Cleft palates

Reproductive Toxicity. No data are available that impHcate either hexavalent or trivalent chromium compounds as reproductive toxins, unless exposure is by way of injection. The observed teratogenic effects of sodium dichromate(VI), chromic acid, and chromium (HI) chloride, adininistered by injection, as measured by dose-response relationships are close to the amount that would be lethal to the embryo, a common trait of many compounds (111). Reported teratogenic studies on hamsters (117,118), the mouse (119—121), and rabbits (122) have shown increased incidence of cleft palate, no effect, and testicular degeneration, respectively. Although the exposures for these experiments were provided by injections, in the final study (122) oral, inhalation, and dermal routes were also tried, and no testicular degeneration was found by these paths. 

Metallic devices have been used to repair and replace parts of the human body for centuries. Archaeological evidence clearly indicates that surgical procedures were performed in several ancient civilisations. The use of surgical metal implants in humans was first recorded in 1562 when a gold prosthesis was used to close a defect in a cleft palate. ... 

Mice homozygous for an ETA receptor gene disruption show craniofacial malformations, such as cleft palate, micrognathia, microtia and microglossia. ETA (—/—) mice die shortly after birth due to respiratory failure. Mice with an ET-l-null mutation show the same cranciofacial malformations and, in addition, cardiovascular disorders (e.g. septal defects, abnormal cardial outflow tract, aortic arch and subclavian arteries). 

SUMOl haploinsufficiency has been linlced to a developmental defect Based on the finding that a patient with a cleft lip and palate had a mutation in the SUMOl gene locus, a mouse model was generated that had reduced SUMOl expression. Increased frequency for a cleft palate or oblique facial cleft was observed in the transgenic mice, suggesting that SUMO haploinsufficiency can lead to developmental defects. 

A significant increase in the incidence of fetal soft-tissue and skeletal anomalies was seen following treatment of pregnant rats with HCDD at the 100 jug/kg/day dose level. The incidence of cleft palate, subcutaneous edema, vertebrae with split or unfused centra, and split sternebrae was significantly greater than among control litters or the control fetal popu-... 

The initial concern for the possible hazard to humans exposed to 2,4,5-T was precipitated by teratologic studies conducted by Bionetics Research Institute under contract from The National Cancer Institute (2). In these studies, large doses of 2,4,5-T were administered to pregnant rats and mice for nine of the 21 days of pregnancy. The incidence of fetal abnormalities was slightly higher in the treated animals than in control animals. Later tests indicated that these abnormalities (cleft palate) may have been caused by 27 8 ppm of 2,3,7,8-tetrachloro-dibenzo-p-dioxin present as a contaminant in the 2,4,5-T sample used in the Bionetic study (3). After the results of the study were made known, the Panel on Herbicides of the President s Science Advisory Committee studied the total 2,4,5-T situation. The report of this committee was published in March, 1971 (4). 

Asada, H, Kawamura, Y, Maruyama, K, Kume, H, Ding, RG, Kanbara, N, Kuzume, H, Sanbo, M, Yagi, T and Obata, K (1997) Cleft palate and decreased brain y-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc. Natl. Acad. Sci. USA 94 6496-6499. 

Smith T.D., Siegel M.I., Mooney M.P., Burdi A.R., et al. (1996). Vomeronasal organ growth and development in normal, and cleft-lip and palate, human fetuses. Cleft Palate-Craniofac J 33, 385-394. 

Most warn of the increased risk of deformities of limb development and defects like cleft palate. A few drugs carry the risk of distinct organ defects. For example, chlorambucil may cause agenesis of the fetal kidneys Penicillamine seems to affect fetal connective tissue, causing relaxation of the skin, hypotonia, and hyper flexion of the hips and shoulders... 

After intraamniotic injection, acrolein is teratogenic to rats in vivo but not in vitro. When administered intraamniotically to the whole embryo culture system of the rat on day 13 of gestation, acrolein caused edema, hydrocephaly, open eyes, cleft palate, abnormal umbilical cord, and defects of the limbs and face (Slott and Hales 1986). Beauchamp etal. (1985) suggest that acrolein-associated teratogenicity is caused by acrylic acid, an acrolein metabolite. Acrylic acid injected into amniotic fluid of rats on day 13 of gestation produced a dose-dependent increase in the percent of fetuses with skeletal and other abnormalities (Beauchamp et al. 1985). 

Intraamniotic injection route. Embryos given 0.1, 1, 10, or 100 pg of acrolein on day 13 of gestation examined on day 20 of gestation Intraperitoneal injection route 98-100% dead at 10 and 100 pg 85% of live fetuses receiving 1 pg were malformed (edema, hydrocephaly, cleft palate, defects of limbs and tail) no teratogenic effects at 0.1 pg 6... 

Interaction effects of PCDDs with other polychlorinated compounds or mixtures are not extensively documented. For example, certain polychlorinated hexachlorobiphenyls (PCBs) have a low toxic potency to induce cleft palate deformities in mice (Bimbaum et al. 1985). However, mixtures of 2,3,7,8-TCDD and 2,3,4,5,3, 4 -hexachlorobiphenyl resulted in a tenfold increase in incidence of cleft palate in mice. Thus, the toxicity of compounds such as 2,3,7,8-TCDD may be enhanced by compounds of relatively low acute toxicity, such as selected PCBs. Bimbaum etal. (1985) concluded that the widespread environmental occurrence of such combinations suggests a need for further evaluation of the mechanism of this interaction. 

Birnbaum, L.S., H. Weber, M.W. Harris, J.C. Lamb IV, and J.D. McKinney. 1985. Toxic interaction of specific polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin increased incidence of cleft palate in mice. Toxicol. Appl. Pharmacol. 77 292-302. 

Mirex has considerable potential for chronic toxicity because it is only partly metabolized, is eliminated very slowly, and is accumulated in the fat, liver, and brain. The most common effects observed in small laboratory mammals fed mirex included weight loss, enlarged livers, altered liver enzyme metabolism, and reproductive failure. Mirex reportedly crossed placental membranes and accumulated in fetal tissues. Among the progeny of mirex-treated mammals, developmental abnormalities included cataracts, heart defects, scoliosis, and cleft palates (NAS 1978 Blus 1995). 

PCB 156, a mixed inducer of microsomal enzymes, significantly increases the incidences of cleft palates by 2,3,7,8-TCDD in rodents (Bimbaum et al. 1985). Interactions among polychlorinated congeners may range from antagonism to additivity to synergism (Safe 1990), and the toxicity of individual PCBs can be raised by interaction with other PCBs (Table 24.5). 

Single oral dose of 25, 50, or 100 mg/kg BW given to Ah-responsive pregnant mice on gestation day 11, 12, or 13 mice killed on day 18 of gestation Dose-dependent increase in embryo deaths, resorption of the conceptus, and frequency of developmental abnormalities (cleft palate, dilated kidney pelvis, thymus hypoplasia). ED50 for cleft palate was about 100 mg PCB 77/kg BW 10... 

Air concentrations of 28.5 mg/m3 for 4 h daily on days 9-12 of gestation caused fetotoxic effects and chromosomal damage to liver cells by day 18 effects included reduced survival, impaired growth, retarded limb ossification, and bone abnormalities. At 2.9 mg/m3, a 9.9% decrease in fetal weight was recorded at 0.26 mg/m3, a 3.1% decrease was measured Oral dosages of 400-600 mg/kg BW on days 7-16 of gestation produces fetal malformations (cleft palate), delayed skeletal ossification, and fetal weight reduction 200-600 mg/kg BW daily for 10 days (DMA) produced fetal and maternal toxicity... 

Homanics, G. E., Delorey, T. M Firestone, L. L., et al. (1997) Mice devoid of y-aminobu-tyrate type A receptor p3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl. Acad. Sci. USA 94,4143-4148. 

M. (1995) Deficiency of the P3 subunit of the type A y-aminobutyric acid receptor causes cleft palate in mice. Nature Genetics 11, 344-346. 

Hemm, R., Arslanoglou, L. and Pollock, J. (1977). Cleft palate following prenatal food restriction in mice Association with elevated maternal corticosteroids. Teratology 15 243-248. 

Szabo, K. and Brent, R. (1975). Reduction of drug-induced cleft palate in mice. Lancet (June), 1296-1297. 

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