cytochalasin-d and Abnormalities--Drug-Induced

During cardiac c-looping, the heart transforms from a straight tube into a c-shaped tube, presenting the first evidence of left-right asymmetry in the embryo. C-looping consists of two primary deformation components: ventral bending and dextral rotation. This study examines the role of actin polymerization in bending of the heart tube. Exposure of stage 9-11 chick embryos to low concentrations of the actin polymerization inhibitors cytochalasin D (5 nM-2.0 microM) and latrunculin A (LA; 25 nM-2.0 microM) suppressed looping in a stage- and concentration-dependent manner in both whole embryos and isolated hearts. Local exposure of either the dorsal or ventral sides of isolated hearts to LA also inhibited looping, but less than global exposure, indicating that both sides contribute to the bending mechanism. Taken together, these data suggest that ongoing actin polymerization is required for the bending component of cardiac c-looping, and we speculate that polymerization-driven myocardial cell shape changes cause this deformation.

Topics: Abnormalities, Drug-Induced; Actins; Animals; Bridged Bicyclo Compounds, Heterocyclic; Chick Embryo; Cytochalasin D; Heart; Heart Defects, Congenital; Microscopy, Confocal; Myocardium; Thiazoles; Thiazolidines

The developmental toxicity of cytochalasins B (CB) and D (CD) was evaluated in protein-deprived mice. Pregnant CD-1 mice were assigned to control (26%), 16%, 8%, or 4% dietary protein groups on gestation day 1 and dosed by gavage with 0 or 1.5 mg/kg CB or CD on gestation day 8 (plug = day 1). They were killed and subjected to teratological examination on day 18. CD, but not CB, increased prenatal mortality but failed to interact significantly with dietary protein level. Fetal weights were decreased in the 4% and 8% dietary protein groups, but cytochalasin treatment did not exacerbate this effect. Cytochalasin treatment was associated with gross fetal malformations, primarily neural tube defects. Although CB and CD did not significantly increase the percentage of grossly malformed fetuses per litter, the data was suggestive of such an effect, and the incidence of affected litters was increased by cytochalasin treatment in all but the 4% protein group. Skeletal defects, such as jaw malformations, rib or sternebrae variations, and unossified skull bones appeared to be increased by both cytochalasin treatment and dietary protein deficiency. The differences from control values were nonsignificant, however, except for some cases of cytochalasin effects on skull ossification. These results show a general lack of effect of protein deprivation on the developmental toxicity of cytochalasins.

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Congenital Abnormalities; Cytochalasin B; Cytochalasin D; Cytochalasins; Embryonic and Fetal Development; Female; Gestational Age; Mice; Pregnancy; Pregnancy Complications; Protein Deficiency

Adult toxicity, embryo lethality, and teratogenicity of cytochalasins D and E (CD and CE) were determined for A/J, C57BL/6JH, aeae, and OELN mouse strains. The adult LD50 for CD (1.9-2.6 mg/kg) and CE (3.1-3.3) were similar for the strains. Although adult LD50s were similar, the embryo lethality and teratogenicity of CD and CE vary from strain to strain when all were treated with intraperitoneal injections on days 7-9 of gestation. CD was more teratogenic than CE and frequently produced exencephaly while CE did not. CD was more teratogenic in OELN and aeae (ED50 +/- 0.7 mg/kg) than in A/J or C57BL/6J (ED50 greater than 1.2 mg/kg). OELN fetuses were more resistant to lethal effects of CD than the other strains which had fetal LD50s +/- 1.2 mg/kg maternal weight. The F1 fetuses of a cross of sensitive aeae and resistant C57BL/6J showed intermediate sensitivity to exencephaly. The results suggest a genetic contribution to the response and differences in action of CD and CE as teratogens.

Topics: Abnormalities, Drug-Induced; Animals; Cytochalasin D; Cytochalasins; Dose-Response Relationship, Drug; Lethal Dose 50; Mice; Mice, Inbred A; Mice, Inbred C57BL; Neural Tube Defects; Skull