%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
%~ 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 Byrne, Maria
%A Oakes, Diana
%A Pollak, John
%A Laginestra, Edwina
%T Toxicity of landfill leachate to sea urchin development with a focus on ammonia.
%B Cell biology and toxicology
%D 2008
%V 24
%N 6
%P 503-12
%@ 1573-6822
%X Sea urchin gametes and embryos serve as a model system to evaluate toxicity in the marine environment. In this study, the toxicity of complex chemical mixtures in leachate samples to sea urchin development was examined with a focus on ammonia, which was the main contaminant of concern in most samples. Two rapid tests, the submitochondrial particle function and bacterial luminescence tests, were also used. Ammonia is highly toxic to sea urchin embryos with an EC50 of 1.3 mg l(-1) for the embryos of the Australian sea urchin Heliocidaris tuberculata. Leachate ammonia levels were well above these EC50 concentrations. To assess the contribution of ammonia to leachate toxicity in sea urchin development, we compared the predicted toxic units (PTU) and observed toxic units (OTU) for ammonia for each sample. The PTU/OTU comparison revealed that the sensitivity of the sea urchin embryos to ammonia were altered (enhanced or decreased) by other chemicals in the leachates. This result emphasises the need for parallel chemical analyses and a suite bioassays for evaluating the toxicity of complex and variable chemical mixtures.
%Z FOR Codes: 111506 60808



%0 Journal Article
%~ Pubmed
%A Warner, Rachelle
%A Ritchie, Helen E
%A Woodman, Patricia
%A Oakes, Diana
%A Pourghasem, Mohsen
%T The effect of prenatal exposure to a repeat high dose of toluene in the fetal rat.
%B Reproductive toxicology (Elmsford, N.Y.)
%D 2008
%V 26
%N 3-4
%P 267-72
%@ 0890-6238
%X Solvent abuse during pregnancy results in a clinical pattern of adverse outcomes including deafness. The aim of this project was to determine whether high doses of toluene for a short duration during pregnancy produced adverse outcomes in the fetal rat. Pregnant rats were given either 1250 mg/kg of toluene or peanut oil by gavage from gestation day 16-19. The study demonstrated that administration of toluene at the dose used did not result in significant maternal toxicity. However, some maternal renal pathology was noted. There was no significant difference in placental or fetal weights nor was there a significant difference in the number of external or skeletal malformations of fetuses between treatment and control groups. Treated fetuses had an increased frequency and severity of enlarged renal pelveses. A pattern of accelerated development in the upper mid-turn and sometimes apical turns in the treated fetal cochleas was observed. This accelerated development suggests that toluene may induce excessive cell death resulting in premature maturation of the cochlea.
%Z FOR Codes: 111401



%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