of the foetal malformations induced by the insecticide, when compared with the control. The current study proves that garlic and ascorbic acid dampen the reproductive toxicity and/or teratogenicity of cypermethrin toxicity in rats; therefore might prove to be effective dietary supplements in developing countries where pesticide pollution is high.

Topics: Abnormalities, Drug-Induced; Animals; Antioxidants; Ascorbic Acid; Embryo, Mammalian; Female; Garlic; Insecticides; Male; Plant Extracts; Pregnancy; Pyrethrins; Rats; Rats, Wistar; Reproduction; Teratogens

The teratogenic effects of ethanol include malformations of the cardiovascular system, which may be abrogated by multivitamin therapy. Chick cardiomyocytes in micromass culture were treated with ethanol alone or with supplementation with folate or vitamin C. Ethanol alone caused a loss of cell viability and differentiation (beating) whereas those cells treated in addition with vitamins were comparable to the control. Chick embryos were injected on day 3 of incubation with PBS, ethanol alone or with additional vitamin C or folic acid. On day 9 embryos were examined for viability, growth retardation and gross malformation and the hearts were processed for histology. Results showed that ethanol significantly decreased survival of embryos or caused growth retardation and gross malformation (p<0.05). Embryos incubated with addition of vitamin C or folic acid were comparable to the control. Data obtained in this study suggest that supplementation with vitamin C or folic acid during pregnancy may prevent defects in heart development brought about by ethanol.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Cell Survival; Cells, Cultured; Chick Embryo; Drug Antagonism; Embryo Loss; Ethanol; Fetal Weight; Folic Acid; Heart; Heart Defects, Congenital; In Vitro Techniques; Myocytes, Cardiac

There is considerable evidence that phenytoin-induced birth defects in the rat are a consequence of a period of bradycardia and hypoxia in the embryos. Experiments were designed to test the hypothesis that phenytoin-induced birth defects result from free-radical damage to the embryos during the reoxygenation period posthypoxia. Female rats (>9 per group) were fed either a control diet or a diet high in antioxidants (vitamins C and E and coenzyme Q(10)) both before and during pregnancy and were then given a teratogenic dose of phenytoin (180 mg/kg) on GD 11. The rats were killed on GD 20 and the fetuses were examined for malformations. The initial results showed that the antioxidant diet had a significant protective effect, with far fewer antioxidant-group fetuses showing cleft lip or maxillary hypoplasia compared with the control group. However, this result was confounded by reduced food intake by the rats fed the antioxidant diet and a significantly lower maternal body weight at the time of phenytoin administration. Since the phenytoin was administered by intraperitoneal injection (i.p.) the control rats received higher absolute doses of phenytoin and it is speculated that this results in higher fetal exposure. A second experiment, in which the rats were pair-fed, failed to demonstrate any protective effect of the high antioxidant diet. These results do not support the reoxygenation hypothesis for phenytoin teratogenesis. An alternative explanation would be hypoxia-induced transcription-related changes resulting in cell cycle arrest and apoptosis.

Topics: Abnormalities, Drug-Induced; Animals; Anticonvulsants; Antioxidants; Ascorbic Acid; Body Weight; Cleft Lip; Coenzymes; Diet; Eating; Female; Male; Maxilla; Phenytoin; Pregnancy; Rats; Rats, Sprague-Dawley; Teratogens; Ubiquinone; Vitamin E

The toxicity of herbicide Paraquat (PQ, 1-1'-dimethyl-4,4'bipyridylium dichloride) in animal cells is related to its rapid reduction and instantaneous reoxidation to produce the reactive oxygen species. Recently, the PQ evaluation with the Frog Embryo Teratogenesis Assay-Xenopus (FETAX) showed its high embryotoxicity. Supposing that the embryos' death was due to PQ-related oxidative damage, we used ascorbic acid (AA), a well known antioxidant, to reduce the PQ embryotoxicity in Xenopus laevis. Embryos were exposed from stage 8 to 47 to 0.1 mg/l PQ alone, and to PQ with AA concentrations ranging from 20 to 200 mg/l, using the FETAX procedure. PQ caused 72.2% mortality, while 17.1% of surviving larvae were affected by abnormal tail flexure. The PQ mortality percentages were reduced in a clear concentration-response by up to 15.2% in the group exposed to PQ with 200 mg/l AA. The histopathologic diagnoses revealed abnormal notochord flexure coupled with vesiculated, pear-shaped myocytes only in the PQ group. After embryo exposure to PQ with 200 mg/l AA, restoration of normal axial tail structures was evident. In conclusion, PQ embryotoxicity in X. laevis was most likely due to oxidative damage that was drastically reduced by AA.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Embryo, Nonmammalian; Female; Herbicides; Larva; Paraquat; Xenopus laevis

Oral administration of sodium fluoride (40 mg/kg body weight) from day 6 to 19 of gestation caused, as compared to control, significant reductions in body weight, feed consumption, absolute uterine weight and number of implantations. Significantly higher incidence of skeletal (wavy ribs, 14th rib, <6 sternal centre, dumbell-shaped second and fifth sternebrae, incomplete ossification of skull and thickening of tibia) and visceral (subcutaneous haemorrhage) abnormalities were also observed in NaF-treated dams than that of control. Oral administration of vitamin C (50 mg/kg body weight) and vitamin E (2 mg/0.2 ml olive oil/animal/day) from day 6 to 19 of gestation along with NaF significantly ameliorates NaF-induced reductions in body weight, feed consumption, absolute uterine weight (only with vitamin E treatment) and number of implantations. As compared with NaF-treated alone, the total percentage of skeletal and visceral abnormalities were significantly lowered in fluoride plus vitamin C-treated animals. Vitamin E was less effective. These findings suggest that vitamin C significantly reduced the severity and incidence of fluoride-induced embryotoxicity in rats.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Ascorbic Acid; Body Weight; Bone and Bones; Eating; Embryo Implantation; Embryo, Mammalian; Female; Organ Size; Pregnancy; Rats; Rats, Wistar; Sodium Fluoride; Teratogens; Uterus; Vitamin E

The aims of this study were (1) to determine and quantify the adverse effects of maternal nicotine exposure during pregnancy and lactation on neonatal rat lung development, and (2) to establish whether ascorbic acid will protect the neonatal rat lung against the adverse effects of maternal nicotine exposure. Pregnant rats received nicotine (1 mg/kg body mass/day) subcutaneously during gestation and lactation. A second group received nicotine and ascorbic acid (1 mg/kg body mass/day). The control animals received saline subcutaneously. The results illustrate that maternal nicotine exposure results in (a) a decreased (P < 0.001) radial alveolar count (RAC), (b) an increase (P < 0.001) in destructive index (DI), (c) an increased (P < 0.001) linear intercept (Lm), (d) an increased (P < 0.001) abnormal alveolar attachment index (AAA) (e) and an increase in septal cellularity. Ascorbic acid does not protect fetal lung development against the adverse effects of maternal nicotine exposure. However, after birth ascorbic acid prevents further deterioration of the DI, AAA and Lm, whereas the RAC and thus the number of alveoli was even higher than in control neonatal rat lung. No further increase in cellularity occurred. The reason for this response to ascorbic acid supplementation is under investigation.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Ascorbic Acid; Cell Count; Female; Injections, Subcutaneous; Lactation; Male; Nicotine; Nicotinic Agonists; Pregnancy; Prenatal Exposure Delayed Effects; Pulmonary Alveoli; Rats; Rats, Wistar

Malathion, an organophosphorus insecticide, has been found previously to cause developmental defects such as enlargement of the atria and aorta and bent notochord in Xenopus laevis. Since these defects are similar to those caused by known lathyrogens, the effects of malathion on collagen biochemistry and structure were studied. Embyros were exposed to malathion or its metabolite malaoxon during the first 4 days of development. Notochords of malathion- and malaoxon-treated embryos were bent ventrally between the third and sixth somites and were enlarged. Ultrastructural examination of the postanal tail notochord showed that the elastic externa was disorganized and less dense and the sheath had fewer, more disorganized fibers. Embryos exposed in culture displayed a concentration-dependent reduction in ascorbate and hydroxyproline. Malathion and malaoxon inhibited the activities of lysyl oxidase (I50s of 0.7 and 8.7 nM, respectively) and proline hydroxylase (I50s of 58 microM and 49.9 nM, respectively) in homogenates of Xenopus embryos. These data suggest that malathion and malaoxon alter posttranslational modification of collagen, with resultant morphological defects in connective tissue.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Bone and Bones; Collagen; Connective Tissue; Embryo, Nonmammalian; Hydroxyproline; Malathion; Microscopy, Electron; Procollagen-Proline Dioxygenase; Protein-Lysine 6-Oxidase; Proteins; Xenopus

Trimethylamine (TMA) is an aliphatic amine, and its blood levels can increase after ingestion of certain foods, such as fish, and during disease states, such as chronic renal failure. We recently reported that TMA can inhibit fetal development in vivo and in vitro in mice. The present studies were done to find out if the inhibitory effects of TMA on embryonic development are caused by a decrease in macromolecular synthesis, using mouse embryo cultures as the experimental model. At a submaximally toxic concentration (0.75mM), TMA inhibited the growth of embryos to approximately 70% of control and caused neural-tube defects in 73% of embryos. By 42 h of culture, DNA, RNA, and protein content of TMA-treated embryos were approximately 50% of the control values. Embryotoxic effects of TMA were not caused by changes in pH and osmolarity of the culture media. The inhibitory effects of TMA on embryonic growth were time dependent and apparent at 2-4 h of culture. The inhibition of growth was accompanied by a decrease in the incorporation of tritium-labeled thymidine, uridine, and leucine into DNA, RNA, and proteins, respectively. Thiols (L- and D-cysteine, glutathione) and the antioxidant L-ascorbic acid did not cause significant antagonism of embryotoxic effects of TMA. It is concluded that TMA exerts teratogenic effects on mouse embryos in culture and inhibits their growth by reducing macromolecular synthesis; these effects may not involve glutathione depletion or generation of free radicals.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Culture Techniques; DNA; Embryo, Mammalian; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Hydrogen-Ion Concentration; Leucine; Macromolecular Substances; Methylamines; Mice; Models, Biological; Osmolar Concentration; Pregnancy; Protein Biosynthesis; RNA; Sulfhydryl Compounds; Thymidine; Tritium; Uridine

The developmental toxicity of five compounds was evaluated with the Frog Embryo Teratogenesis Assay: Xenopus (FETAX) and the results were compared to mammalian literature. Small cell Xenopus laevis blastulae were exposed to ascorbic acid, sodium selenate, coumarin, serotonin and 13-cis retinoic acid for 96 hr. Three separate static-renewal assays were conducted for each compound. Teratogenic potential of the test materials was determined based on Teratogenic Index values [TI = LC50/EC50 (malformation)], types and severity of induced malformations and embryo growth. Ascorbic acid had little or no teratogenic potential. Sodium selenate and coumarin tested as having moderately positive teratogenic potential. Serotonin scored as having moderately strong teratogenic potential and 13-cis retinoic acid scored as having strong teratogenic potential. Results were consistent with mammalian data and support the use of FETAX for the screening of developmental toxicants.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Coumarins; Dose-Response Relationship, Drug; Isotretinoin; Lethal Dose 50; Selenic Acid; Selenium; Selenium Compounds; Serotonin; Xenopus laevis

A single intraperitoneal injection of urethane (ethyl carbamate) induces lung tumours in 80 per cent of male and 100 per cent of female NMRI mice, respectively. In the course of time the initially benign adenomatous tumours can develop into malignant adenomatosis of the lung (alveolar cell carcinoma). For an analysis of the mechanisms of tumour development and the possible interactions involved, low doses of X-rays (5-100 cGy) were administered 6 hours after urethane treatment. A significant anticarcinogenic and, also, anti-teratogenic action was observed. This implies that in both cases similar mechanisms are involved. Single injections of vitamin C or chloroquine counteract the urethane effects in the same manner as do the low doses of X-rays, but probably by different mechanisms.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Chloroquine; Female; Lung Neoplasms; Male; Mice; Pregnancy; Urethane

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Caffeine; Female; Pregnancy; Rats; Rats, Inbred Strains

Nitrites are present in a wide variety of foods and their daily intake in man has been estimated at 1.5 mg. Ethylenethiourea (ETU), a major food contaminant resulting from degradation of ethylenebisdithiocarbamate fungicides, is a potent rat teratogen. The co-administration of ETU (60 or 40 mg/kg) and NaNO2 (80 mg/kg) to rats by gavage on day 15 of gestation resulted in a higher survival of progeny than occurred with the corresponding dose of ETU alone. In a second study, ETU (60 mg/kg) and NaNO2 (80, 100 or 120 mg/kg) were administered, either individually or in combination, as a single dose on day 13 of gestation. Administered alone, NaNO2 did not produce any teratogenic response in full-term foetuses, whereas ETU produced a high incidence of various anomalies. However, the combined dosing resulted in the elimination of almost all the anomalies. The reducing effect of NaNO2 on ETU-induced malformations was reversed when the animals were pretreated with 200 mg ascorbic acid/kg or 360 mg sodium ascorbate/kg. Since both of these are well-known inhibitors of N-nitrosation reactions, it was presumed that the simultaneous oral dosing of ETU and NaNO2 resulted in the formation of N-nitrosoethylenethiourea.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Drug Interactions; Ethylenethiourea; Female; Imidazoles; Nitrites; Pregnancy; Rats; Rats, Inbred Strains; Sodium Nitrite

Embryos died and a teratogenic effect followed combined intragastric administration of methylurea (MU) and sodium nitrite (SN) to rats on the 9th day of pregnancy; this was caused by the endogenous synthesis of nitroso-methylurea which produced a pathogenic action. Ascorbic acid and urotropine completely blocked the possibility of manifestation of the embryotoxic and teratogenic effect occuring after combined administration of MU and SN. Sodium sulfomate decreased the embryotoxic and partially the teratogenic effect considerably, whereas urea failed to prevent the expression of the harmful effect of MU and SN on the embryo.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Female; Fetal Death; Maternal-Fetal Exchange; Methenamine; Methylurea Compounds; Nitrites; Pregnancy; Rats; Sulfonic Acids; Teratogens

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Ascorbic Acid; Female; Fetus; Growth; Lactation; Mice; Mice, Inbred Strains; Pregnancy; Rats; Reproduction; Sexual Behavior, Animal

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Administration, Oral; Animals; Ascorbic Acid; Birth Weight; Body Weight; Dose-Response Relationship, Drug; Female; Fetal Death; Fetus; Gestational Age; Lactation; Mice; Pregnancy; Rats; Reproduction

Topics: Abnormalities, Drug-Induced; Alkaline Phosphatase; Animals; Ascorbic Acid; Body Weight; Corpus Luteum; Depression, Chemical; Embryo, Mammalian; Female; Fertility; Fetal Death; Gestational Age; Glycogen; Histocytochemistry; Nucleic Acids; Organ Size; Placenta; Placenta Diseases; Pregnancy; Rats; Tetracycline

Topics: Abnormalities, Drug-Induced; Acetazolamide; Animals; Ascorbic Acid; Chick Embryo; Drug Synergism; Glycerophosphates; Insulin; Mitochondria; Niacinamide; Pyridines; Succinates; Sulfanilamides

Topics: Abnormalities, Drug-Induced; Aniline Compounds; Animals; Animals, Newborn; Ascorbic Acid; Body Weight; DNA; Enzyme Induction; Female; Fetus; Lactation; Liver; Mammary Glands, Animal; Microsomes, Liver; Milk; Organ Size; Phenobarbital; Placenta; Pregnancy; Pregnancy, Animal; Rats; RNA; Steroids

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Brain; Brain Chemistry; Capillaries; Carotid Arteries; Depression, Chemical; Embryo, Mammalian; Embryonic and Fetal Development; Female; Glycogen; Hemoglobins; Hemorrhage; Histocytochemistry; Insecticides; Liver; Nucleic Acids; Osteogenesis; Placenta; Pregnancy; Rats; Stimulation, Chemical; Trophoblasts

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Benzene; Chemical and Drug Induced Liver Injury; Female; Formaldehyde; Liver; Maternal-Fetal Exchange; Nucleic Acids; Pregnancy; Rats