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Developmental Toxicity (developmental + toxicity)

Distribution by Scientific Domains

Life Sciences	60%
Medical Sciences	10%

Selected Abstracts

Developmental toxicity of indium: Embryotoxicity and teratogenicity in experimental animals

CONGENITAL ANOMALIES, Issue 4 2008
Mikio Nakajima
ABSTRACT Indium, a precious metal classified in group 13 (IIIB) in the periodic table, has been used increasingly in the semiconductor industry. Because indium is a rare metal, technology for indium recycling from transparent conducting films for liquid crystal displays is desired, and its safety evaluation is becoming increasingly necessary. The developmental toxicity of indium in experimental animals was summarized. The intravenous or oral administration of indium to pregnant animals causes growth inhibition and the death of embryos in hamsters, rats, and mice. The intravenous administration of indium to pregnant animals causes embryonic or fetal malformation, mainly involving digit and tail deformities, in hamsters and rats. The oral administration of indium also induces fetal malformation in rats and rabbits, but requires higher doses. No teratogenicity has been observed in mice. Caudal hypoplasia, probably due to excessive cell loss by increased apoptosis in the tailbud, in the early postimplantation stage was considered to account for indium-induced tail malformation as a possible pathogenetic mechanism. Findings from in vitro experiments indicated that the embryotoxicity of indium could have direct effects on the conceptuses. Toxicokinetic studies showed that the embryonic exposure concentration was more critical than the exposure time regarding the embryotoxicity of indium. It is considered from these findings that the risk of the developmental toxicity of indium in humans is low, unless an accidentally high level of exposure or unknown toxic interaction occurs because of possible human exposure routes and levels (i.e. oral, very low-level exposure). [source]

Antiandrogenic effects of dibutyl phthalate and its metabolite, monobutyl phthalate, in rats

CONGENITAL ANOMALIES, Issue 4 2002
Makoto Ema
ABSTRACT, Developmental toxicity following administration of dibutyl phthalate (DBF) and its major metabolite, monobutyl phthalate (MBuP), by gavage was determined in Wistar rats. DBF on days 0,8 of pregnancy induced an increase in the incidence of preimplantation loss at 1250 mg/kg and higher and postimplantation loss at 750 mg/kg and higher. MBuP on days 0,8 of pregnancy produced an increase in the incidence of pre-and postimplantation loss at 1000 mg/kg. DBF on days 7,15 of pregnancy caused an increase in the incidence of fetuses with malformations at 750 mg/kg. MBuP on days 7,15 of pregnancy produced an increased incidence of fetuses with malformations at 500 mg/kg and higher. DBF on days 15,17 of pregnancy resulted in a decrease in the anogenital distance (AGD) of male fetuses and increase in the incidence of fetuses with undescended testes at 500 mg/kg and higher. MBuP on days 15,17 of pregnancy caused a decreased male AGD and increased incidence of fetuses with undescended testes at 250 mg/kg and higher. No effect of DBF and MBuP on the AGD was found in female offspring. The spectrum of fetal malformations, dependence of gestational days of treatment on the manifestation of teratogenicity, and alterations in development of the male reproductive system observed after administration of DBF were in good agreement with those observed after administration of MBuP. These findings suggest that MBuP may be responsible for the induction of developmental toxic effects of DBP. The doses that produced a decrease in the AGD and undescended testes in male offspring were lower than those producing maternal toxicity, fetal malformations after administration during major organogenesis, and embryonic loss. The male reproductive system may be more susceptible than other organ systems to DBP and MBuP toxicity after maternal exposure. [source]

Developmental toxicity of estrogenic chemicals on rodents and other species

CONGENITAL ANOMALIES, Issue 2 2002
Taisen Iguchi
ABSTRACT, Antenatal sex-hormone exposure induces lesions in mouse reproductive organs, which are similar to those in humans exposed in utero to a synthetic estrogen, diethylstilbestrol. The developing organisms including rodents, fish and amphibians are particularly sensitive to exposure to estrogenic chemicals during a critical window. Exposure to estrogens during the critical period induces long-term changes in reproductive as well as non-reproductive organs, including persistent molecular alterations. The antenatal mouse model can be utilized as an indicator of possible long-term consequences of exposure to exogenous estrogenic compounds including possible environmental endocrine disrupters. Many chemicals released into the environment potentially disrupt the endocrine system in wildlife and humans, some of which exhibit estrogenic activity by binding to the estrogen receptors. Estrogen responsive genes, therefore, need to be identified to understand the molecular basis of estrogenic actions. In order to understand molecular mechanisms of estrogenic chemicals on developing organisms, we are identifying estrogen responsive genes using cDNA microarray, quantitative RT-PCR, and differential display methods, and genes related to the estrogen-independent vaginal changes in mice induced by estrogens during the critical window. In this review, discussion of our own findings related to endocrine distuptor issue will be provided. [source]

Developmental toxicity in zebrafish (Danio rerio) embryos after exposure to manufactured nanomaterials: Buckminsterfullerene aggregates (nC60) and fullerol

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2007
Xiaoshan Zhu
Abstract The present paper summarizes, to our knowledge, the first study regarding the developmental toxicity of stable buck-minsterfullerene aggregates suspended in water (nC60) using zebrafish (Danio rerio) as a vertebrate model. Zebrafish embryo survival, hatching rate, heartbeat, and pericardial edema were noted and described within 96 h of exposure. Fullerol (a hydroxylated C60 derivative, C60(OH)16,18) at 50 mg/L did not exert toxicity to zebrafish embryos. In contrast, nC60 at 1.5 mg/L delayed zebrafish embryo and larval development, decreased survival and hatching rates, and caused pericardial edema. Toxicity was mitigated by adding an antioxidant (glutathione), which suggests that a free radical,induced mechanism or another form of oxidative stress played a role in developmental toxicity. [source]

Developmental toxicity of in ovo exposure to polychlorinated biphenyls: I. Immediate and subsequent effects on first-generation nestling American kestrels (Falco sparverius)

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2003
Kim Fernie
Abstract We determined that in ovo exposure to polychlorinated biphenyls (PCBs) alters growth off first-generation nestlings during and one year after parental exposure. Captive American kestrels (Falco sparverius) laid eggs with environmentally relevant total PCB levels (34.1 ,g/g whole-egg wet wt) when fed PCB-spiked (Aroclor® 1248, 1254, and 1260) food (7 mg/kg body wt/d) for 100 d in 1998. In 1999, the same adults laid eggs with estimated total PCBs of 29.0 ,g/g. Nonsurviving PCB-exposed chicks were small (mass, bones) in 1998. Survivors showed a strong sex-specific growth response (mass, bones) compared to respective sex controls: Only female hatchlings were larger, and only male nestlings had longer feathers (1998); maximal growth and bone growth rates also differed (males were advanced, faster; females delayed, slower) (1999); and male nestlings fledged earlier and were smaller, while females were larger (1998, 1999). However, regardless of sex, PCB-exposed nestlings generally grew at faster rates in both years. In 1998, greater contaminant burdens and toxic equivalent concentrations in sibling eggs were associated with nestlings being lighter, having longer bones and feathers, and growing at faster rates (mass, bone) for females but slower rates (mass) for males. Both physiological-biochemical and behavioral changes are likely mechanisms. This study supports and expands on the Great Lakes embryo mortality, edema, and deformities syndrome: While PCB exposure alters nestling size, maximal growth and growth rates also change immediately, are sustained, and are sex specific. [source]

Developmental toxicity of estrogenic alkylphenols in killifish (Fundulus heteroclitus)

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2000
Sue A. Kelly
Abstract Estrogenic alkylphenols have been identified in the aquatic environment, and concern has arisen over the ability of these compounds to interact with and potentially disrupt vertebrate endocrine systems. Here we report that waterborne nonylphenol (NP) and 4- tert -octylphenol (4- t -OP) are toxic to the embryos and larvae of Fundulus heteroclitus, an estuarine teleost, causing both lethal and sublethal developmental abnormalities. Hatch success in surviving embryos is also adversely affected by alkylphenol exposure. Correlation analysis has indicated that decreased hatch success is strongly correlated to deformities in the torso/abdomen and tail of embryos. Larval exposure to the alkylphenols demonstrates that NP and 4- t -OP are lethal at concentrations an order of magnitude less than those lethal to embryos (NP larval 96-h LC50 = 0.95 ,M [204 ,g/L]; NP embryo 96-h LC50 = 24 ,M [5 mg/L]). In evaluating the role of estrogenicity in developmental toxicity of the alkylphenols, we have found that tamoxifen, an estrogen receptor antagonist, can prevent embryo-lethality for NP and 4- t -OP While these embryos survive, some sublethal abnormalities are still evident, particularly in the torso and tail. The results of these studies suggest that the alkylphenols have the potential to cause developmental toxicity in aquatic organisms and that this may occur through disruption of estrogen-based signals. [source]

Developmental toxicity of UV filters and environmental exposure: a review

INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2008
Margret Schlumpf
Summary Several ultraviolet (UV) filters exhibit estrogenic, some also anti-androgenic activity. They are present in waste water treatment plants, surface waters and biosphere including human milk, suggesting potential exposure during development. Developmental toxicity was studied in rats for the UV filters 4-methylbenzylidene camphor (4-MBC, 0.7, 7, 24, 47 mg/kg/day) and 3-benzylidene camphor (3-BC, 0.07, 0.24, 0.7, 2.4, 7 mg/kg/day) administered in chow to the parent generation before mating, during pregnancy and lactation, and to the offspring until adulthood. Neonates exhibited enhanced prostate growth after 4-MBC and altered uterine gene expression after both chemicals. 4-MBC and 3-BC delayed male puberty and affected reproductive organ weights of adult offspring. Effects on the thyroid axis were also noted. Expression and oestrogen sensitivity of oestrogen-regulated genes and nuclear receptor coregulator levels were altered at mRNA and protein levels in adult uterus, prostate and brain regions involved in gonadal control and sexual behaviour. Female sexual behaviour was impaired by both filters; 3-benzylidene camphor caused irregular cycles. Classical endpoints exhibited lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) of 7/0.7 mg/kg for 4-MBC and 0.24/0.07 mg/kg for 3-BC. Molecular endpoints were affected by the lowest doses studied. Our data indicate that the potential risk posed by endocrine active UV filters warrants further investigations. [source]

Relevance of the developmental toxicity of ethanol in the occupational setting: a review,

JOURNAL OF APPLIED TOXICOLOGY, Issue 5 2003
Lorraine F. H. Irvine
Abstract Numerous studies have been conducted investigating the reproductive toxicology of ethanol, the overwhelming majority concerning the adverse effects of consuming alcohol in beverages during pregnancy. Because many of the in vivo studies were designed to model alcoholism, they used comparatively high doses and assessed relatively few endpoints. Outcomes may have been affected by disturbances of metabolism at such high exposures, giving rise to secondary effects on development. The available data on ethanol from ,conventional' developmental toxicity study test methods of the type used for regulatory hazard assessment of chemicals are limited. It is in this context, however, i.e. the use of ethanol as an industrial chemical rather than as a component of beverages, that this review is based. Using the usual criteria applied for the purpose of hazard assessment of industrial chemicals, it is concluded that there is no evidence that industrial exposure to ethanol is a developmental toxicity hazard. Developmental toxicity may result from drinking alcoholic beverages, the threshold level for all aspects of which has yet to be de,ned. This is not, however, considered relevant to the low blood alcohol concentrations resulting from any conceivable inhalation or dermal exposure in the workplace or through the directed use of any consumer product containing ethanol. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Developmental toxicity of methanol: Pathogenesis in CD-1 and C57BL/6J mice exposed in whole embryo culture,,

BIRTH DEFECTS RESEARCH, Issue 4 2004
Sigmund J. Degitz
BACKGROUND Methanol causes axial skeleton and craniofacial defects in both CD-1 and C57BL/6J mice during gastrulation, but C57BL/6J embryos are more severely affected. We evaluated methanol-induced pathogenesis in CD-1 and C57BL/6J embryos exposed during gastrulation in whole embryo culture. METHODS Conceptuses with five to seven somites were exposed to 0, 1, 2, 3, 4, or 6 mg methanol/ml culture medium for 24 hr and embryonic morphology was assessed. Cell death was evaluated by histology and LysoTracker red staining, and cell-cycle distribution was evaluated by flow cytometry. RESULTS In C57BL/6J embryos, craniofacial defects were observed at 3 mg methanol/ml and greater. The response for CD-1 embryos was different, with increased dysmorphology only at 6 mg/ml. However, protein content in CD-1 embryos was reduced at 3 mg methanol/ml and above, indicating growth retardation. Yolk sac toxicity occurred only at 6 mg methanol/ml in both strains. Methanol caused only small changes in cell-cycle distribution, while cell death was induced at 4 and 6 mg methanol/ml in both strains after 8 hr. The extent of cell death after 8 hr was greater in C57BL/6J embryos, and increased over time through 18 hr; in contrast, CD-1 embryos showed less cell death at 18 than at 8 hr, suggesting recovery. CONCLUSIONS Cell death plays a prominent role in methanol-induced dysmorphogenesis, while cell-cycle perturbation may not. Differences in the extent of cell death between CD-1 and C57BL/6J embryos correlated with differences in the severity of dysmorphogenesis. Birth Defects Research (Part A), 2004. Published 2004 Wiley-Liss, Inc. [source]

Dual enantioselective effect of the insecticide bifenthrin on locomotor behavior and development in embryonic,larval zebrafish

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2010
Meiqing Jin
Abstract Bifenthrin (BF) is a synthetic pyrethroid that targets the nervous system of insects and may have adverse effects on the behavior and development of nontarget organisms. However, no reports have been issued on the effects of different enantiomers on locomotor behavior for synthetic pyrethroids (SPs) in zebrafish, and whether locomotor activity is associated with the developmental toxicities remains unclear. In this study, enantioselectivity of BF (1S and 1R) on the acute locomotor activity and developmental toxicities of embryonic,larval zebrafish were first evaluated. The results indicated that 1R -BF was more toxic, causing morphological impairments, with a 96-h median effective concentration (EC50) of 226,µg/L for pericardial edema and 145,µg/L for curved body axis. Administration of 20,µg/L of one enantiomer of BF had differential effects on the locomotor activity of zebrafish larvae at 4 d postfertilization (dpf) under alternating light and dark conditions. Larvae treated with 1R -BF were not sensitive to the alteration of light to dark, and the locomotor activities were reduced to a level similar to that observed in light, which otherwise increased rapidly and markedly. However, 1S -BF did not alter the general pattern of zebrafish response to the light or dark compared with the control. The results demonstrated that the differential effects on development might have contributed to the enantioselectivity in the locomotor activity. The consistency of enantioselectivity with insecticidal activity may also indicate a common mode of action. Furthermore, 1R -BF accelerated the spontaneous movement and hatching process, whereas 1S -BF seemed to be inhibitory. The results suggest the need to link behavioral changes to developmental toxicities in order to achieve more comprehensive health risk assessments of chiral pesticides. Environ. Toxicol. Chem. 2010;29:1561,1567. © 2010 SETAC [source]

Differential developmental toxicities of di- n -hexyl phthalate and dicyclohexyl phthalate administered orally to rats

JOURNAL OF APPLIED TOXICOLOGY, Issue 6 2009
Anne-Marie Saillenfait
Abstract The objective of this study was to evaluate the developmental toxic potential of di- n -hexyl phthalate (DnHP) and dicyclohexyl phthalate (DCHP) in rats. Pregnant Sprague,Dawley rats were exposed to DnHP or DCHP at doses of 0 (olive oil), 250, 500 and 750 mg kg,1 per day, by gavage, on gestational days (GD) 6,20. Maternal food consumption and body weight gain were significantly reduced at 750 mg kg,1 per day of DnHP and at the two high doses of DCHP. Slight changes in liver weight associated with peroxisomal enzyme induction were seen in dams treated with DnHP or DCHP. DnHP caused dose-related developmental toxic effects, including marked embryo mortality at 750 mg kg,1 per day, and presence of malformations (mainly cleft palate, eye defects and axial skeleton abnormalities) and significant decreases in fetal weight at 500 and 750 mg kg,1 per day. Significant delay of ossification and increase in the incidence of skeletal variants (e.g. supernumerary lumbar ribs) also appeared at 250 mg kg,1 per day. DCHP produced fetal growth retardation at 750 mg kg,1 per day, as evidenced by significant reduction of fetal weight. DnHP and DCHP induced a significant and dose-related decrease in the anogenital distance of male fetuses at all doses, and there was a significant increase in the incidence of male fetuses with undescended testis at 500 and 750 mg kg,1 per day of DnHP. In conclusion, DnHP showed clear embryolethality and teratogenicity, but not DCHP. There was evidence that both phthalates could alter the development of the male reproductive system after in utero exposure, DnHP being much more potent than DCHP. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Developmental toxicity of indium: Embryotoxicity and teratogenicity in experimental animals

Principles of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2-ethylhexyl) phthalate

CONGENITAL ANOMALIES, Issue 2 2004
Ryuichi Hasegawa
ABSTRACT Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose,response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose,response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established ,safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity. [source]

Prenatal developmental toxicity studies of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p, p,-DDT) in rats and rabbits

CONGENITAL ANOMALIES, Issue 4 2001
Ken L. Takahashi
ABSTRACT, The studies were conducted in rats and rabbits to elucidate the potential developmental toxicity of p, p'-DDT in general accordance with the improved Japanese MAFF guidelines (12-Nousan-No. 8147,2,1,18, 2000). p, p'-DDT suspended in 1% aqueous solution of CMC was administered orally to pregnant Jcl:SD rats on gestational days (GD) 6,19 at a dose of 0,5, 25, or 100 mg/kg/day and to pregnant KbI: JW rabbits on GD 6,27 at a dose of 0,5,20, or 80 mg/kg/day. Maternal animals were killed on the day after the last day of administration for morphological examination of their fetuses with special attention to the reproductive organs. Adverse effects on maternal animals were found only at the highest dose in both species; i.e., clonic convulsion (2/24 in rats, 5/22 in rabbits), mortality (1/24 in rats), abortion or premature delivery (4/22 in rabbits), and reduced body weight gains and food consumption. However, the control and treated groups showed comparable values for the numbers of corpora lutea and implants, percent preimplantation losses, number of live fetuses, percent resorptions and fetal deaths, sex ratio, fetal body weights, and placental weights in both species, and anogenital distance and testicular histology in rats. Although fetal examination revealed slightly increased incidence of 27 presacral vertebrae in the highest dose group in rats, there was no treatment-related increase in the incidence of malformations in any of the species. Based on these results, it is concluded that p, p'-DDT causes no malformations, including male reproductive organ abnormalities, in either rats or rabbits, although it results in an increased incidence of skeletal variations in rats at a maternally toxic dose. [source]

Developmental toxicity in zebrafish (Danio rerio) embryos after exposure to manufactured nanomaterials: Buckminsterfullerene aggregates (nC60) and fullerol

Developmental toxicity of estrogenic alkylphenols in killifish (Fundulus heteroclitus)

Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats

JOURNAL OF APPLIED TOXICOLOGY, Issue 6 2003
Frank Welsch
Abstract This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identi,cation study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD®(Sprague-Dawley) rats and CD-1® mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6,16 (mice) or 6,19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, signi,cantly reduced fetal body weights per litter and increased incidences of cleft palate (classi,ed as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Relevance of the developmental toxicity of ethanol in the occupational setting: a review,

Lack of teratogenicity of microcystin-LR in the mouse and toad

JOURNAL OF APPLIED TOXICOLOGY, Issue 1 2002
N. Chernoff
Abstract Microcystin-LR (MC-LR) is a cyanobacterial toxin generated by the organism Microcystis aeruginosa. Although the hepatotoxicity of this chemical has been characterized, the potential developmental toxicity in vertebrates has not been well studied. The purpose of this study was to elucidate the effects of this toxin on the in vivo and in vitro development of mammals and the development of an Anuran (toad). Initial acute toxicity experiments with female CD-1 mice were accomplished with MC-LR administered i.p. in saline. Lethality occurred at 128 and 160 µg kg ,1 and histopathology revealed massive hepatic necrosis with diffuse hemorrhage. Developmental toxicity studies were done with MC-LR administered i.p. for 2-day periods: gestation days 7,8, 9,10 or 11,12. Doses used ranged from 2 to 128 µg kg,1. On gestation day 17, fetuses were weighed and analyzed for gross morphological and skeletal defects. No treatment-related differences were seen in litter size, viability, weight or the incidence of anomalies. Groups of dams dosed with 32,128 µg kg,1 on gestation days 7,8, 9,10 or 11,12 were allowed to give birth and the growth and development of their pups were followed postnatally. There were no significant effects noted in the offspring of the treated dams. Neurulation-staged CD-1 mouse conceptuses were exposed to 50,1000 nM MC-LR in whole embryo culture for 24 h. No significant increase in abnormalities or developmental delays was observed. Finally, exposure of the developing toad. Bufo arenarum was done from stage 17 (tail bud) for 10 days at concentrations of 1,20 mg l,1. No effect on morphological development or survival was noted in any exposed groups. These data indicate that microcystin does not appear to affect development adversely in the mouse (in vivo or in vitro) or the toad at the doses and exposure parameters used. Copyright © 2002 John Wiley & Sons, Ltd. [source]

Investigation of Direct Toxic and Teratogenic Effects of Anticoagulants on Rat Embryonic Development Using In Vitro Culture Method and Genotoxicity Assay

ANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2 2006
I. I. Uysal
Summary Heparin and low molecular weight heparins (LMWHs) are used to reduce the incidence of venous thromboembolism in pregnancy. Although, these agents have been shown to be safe when used during pregnancy, the studies about direct toxic and teratogenic effects of these drugs on embryonic development are limited. In this study, the effects of heparin and LMWHs on rat embryonic development were investigated by using in vitro embryo culture and micronucleus (MN) assay methods. Rat embryos were cultured in vitro in the presence of different concentrations of heparin (5,40 IU/ml), dalteparin (2.5,20 IU/ml), enoxaparin (25,100 ,g/ml) and nadroparin (1,4 IU/ml). Effects of anticoagulants on embryonic developmental parameters were compared and embryos were evaluated for the presence of any malformations. After culturing the embryos, classic MN assay was performed. Anticoagulants significantly decreased all growth and developmental parameters dose-dependently. Dalteparin and enoxaparin were found to cause more developmental toxicity than heparin and nadroparin. Along with haematoma in general, heparin and nadroparin caused maxillary deformity, situs inversus and oedema most frequently, while neural tube defects were observed with dalteparin and enoxaparin. All agents also significantly induced MN formation in rat embryonic blood cells. These results indicate the possible genotoxic effects of anticoagulant agents on the developing rat embryo when applied directly. [source]

Alternative Methods for Developmental Toxicity Testing

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2006
Aldert H. Piersma
The aims of these investigations have been to reduce animal experimentation, to refine effect assessment and mechanistic studies, and to accelerate and simplify safety testing in an area of toxicology that uses relatively many animals. Many alternatives have been developed over the years with different compexities, using biologic material ranging from continuous cell lines to complete embryos. The validation of alternatives and their application in testing strategies is still in its infancy, although significant steps towards these aims are currently being made. The introduction of the genomics technology is a promising emerging area in developmental toxicity testing in vitro. Future application of alternatives in testing strategies for developmental toxicity may significantly gain from the inclusion of gene expression studies, given the unique programme of gene expression changes in embryonic and foetal development. [source]

Developmental toxicity evaluation of ELF magnetic fields in Sprague,Dawley rats

BIOELECTROMAGNETICS, Issue 4 2003
Moon-Koo Chung
Abstract To identify possible effects of horizontally polarized magnetic field (MF) exposure on maintenance of pregnancy and embryo-fetal development, an MF exposure system was designed and constructed and 96 time-mated female Sprague,Dawley (SD) rats (24/group) received continuous exposure to 60 Hz MF at field strengths of 0 (sham control) and 5, 83.3, or 500 ,T (50, 833, or 5000 mG). Dams received MF or sham exposures for 22 h/day on gestational day 6,20. MF was monitored continuously throughout the study. There were no evidences of maternal toxicity or developmental toxicity in any MF exposed groups. Mean maternal body weight, organ weights, and hematological and serum biochemical parameters in groups exposed to MF did not differ from those in sham control. No exposure related differences in fetal deaths, fetal body weight, and placental weight were observed between MF exposed groups and sham control. External, visceral, and skeletal examination of fetuses demonstrated no significant differences in the incidence of fetal malformations between MF exposed and sham control groups. In conclusion, exposure of pregnant rats to 60 Hz at MF strengths up to 500 ,T during gestation day 6,20 did not produce any biologically significant effect in either dams or fetuses. Bioelectromagnetics 24:231-240, 2003. © 2003 Wiley-Liss, Inc. [source]

Test of Marginal Compatibility and Smoothing Methods for Exchangeable Binary Data with Unequal Cluster Sizes

BIOMETRICS, Issue 1 2007
Zhen Pang
Summary Exchangeable binary data are often collected in developmental toxicity and other studies, and a whole host of parametric distributions for fitting this kind of data have been proposed in the literature. While these distributions can be matched to have the same marginal probability and intra-cluster correlation, they can be quite different in terms of shape and higher-order quantities of interest such as the litter-level risk of having at least one malformed fetus. A sensible alternative is to fit a saturated model (Bowman and George, 1995, Journal of the American Statistical Association90, 871,879) using the expectation-maximization (EM) algorithm proposed by Stefanescu and Turnbull (2003, Biometrics59, 18,24). The assumption of compatibility of marginal distributions is often made to link up the distributions for different cluster sizes so that estimation can be based on the combined data. Stefanescu and Turnbull proposed a modified trend test to test this assumption. Their test, however, fails to take into account the variability of an estimated null expectation and as a result leads to inaccurate p -values. This drawback is rectified in this article. When the data are sparse, the probability function estimated using a saturated model can be very jagged and some kind of smoothing is needed. We extend the penalized likelihood method (Simonoff, 1983, Annals of Statistics11, 208,218) to the present case of unequal cluster sizes and implement the method using an EM-type algorithm. In the presence of covariate, we propose a penalized kernel method that performs smoothing in both the covariate and response space. The proposed methods are illustrated using several data sets and the sampling and robustness properties of the resulting estimators are evaluated by simulations. [source]

Better data needed from pregnancy registries,

BIRTH DEFECTS RESEARCH, Issue 2 2009
Gerald G. Briggs
Abstract This article is a consensus position statement from the Research Committee of the Organization of Teratology Information Specialists (OTIS). The Committee believes that more specific information on the timing and dose of drug exposures from pregnancy birth defect registries sponsored by pharmaceutical companies (herein called pregnancy registries) would improve the estimation of risk for developmental toxicity (i.e., growth alteration, structural anomalies, functional/neurobehavioral deficits, or death). Specifically, the Committee believes that the exposure timing should be stated in gestational weeks and days rather than simply weeks. In addition, the Committee believes that the exposure dose should be stated in patient-specific terms, such as body weight (mg/kg) or body surface area (mg/m2) rather than simply dose strength. Although the focus of this position is pregnancy registries, it also is applicable to any source of medication-induced embryo-fetal toxicity. Birth Defects Research (Part A), 2009. © 2008 Wiley-Liss, Inc. [source]

Zebrafish as a model for developmental neurotoxicity testing,,

BIRTH DEFECTS RESEARCH, Issue 7 2006
Christopher Ton
Abstract BACKGROUND: To establish zebrafish as a developmental toxicity model, we used 7 well-characterized compounds to examine several parameters of neurotoxicity during development. METHODS: Embryos were exposed by semistatic immersion from 6 hrs postfertilization (hpf). Teratogenicity was assessed using a modified method previously developed by Phylonix. Dying cells in the brain were assessed by acridine orange staining (these cells are likely to be apoptotic). Motor neurons were assessed by antiacetylated tubulin staining and catecholaminergic neurons were visualized by antityrosine hydroxylase staining. RESULTS: Atrazine, dichlorodiphenyltrichloroethane (DDT), and 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) were primarily teratogenic and not specifically neurotoxic. 2,4-dichlorophenoxyacetic acid (2,4-D), dieldrin, and nonylphenol showed specific neurotoxicity; dieldrin and nonylphenol were specifically toxic to catecholaminergic neurons. Malathion, although not teratogenic, showed some nonspecific toxicity. CONCLUSIONS: Teratogenicity measured in 96-hpf zebrafish is predictive of mammalian teratogenicity and is useful in determining whether a compound causes specific neurotoxicity or general developmental toxicity. Induction of apoptosis or necrosis is an indicator of neurotoxicity. An effect on motor neurons in the caudal third of the embryo correlates with expected defects in motility. Overall, our results showed a strong correlation with mammalian data and suggest that zebrafish is a predictive animal model for neurotoxicity screening. Birth Defects Research (Part A) 76:553,567, 2006. Published 2006 Wiley-Liss, Inc. [source]

Combined repeated dose and reproductive/developmental toxicity screening test of the nitrophenolic herbicide dinoseb, 2- sec -butyl-4,6-dinitrophenol, in rats

ENVIRONMENTAL TOXICOLOGY, Issue 2 2008
Mariko Matsumoto
Abstract In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, Crj:CD(SD)IGS rats were dosed with dinoseb, 2- sec -butyl-4,6-dinitrophenol, by gavage at 0 (vehicle), 0.78, 2.33, or 7.0 mg/kg bw/day. Six males per group were dosed for a total of 42 days beginning 14 days before mating. Twelve females per group were dosed for a total of 44,48 days beginning 14 days before mating to day 6 of lactation throughout the mating and gestation period. Recovery groups of six males per group and nonpregnant six females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in males of any dose group or in females of the recovery groups. At 7.0 mg/kg bw/day, eight females died and two animals were moribund during late pregnancy, and a significant decrease in body weight gain was found in both sexes. Hematocrit was significantly higher at 0.78 mg/kg bw/day and above in the main group males at the end of administration period. Reduction in extramedullary hematopoiesis in the spleen was significant at 2.33 mg/kg bw/day in the main group females. Sperm analysis revealed a decrease in sperm motility and an increase in the rates of abnormal sperm, abnormal tail, and abnormal head at 7.0 mg/kg bw/day. A number of dams delivered their pups and of dams with live pups at delivery was significantly lowered in the 7.0 mg/kg bw/day group. Based on these findings, the LOAEL for males and NOAEL for females were 0.78 mg/kg bw/day, and the NOAEL for reproductive/developmental toxicity was considered to be 2.33 mg/kg bw/day. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2008. [source]