%0 Journal Article %~ Pubmed %A Ababneh, Deena %A Ritchie, Helen %A Webster, William S %T Antidepressants cause bradycardia and heart block in GD 13 rat embryos in vitro. %B %D 2012 %V 95 %N 2 %P 184-93 %@ 1542-9741 %X This study investigated the effects of a range of antidepressant drugs on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the drugs would adversely affect the function of the embryonic heart since they all have some cardiac ion channel blocking activity in addition to their main pharmacological effect on neurotransmitters. The results showed that all the tested drugs caused bradycardia in a generally concentration-dependent manner. At higher concentrations most of the drugs caused some degree of heart block consistent with sodium channel blockade and some drugs also showed negative inotropy associated with blockade of the L-type calcium channel. One drug, trazodone, caused arrhythmia consistent with blockade of the hERG (human ether-a-go-go related gene) potassium channel. In general the effects on the embryonic rat heart were only seen at "free drug" concentrations much greater than those likely to occur in pregnant women taking antidepressant medication. The least margin of safety was seen with the tricyclic antidepressants and the serotonin antagonist and reuptake inhibitor trazodone. %Z FOR Codes: 111506 111402 %0 Journal Article %~ Pubmed %A Gunnstr??m, M %A Ababneh, D %A Webster, W S %A Oakes, D %A Ritchie, H %T Antipsychotic drugs cause bradycardia in GD 13 rat embryos in vitro. %B Reproductive toxicology (Elmsford, N.Y.) %D 2012 %V %N %P %@ 1873-1708 %X This study investigated the effects of antipsychotic drugs on heart function of gestational day (GD) 13 rat embryos in vitro since they all block the I(Kr)/hERG potassium ion channel in addition to their main pharmacological effect on neurotransmitters. The results showed that all the tested antipsychotic drugs caused bradycardia of the rat embryonic heart in a concentration-dependent manner. However, with the possible exception of haloperidol the tested drugs did not cause arrhythmias typically seen with the highly selective I(Kr)/hERG blocking drug dofetilide. For six of the eight drugs tested the effects on the embryonic rat heart were only seen at free drug concentrations that were much greater than those likely to occur in pregnant women taking antipsychotic medication. However, the safety margins for haloperidol and quetiapine were lower. %Z FOR Codes: 110299 111506 %0 Journal Article %~ Isi %A Nilsson, M. F. %A Danielsson, C. %A Skold, A. C. %A Johansson, A. %A Blomgren, B. %A Wilson, J. %A Khan, K. M. %A Bengtsson, E. %A Kultima, K. %A Webster, W. S. %A Danielsson, B. R. %T Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs %B Reproductive Toxicology %D 2010 %C United States, Germa %I Elsevier Inc. %V 29 %N 2 %P 156-163 %@ 0890-6238 %X %Z FOR Codes: 111506 %0 Journal Article %~ Pubmed %A Abela, Dominique %A Ritchie, Helen %A Ababneh, Deena %A Gavin, Caroline %A Nilsson, Mats F %A Khan, Muhammad Khalid %A Carlsson, Kristin %A Webster, William S %T The effect of drugs with ion channel-blocking activity on the early embryonic rat heart. %B %D 2010 %V 89 %N 5 %P 429-40 %@ 1542-9741 %X This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2???hr in culture, 1???hr to acclimatize, and 1???hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing. Birth Defects Res (Part B) 89:429-440, 2010. ?? 2010 Wiley-Liss, Inc. %Z FOR Codes: 111506 %0 Journal Article %~ Pubmed %A Oakes, D J %A Ritchie, H E %A Woodman, P D C %A Narup, E %A Moscova, M %A Picker, K %A Webster, W S %T Genotoxicity studies of a desealant solvent mixture, SR-51. %B Toxicology and industrial health %D 2009 %V 25 %N 1 %P 5-13 %@ 0748-2337 %X The Royal Australian Air Force (RAAF) has reported that personnel involved in F-111 fuel tank maintenance were concerned that exposure to a range of chemicals during the period 1977 to mid-1990s was the cause of health problems, including cancer. Particular concern was directed at SR-51, a desealant chemical mixture containing the following four solvents: aromatic 150 solvent (Aro150), dimethylacetamide, thiophenol (TP), and triethylphosphate. The present study examined the mutagenic potential of SR-51 using a range of well-known mutagen and genotoxin assays. The tests used were i) a modified version of the Ames test, ii) the mouse lymphoma assay, iii) the comet assay (a single-cell gel electrophoresis assay), and iv) a mouse micronucleus test. The modified Ames test used mixed bacterial strains in liquid suspension media. The Ames test results showed that SR-51 (tested up to the cytotoxic concentration of 36 microg/ml, 30 min incubation) in the presence and absence of S9 metabolic activation was not mutagenic. The mouse lymphoma assay used cultured mouse lymphoma cells in a microwell suspension method. The mouse lymphoma assay was also negative with SR-51 (tested up to the cytotoxic concentration of 22.5 microg/ml, 3 h incubation) in the presence and absence of S9 metabolic activation. The Comet assay, using cultured mouse lymphoma cells, showed no evidence of DNA damage in cells exposed up to the cytotoxic concentration of SR-51 at 11.25 microg/ml. The in-vivo mouse micronucleus test was undertaken in wild-type C57Bl6J male mice dosed orally with SR-51for 14 days with a single daily dose up to 360 mg/kg/day (the maximum-tolerated dose). No increases were observed in micronuclei (MN) frequency in bone marrow collected (24 h after final dose) from SR-51-treated mice compared to the number of MN observed in bone marrow collected from untreated mice. Tissues collected from treated mice at necropsy demonstrated a significant increase in spleen weights in the high dose mice. Gas chromatography analysis of SR-51 identified more than 40 individual components and an oxidation product, diphenyldisulfide derived from TP under conditions of mild heating. In conclusion, there was no evidence that SR-51 is mutagenic. %Z FOR Codes: 69999 %0 Journal Article %~ Pubmed %A Jones, Kenneth Lyons %A Webster, William S %A Vaux, Keith K %A Benirschke, Kurt %T Acardiac fetus: evidence in support of a vascular/hypoxia pathogenesis for isolated oral clefting. %B %D 2008 %V 82 %N 8 %P 597-600 %@ 1542-0760 %X BACKGROUND: The acardiac human fetus represents an accident of monozygotic twinning or higher multiple births due to an artery-to-artery and a vein-to-vein anastomosis in the monochorial placenta. Blood returning to the placenta through the umbilical artery of a normal cotwin is directed into the umbilical artery of the acardiac twin such that blood reaching the cranial end of the embryo is likely to be poorly oxygenated resulting in a number of structural defects including oral clefts. Although retrograde perfusion as a cause of hypoxia is unique to the acardiac fetus, there is ample evidence from animal studies that hypoxia is associated with facial clefting. METHODS: Twenty-six acardiac fetuses were examined at UCSD Medical Center between 1974 and 2003. RESULTS: In 12 of the 26, the cephalic end of the fetus was sufficiently intact to document the structures of the face. Of these, cleft lip +/- palate was present in five and cleft palate alone was present in one. In all six, the oral cleft followed the normal planes of facial closure. The cotwin in all six cases was normal. CONCLUSIONS: This article suggests that decreased blood flow/hypoxia to the cephalic end of the fetus may be an important contributor to the development of cleft lip +/- palate and cleft palate alone in the acardiac fetus and raises the possibility that this may also be a mechanism responsible for oral clefting in singletons. %Z FOR Codes: 111401 %0 Journal Article %~ Pubmed %A Karlsson, Miriam %A Danielsson, Bengt R %A Nilsson, Mats F %A Danielsson, Christian %A Webster, William S %T New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential. %B Current Pharmaceutical Design %D 2007 %V 13 %N 29 %P 2979-88 %@ 1873-4286 %X Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential. %Z FOR Codes: 110502 %0 Journal Article %~ Pubmed %A Webster, William S %A Abela, Dominique %T The effect of hypoxia in development. %B %D 2007 %V 81 %N 3 %P 215-28 %@ 1542-975X %X There is increasing evidence that the oxygen supply to the human embryo in the first trimester is tightly controlled, suggesting that too much oxygen may interfere with development. The use of hypoxia probes in mammalian embryos during the organogenic period indicates that the embryo is normally in a state of partial hypoxia, and this may be essential to control cardiovascular development, perhaps under the control of hypoxia-inducible factor (HIF). A consequence of this state of partial hypoxia is that disturbances in the oxygen supply can more easily lead to a damaging degree of hypoxia. Experimental mammalian embryos show a surprising degree of resilience to hypoxia, with many organogenic stage embryos able to survive 30-60 min of anoxia. However, in some embryos this degree of hypoxia causes abnormal development, particularly transverse limb reduction defects. These abnormalities are preceded by hemorrhage/edema and tissue necrosis. Other parts of the embryo are also susceptible to this hypoxia-induced damage and include the genital tubercle, the developing nose, the tail, and the central nervous system. Other frequently observed defects in animal models of prenatal hypoxia include cleft lip, maxillary hypoplasia, and heart defects. Animal studies indicate that hypoxic episodes in the first trimester of human pregnancy could occur by temporary constriction of the uterine arteries. This could be a consequence of exposure to cocaine, misoprostol, or severe shock, and there is evidence that these exposures have resulted in hypoxia-related malformations in the human. Exposure to drugs that block the potassium current (IKr) can cause severe slowing and arrhythmia of the mammalian embryonic heart and consequently hypoxia in the embryo. These drugs are highly teratogenic in experimental animals. There is evidence that drugs with IKr blockade as a side effect, for example phenytoin, may cause birth defects in the human by causing periods of embryonic hypoxia. The strongest evidence of hypoxia causing birth defects in the human comes from studies of fetuses lacking hemoglobin (Hb) F. These fetuses are thought to be hypoxic from about the middle of the first trimester and show a range of birth defects, particularly transverse limb reduction defects. %Z FOR Codes: 110502 %0 Journal Article %~ Pubmed %A Webster, William S %A Howe, Andrew M %A Abela, Dominique %A Oakes, Diana J %T The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin. %B Current Pharmaceutical Design %D 2006 %V 12 %N 12 %P 1431-48 %@ 1381-6128 %X Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects. %0 Journal Article %~ Pubmed %A Abela, Dominique %A Howe, Andrew M %A Oakes, Diana A %A Webster, William S %T Maternal antioxidant supplementation does not reduce the incidence of phenytoin-induced cleft lip and related malformations in rats. %B %D 2005 %V 74 %N 2 %P 201-6 %@ 1542-9733 %X 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. %Z FOR Codes: 111401 111506 %0 Journal Article %~ Pubmed %A Howe, A M %A Hawkins, J K %A Webster, W S %T The growth of the nasal septum in the 6-9 week period of foetal development--Warfarin embryopathy offers a new insight into prenatal facial development. %B Australian Dental Journal %D 2004 %V 49 %N 4 %P 171-6 %@ 0045-0421 %X BACKGROUND: The aim of this study was to de the role of the nasal septum in embryonic facial development. METHODS: Nasal septal growth and facial development were examined in sagittally-sectioned 6-9 week human foetuses and compared to previously published data for later prenatal periods. To complement this data a cephalometric study of a child with untreated warfarin embryopathy was undertaken since a previous study in rats had shown warfarin exposure interferes with septal growth. RESULTS: The results showed that prenatal septal growth was maximal during the 6-9 week period and resulted in the establishment of a facial profile that was maintained until birth. This critical of growth corresponds to the period of warfarin exposure of the human foetus that results warfarin embryopathy. The cephalometric examination of a child with untreated warfarin embryopathy showed a combination of short anterior cranial base and a short maxilla had contributed to a significant retrusion of the maxilla suggestive of failure of the midface to devel the 6-9 week period. CONCLUSION: These findings would support the hypothesis that the nasal septum plays an active role in embryonic midfacial development. %0 Journal Article %A Webster, WS %A Freeman, JAD %T Prescription drugs and pregnancy %B Expert Opinion On Pharmacotherapy %D 2003 %C UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, ENGLAND, N3 1Q %I Ashley Publications Ltd %V 4 (6) %N %P 949-961 %@ 1465-6566 %X %0 Journal Article %A Oakes, DJ %A Webster, WS %A Woodman, PD %A Ritchie, HE %T Testicular changes induced by chronic exposure to the herbicide formulation, Tordon 75D(R) (2,4-dichlorophenoxyacetic acid and picloram)in rats %B Reproductive Toxicology %D 2002 %C The Boulevard, Langford Lane,Kidlington, Oxford, England, Ox5 1Gb %I Pergamon-Elsevier Science Ltd %V 16 %N %P 281-289 %@ 0890-6238 %X %0 Journal Article %A Oakes, DJ %A Webster, WS %A Woodman, PD %A Ritchie, HE %T A Study of the Potential for a Herbicide Formulation Containing 2,4-D and Picloram to Cause Male-Mediated developmental Toxicity in Rats %B Toxicological Sciences %D 2002 %C Great Clarendon St, Oxford, England, Ox2 6Dp %I Oxford Univ Press %V 68 #1 %N %P 200-206 %@ 1096-6080 %X %0 Journal Article %A Webster, WS %A Freeman, JAD %T Is this drug safe in pregnancy? %B Reproductive Toxicology %D 2001 %C P O Box 88,Osney Mead, Oxford, England, Ox2 0Ne %I Blackwell Science Ltd %V 31 %N %P 570-575 %@ 0954-7894 %X %0 Conference Proceedings %A Ritchie, HE %A Webster, WS %A Arnhold, T %A Gustafson, AL %A Renwick, A %A Nau, H %T Whole embryo culture in human serum following vitamin A intake from supplements %B European Teratology Society Annual Meeting %D 2000 %C Ferrara Italy %I Pergamon-Elsevier Science Ltd, Uk %V 14 %N %P 571-572 %@ %X %0 Journal Article %A Howe, A %A Webster, WS %T Warfarin exposure & calcification of the arterial system in the rat %B International Journal of Experimental Pathology %D 2000 %C %I Blackwell Science Ltd %V 81 (1) %N %P 51-56 %@ 0959-9673 %X %0 Journal Article %A Webster, WS %A Vaghef, H %A Ryan, B %A Dencker, L %A Hellman, B %T Measurement of DNA Damage by the Comet Assay in Rat Embryos Grown in Media Containing High Concentrations of Vitamin K1 %B Toxicology in Vitro %D 2000 %C %I Pergamon-Elsevier Science Ltd %V 14 (1) %N %P 95-99 %@ 0887-2333 %X %0 Journal Article %A Danielsson, B %A Skold, A-C %A Azarbayjani, F %A Ohman, I %A Webster, WS %T Pharmacokinetic Data Support Pharmacologically Induced Embryonic Dysrhythmia as Explanation to Fetal Hydantoin Syndrome in Rats %B Toxicology & Applied Pharmacology %D 2000 %C %I Academic Press Inc %V 163 (2) %N %P 164-175 %@ 0041-008X %X %0 Conference Proceedings %A Oakes, D %A Webster, WS %A Woodman, PD %A Ritchie, HE %T Testicular tubule degeneration in the rat after chronic oral administration of a herbicide containing 2, 4-D and picloram %B European Teratology Society Annual Meeting %D 2000 %C Oxford UK %I Pergaomn-Elsevier Science Ltd, Uk %V 14 %N %P 176-176 %@ %X %0 Conference Proceedings %A Oakes, D %A Webster, WS %A Woodman, PD %A Ritchie, HE %T Testicular tubule degeneration in the rat after chronic oral administration of a herbicide containing 2,4-D and picloram %B European Teratology Society Annual Meeting %D 2000 %C %I Elsevier Science Inc, %V %N %P %@ %X