stilbenes and Abnormalities--Drug-Induced

1. Valproic acid (VPA) induces haemorrhagic liposis of the cervical muscles in the chicken embryo model (CEM). Vitamin E and resveratrol (RV) exhibit prominent anti-oxidative and glutathione (GSH)-protecting effects. 2. In the present study we hypothesized that vitamin E and RV would ameliorate VPA induced haemorrhagic liposis in chick embryos. To this end, 120 Day 0 fertilized eggs were divided into 10 groups (n = 12 in each). The effects of different combinations of VPA (60 mmol/L), RV (0.2 and 2.0 mmol/L) and vitamin E (0.2 and 2.0 mmol/L) applied to Hamburger and Hamilton (HH) Stage 10 (Day 1.5) embryos were tested in the CEM using established methods. 3. Both RV and vitamin E (both at 2.0 mmol/L) effectively rescued neural tube defects in the early stage CEM and inhibited the malformation rate compared with that in the control group (8.4% and 5.0% vs 36.5 ± 3.0%, respectively; P < 0.05) and suppressed serum homocysteine and S-adenosylhomocysteine concentrations, downregulated cervical muscular carnitine, triglycerides, H2 O2 , malondialdehyde, interleukin-6 and ACC expression (P < 0.05 for all) and upregulated CPT1 expression and GSH (P < 0.05 for both). 4. The haemorrhagic liposis of cervical muscles can be alleviated by RV and vitamin E. It appears that the main mechanism of action of RV and vitamin E in rescuing VPA-induced teratogenicity is through the suppression of reactive oxygen species and upregulation of GSH.

Topics: Abnormalities, Drug-Induced; Animals; Antioxidants; Chick Embryo; Glutathione; Reactive Oxygen Species; Resveratrol; Stilbenes; Teratogenesis; Valproic Acid; Vitamin E

To evaluate whether or not administration of folic acid and resveratrol have preventive effects on cleft palate formation as well as the comparison of the two drugs' s effects.. Pregnant mice were randomly divided into 9 groups, with 8 mice in each group. The TCDD group mice were dosed with TCDD 28 microg/kg body weight on gestation day 10 (GD 10) animals in folic acid group were respectively dosed with folic acid 15, 10, 5 mg/kg and TCDD 28 microg/kg; resveratrol treated mice were divided into 3 groups: resveratrol 50 mg/kg were orally administered for 6 consecutive days, from gestational day GD 8 to GD13 in resveratrol (GD8-13 ) group; resveratrol 50 mg/kg were orally administered for 6 consecutive days, from gestational day GD 8 to GD13, followed hy an oral administered with TCDD on GD10 in resveratrol (GD8-13) + TCDD group; resveratrol 50mg/kg and TCDD 28 microg/kg were used by gavage administration at GD10 in resveratrol (GD10) + TCDD group. Control mice were treated with the same volume of water for 6 consecutive days from GD8 to GD13 and were given a single dose of corn oil on GD10. The pregnant mice weight and embryos, the number of live, cleft palate, dead and resorption fetal mice were recorded on GD 17.5. The coronal sections of the fetal mice heads were prepared at GD 17.5 and observed by microscopy.. Total frequency of clefts was 92.86% in TCDD group, 84.00% (15 mg), 73.08% (10 mg), 84.00% (5 mg) in folic acid + TCDD groups, 0% in resveratrol (GD10) group, 74.51% (GD10), 57.78% (GD8-13) in resveratrol + TCDD groups. The frequency of cleft was 0% in the control group. Compared with the control and the TCDD groups, there were significant differences in the number of live, dead and resorption fetal mice in TCCD + resveratrol (GD8-13) group (P < 0.05). No significant differences in embryonic weight, live fetuses weight, the number of live, dead and resorption fetal mice were found in the other groups (P > 0.05).. Test dose of folic acid and resveratrol both had certain antagonistic effect on cleft palate in mice induced by TCDD, with folic acid 10 mg/kg, resveratrol 50 mg/kg GD8-13 doses having stronger antagonistic action. Effects of both the two drugs have no significant difference, but resveratrol (50 mg/kg, GD8-13) significantly affects the fetal mice's growth and development under TCDD exposure in utero.

Topics: Abnormalities, Drug-Induced; Animals; Cleft Palate; Female; Fetus; Folic Acid; Humans; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Pregnancy; Random Allocation; Resveratrol; Stilbenes; Teratogens

Nicotine, a major toxic component in tobacco smoke, leads to severe embryonic damage during organogenesis in embryos. We investigated whether resveratrol would positively influence nicotine-induced teratogenesis in mouse embryos (embryonic day 8.5) cultured for 48 h using a whole embryo culture system. Embryos exposed to nicotine (1mM) revealed significantly severe morphological anomalies, increased levels of caspase-3 mRNA and lipid peroxidation, and decreased levels of cytoplasmic superoxide dismutase (SOD), mitochondrial manganese SOD, cytosolic glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, hypoxia-inducible factor 1α, Bcl-x(L), and sirtuin1 (SIRT1) mRNAs and SOD activity compared to those in the normal control group. However, when resveratrol (1×10(-8) μM or 1×10(-7) μM) was added concurrently to the embryos exposed to nicotine, all the parameters in above improved conspicuously. These findings indicate that resveratrol has a noted protective effect against nicotine-induced teratogenesis in mouse embryos through its antioxidative and anti-apoptotic effects.

Topics: Abnormalities, Drug-Induced; Animals; bcl-X Protein; Caspase 3; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hypoxia-Inducible Factor 1, alpha Subunit; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Nicotine; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; Protective Agents; Resveratrol; Sirtuin 1; Stilbenes; Superoxide Dismutase; Teratogens

The genes mediating developmental aryl hydrocarbon (AhR)-induced cardiovascular deformities remain unclear, with many cytochrome P450 monooxygenase (CYP)-1 isoforms known to be AhR-responsive and now a cyclo-oxygenase (COX) isoform suspected to contribute developmental toxicity. More importantly, no previous study has examined the role of these genes in producing deformities using low enough concentrations of AhR agonists to permit survival beyond early larval stages. Zebrafish (Danio rerio) eggs were aqueously exposed to a variety of agents that had multiple modes of action, but all of which are reported to be AhR ligands; benzo-a-pyrene (BaP) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alone and in combination with resveratrol or alpha-naphthoflavone (ANF). Whole larvae CYP (subtypes 1A, 1B1, 1C1, and 1C2) and COX (subtypes 1, 2a, and 2b) mRNA expression was quantified at 5 and 10 dpf and correlated with developmental phenotype. Both TCDD and BaP caused dose-dependent AhR-associated deformities and mortalities by 10 dpf, while BaP/ANF co-exposure exhibited the highest rate of deformities and mortalities at 5 dpf with all of these larvae having died at the highest rate by 10 dpf. Furthermore, BaP/ANF co-exposure caused the most marked alterations in cardiac and vascular morphology at 10 dpf at the concentrations used, namely decreased ventricular length and chamber width with increased ventricular wall thickness, as well as increased blood vessel luminal diameter. Exposure to TCDD, BaP and ANF alone all significantly increased CYP1A mRNA expression, while only TCDD consistently increased CYP1C1 expression. In contrast, TCDD transiently decreased CYP1C2 expression. BaP alone had no effect on CYP1C1 expression, but decreased COX2b expression when alone or in combination with ANF. In fact, ANF exhibited additive agonistic effects on expression of CYP1A and CYP1C1 with both BaP and TCDD, although additive or potentiating effects of ANF on CYP1C2 and COX2b were observed with only BaP. Correlation analyses revealed that gene expression at 5 dpf, but not 10 dpf, was strongly linked to abnormal cardiac and vascular phenotypes at 10 dpf. Principal components analysis suggests that cardiac deformities and blood vessel dilation were related positively to CYP1A and negatively to COX-2b gene expression. These relationships were separate from the one gene, CYP1C1, that was negatively associated with increased vascular wall thickness. However, further experiments are

Topics: Abnormalities, Drug-Induced; Animals; Aorta; Benzo(a)pyrene; Cytochrome P-450 Enzyme System; Gene Expression; Growth and Development; Heart; Larva; Ligands; Phenotype; Polychlorinated Dibenzodioxins; Prostaglandin-Endoperoxide Synthases; Receptors, Aryl Hydrocarbon; Resveratrol; RNA, Messenger; Stilbenes; Veins; Water Pollutants, Chemical; Zebrafish

The effect of resveratrol, an aryl hydrocarbon receptor antagonist, on the teratogenicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated. Pregnant C57BL/6J mice were orally administered resveratrol (50 mg/kg) for 6 consecutive days, from gestational day (GD) 8 to GD13, followed by an oral challenge with TCDD (14 mug/kg) on GD12. TCDD caused severe fetal malformations including cleft palate (40.7%), renal pelvic dilatation (100%, mean score 3.060), and ureteric dilatation (100%, mean score 3.210) and tortuosity (95.1%). Resveratrol significantly reduced both the incidence of TCDD-induced cleft palate to 18.4% and the degrees of renal pelvic and ureteric dilatations caused by TCDD. The results suggest that pretreatment with resveratrol might bring a beneficial outcome for reducing the incidence and severity of fetal malformations caused by TCDD exposure in utero.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Cleft Palate; Dilatation, Pathologic; Female; Hydronephrosis; Male; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Pregnancy; Receptors, Aryl Hydrocarbon; Resveratrol; Severity of Illness Index; Stilbenes; Teratogens

Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.

Topics: Abnormalities, Drug-Induced; Animals; Antineoplastic Agents; Benzoates; Female; Gene Expression; Humans; Mice; Mice, Hairless; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptors; Retinoids; Stereoisomerism; Stilbenes; Structure-Activity Relationship; Substrate Specificity; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection

Topics: Abnormalities, Drug-Induced; Animals; Cervix Uteri; Diethylstilbestrol; Estradiol; Fallopian Tubes; Female; Genital Neoplasms, Female; Genitalia, Female; Hyperplasia; Metaplasia; Mice; Ovary; Pregnancy; Stilbenes; Uterus; Vagina

Topics: Abnormalities, Drug-Induced; Carcinogens; Caustics; Coumarins; Dermatitis, Contact; Environmental Exposure; Fluorescent Dyes; Naphthalenes; Neoplasms, Experimental; Photosensitivity Disorders; Pyrazoles; Stilbenes

Topics: Abnormalities, Drug-Induced; Abortion, Threatened; Allyl Compounds; Aminopyrine; Chlordiazepoxide; Chlorpromazine; Estranes; Female; Humans; Hydroxysteroids; Metronidazole; Pregnancy; Pregnancy Complications, Cardiovascular; Progesterone; Progestins; Romania; Stilbenes; Uterine Hemorrhage