Abstract: The artemisinins are playing an increasingly important role in treating multidrug-resistant malaria. The artemisinin, artesunate, is currently in use in Southeast Asia and is advocated for use in Africa. In these areas, more than one million people die of malaria each year, with the highest mortality occurring in children and pregnant women. To test the developmental toxicity in ICH-compliant animal studies, embryofetal development studies were conducted in rats and rabbits treated with artesunate alone or a three-drug combination (CDA) consisting of chlorproguanil hydrochloride, Dapsone, and artesunate in the ratio 1.00:1.25:2.00. Developmental toxicity seen with CDA could be attributed to the administered dose of artesunate. The hallmark effect of artesunate exposure was a dramatic induction of embryo loss, apparent as abortions in rabbits and resorptions in both rats and rabbits. In addition, low incidences of cardiovascular malformations and a syndrome of skeletal defects were induced at or close to embryolethal doses of artesunate in both rats and rabbits. The cardiovascular malformations consisted of ventricular septal and vessel defects. The skeletal syndrome consisted of shortened and/or bent long bones and scapulae, misshapen ribs, cleft sternebrae, and incompletely ossified pelvic bones. These developmental effects were observed largely in the absence of any apparent maternal toxicity. The no or low adverse effect levels were in the range of 5 to 7 mg/kg/day artesunate. Encouragingly, no adverse drug-related developmental effects have been observed in a limited number of pregnant women (more than 100 first trimester and 600 second and third trimester) treated with artemisinins, primarily artesunate. Investigations of the mechanism of developmental toxicity are ongoing to attempt to determine whether rats and rabbits are more sensitive to artemisinins than humans.

Abstract: The developmental toxicity potential of butylparaben (CAS No. 94-26-8) was evaluated in rats. Sprague-Dawley rats were administered butylparaben in 0.5% carboxymethylcellulose by oral gavage at dose levels of 0, 10, 100, or 1,000 mg/kg/day on gestation days (GD) 6-19 (sperm positive day = GD 0). Caesarean sections were performed on GD 20 and fetuses were evaluated for viability, growth, and external, visceral, and skeletal abnormalities. Each group consisted of 25 females, with at least 21 per group being pregnant. The highest dose level caused decreases in maternal weight gain during some of the measurement intervals and was statistically significant during the GD 18-20 interval. Maternal food consumption was significantly decreased in the highest dose group over the dosing period (GD 6-20). There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Based on the results of this study, the maternal NOAEL for butylparaben was 100 mg/kg/day. Butylparaben does not have the potential to cause developmental toxicity in the Sprague-Dawley rat at oral dosages up to 1000 mg/kg/day.

Abstract: Background The major alkaloid in the betel nut, arecoline, has been reported to be potent in inducing developmentally toxic effects by generally lowering the embryo weight and retarding development of the embryo. This study examined the adverse effects of arecoline and tried to unravel the mechanism through the tools of molecular biology. METHODS Arecoline was administered to zebrafish embryos by incubation at concentrations ranging from 0.01–0.04% (wt/vol) and lethality and morphological changes were recorded. The expression of genes was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and whole-mount in situ hybridization. In addition, the protective effects of several antioxidants were tested. RESULTS The survival rate of treated embryos during a three-day incubation significantly declined as the arecoline concentration increased. Treated embryos showed general growth retardation and lower rate of heartbeat. When examined at the 24-hr stage, the relative amounts of transcripts of p53, p21, and cyclin D1, and the spatial expression patterns of these genes in treated groups, were comparable to those of the untreated early stages of embryos. Finally, the addition of glutathione (GSH) or its precursor, N-acetyl-L-cysteine (NAC), ameliorated the developmental retardation of embryos by arecoline. CONCLUSIONS Arecoline-treated embryos exhibited general developmental retardation in a dose-dependent manner. Our results from RT-PCR, in situ hybridization, and antioxidant-protection experiments indicate that the mechanism underlying growth retardation by arecoline in embryos is predominately due to a general cytotoxic effect induced by depletion of intracellular thiols. Birth Defects Research (Part A) 67:000–000, 2003. © 2003 Wiley-Liss, Inc.

Abstract: The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (−5 to −16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p≤0.05) decreases in mean fetal weights in groups given ≥200 mkd (−2 to −5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels ≥100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake. Birth Defects Res B 71:111–123, 2004. © 2004 Wiley-Liss, Inc.

Abstract: BACKGROUND: Emodin, a widely available herbal remedy, was evaluated for potential effects on pregnancy outcome. METHODS: Emodin was administered in feed to timed-mated Sprague–Dawley (CD) rats (0, 425, 850, and 1700 ppm; gestational day [GD] 6–20), and Swiss Albino (CD-1) mice (0, 600, 2500 or 6000 ppm; GD 6–17). Ingested dose was 0, 31, 57, and ∼80–144 mg emodin/kg/day (rats) and 0, 94, 391, and 1005 mg emodin/kg/day (mice). Timed-mated animals (23–25/group) were monitored for body weight, feed/water consumption, and clinical signs. At termination (rats: GD 20; mice: GD 17), confirmed pregnant dams (21–25/group) were evaluated for clinical signs: body, liver, kidney, and gravid uterine weights, uterine contents, and number of corpora lutea. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations/variations. RESULTS: There were no maternal deaths. In rats, maternal body weight, weight gain during treatment, and corrected weight gain exhibited a decreasing trend. Maternal body weight gain during treatment was significantly reduced at the high dose. In mice, maternal body weight and weight gain was decreased at the high dose. CONCLUSIONS: Prenatal mortality, live litter size, fetal sex ratio, and morphological development were unaffected in both rats and mice. At the high dose, rat average fetal body weight per litter was unaffected, but was significantly reduced in mice. The rat maternal lowest observed adverse effect level (LOAEL) was 1700 ppm; the no observed adverse effect level (NOAEL) was 850 ppm. The rat developmental toxicity NOAEL was ≥1700 ppm. A LOAEL was not established. In mice, the maternal toxicity LOAEL was 6000 ppm and the NOAEL was 2500 ppm. The developmental toxicity LOAEL was 6000 ppm (reduced fetal body weight) and the NOAEL was 2500 ppm. Birth Defects Res B 71:89–101, 2004. © 2004 Wiley-Liss, Inc.

Abstract: BACKGROUND: Exposure of pregnant outbred CD-1 mice to methanol during the period of gastrulation results in exencephaly, cleft palate, and cervical vertebra malformations [Rogers and Mole, Teratology 55: 364, 1997], while inbred C57BL/6J mice are sensitive to the teratogenicity of ethanol. C57BL/6J fetuses exhibit the holoprosencephaly spectrum of malformations after maternal exposure to ethanol during gastrulation, but the sensitivity of C57BL/6J mice to methanolinduced teratogenesis has not been previously described. METHODS: Pregnant C57BL/6J mice were administered two i.p. injections totaling 3.4 or 4.9 g/kg methanol or distilled water four hrs apart on gestation day (GD) 7. On GD 17, litters were examined for numbers of live, dead and resorbed conceptuses, fetuses were weighed as a litter and examined externally, and all fetuses were double stained for skeletal analysis. RESULTS: No maternal intoxication was apparent, but the high dosage level caused a transient deficit in maternal weight gain. The number of live fetuses per litter was reduced at both dosages of methanol, and fetal weight was lower in the high dosage group. Craniofacial defects were observed in 55.8% of fetuses in the low dosage group and 91.0% of fetuses in the high dosage group, including micro/ anophthalmia, holoprosencephaly, facial clefts and gross facial angenesis. Skeletal malformations, particularly of the cervical vertebrae, were observed at both dosages of methanol, and were similar to those previously reported in the CD-1 mouse following methanol exposure. CONCLUSIONS: The types of craniofacial malformations induced in the C57BL/ 6J mouse by methanol indicate that methanol and ethanol have common targets and may have common modes of action. Birth Defects Res B 71:80–88, 2004. Published 2004 Wiley-Liss, Inc. w

Abstract: Animal studies indicate male-mediated teratogenicity for certain carcinogens/mutagens. Nevertheless, paternal occupational determinants of malformations in humans have been sparsely investigated. Data on male employees at Swedish universities from 1970 to 1989 were linked to the Medical Birth Register. The relationship between major malformations and exposure to laboratory work and to specific laboratory agents/techniques before the third trimester were analyzed using logistic regression. For major malformations, "laboratory work in general" (n = 3237) gave an adjusted odds ratio (OR) of 1.3 (95% CI = 0.8-2.1) and carcinogenic solvent use (n = 2489) of 2.0 (95% CI = 0.8-4.9) around the time of conception. For carcinogenic solvents and neural crest malformations, OR was 4.9 (95% CI =1.5-15.8). In conclusion, the prevalence of congenital malformations was not increased in offspring of males with laboratory work in general (1970-1989). Paternal work with agents such as carcinogens could, however, be of concern.

Abstract: Exposure of the embryo to environmental chemicals can result in congenital malformations or abortion Although experimental teratology data are considered sufficient for risk assessment, only knowledge of their mechanisms of action permits a justifiable extrapolation of animal data to humans Mechanistic studies of some teratogenic agents such as retinoic acids, valproic acid, diethylstilbestrol, and cyclopamine provided evidence of interference with regulation of genes controlling the embryonic development The new genomic technologies are important tools in this field and may represent a real improvement in understanding the mechanisms of action of chemical teratogens

Abstract: Vitamin A metabolites are potent teratogens in a wide variety of species, including man. Transforming growth factor betas (TGF-βs) are involved in several mammalian prenatal developmental processes. The aim of this study was to determine the effects of exogenous and excessive all-trans retinoic acid on TGFβ2 expression in the developing cerebral cortex of the rat. Many of the malformations including exencephaly, exophtalmus, abdominal wall defects, extremity reduction defects observed in this study were dependent on the time of administration of retinoic acid. TGF-β2 was diversely expressed, as revealed immunohistochemically, in the cerebral cortex and plexus choroideus. The diversity depended on the gestational day and the was affected by the administration of retinoic acid. In the 15-day-old fetus from mothers who had been fed by gavage a single dose of 60 mg/kg body weight of all-trans retinoic acid on the 8th day of gestation, TGF-β2 immunoreactivity in the brain was decreased. However, by the 18th day of gestation, TGF-β2 expression increased. The expression of TGF-β2 in fetuses whose mothers had been given all-trans retinoic acid after the neurulation period (on day 12 of gestation) was generally similar to that in a control group. We conclude that all-trans retinoic acid leads to severe congenital malformations if administered before neurulation whereas if given after neurulation, it is not so teratogenic. Further, retinoic acid has a variable effect on the expression of TGF-β2.

Abstract: BACKGROUND Drosophila and vertebrates show similarities that suggest that the mechanisms involved in the induction of developmental defects may be similar in both. Therefore, Drosophila has been proposed as a useful, rapid, and economical model in the preliminary screening for teratology studies. The objective of the present study was to investigate the effect of metronidazole (MTZ) and ornidazole (ONZ) on the developmental stages of Drosophila melanogaster. METHODS Samarkand wild-type females were allowed to lay eggs for 24 hr in media containing MTZ or ONZ at concentrations of 0, 500, 1000, and 2000 μg/ml. When larvae completed their development, the emerging flies were counted and examined for morphological abnormalities. RESULTS After the analysis of 400–1000 flies for each concentration, ONZ-treated flies did not show an incidence of malformations above control values, although a significant high number of individuals with reduced body size was observed (p < 0.005, χ2 test). On the other hand, the 1000- and 2000-μg/ml MTZ-treated series presented higher frequencies of total abnormalities than did concurrent and historic controls (p < 0.05, χ2 test), indicating an MTZ effect during developmental morphogenesis. CONCLUSIONS These findings contribute to the characterization of both nitroimidazoles, which are widely used, especially in underdeveloped countries. At the same time, this Drosophila bioassay is sensitive enough to detect differential effects of MTZ and ONZ (abnormalities vs. growth effects), showing specificity and selectivity. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc.

Abstract: BACKGROUND: Integrins such as VLA-4 (Very late antigen 4, integrin α4β1) play key roles in cell–cell interactions that are critical for development. Homozygous null knockouts of the VLA-4 α4-subunit or VCAM-1 (VLA-4 cell surface ligand) in mice result in failure of the allantois and chorion to fuse leading to interrupted placentation and cardiac development and embryo lethality. Embryo-fetal studies of three VLA-4 antagonists, IVL745, IVL984, and HMR1031 [Crofts et al., Birth Defects Res B 71:55–68 (this issue), 2004] with exposure on gestation days (GD) 6–17 (rat), 6–18 (rabbit) or 6–15 (mouse) showed that only IVL984 treatment resulted in embryo lethality and cardiac defects. Objectives of the current study were to determine the critical period for inducing IVL984-related embryo-fetal effects, and to test the hypothesis that these effects were due to higher embryo drug concentrations. METHODS: IVL984 was administered at 40 mg/kg/day to pregnant rats on GD 4 and 5, GD 6 and 7, GD 8 and 9, GD 10 and 11, or GD 12 and 13. Animals were euthanized on GD 21 and uteri and fetuses were examined. A treatment period of GD 10–12 was selected for subsequent toxicokinetic (TK) studies in which IVL984, HMR1031, or IVL745 was administered to pregnant rats and rabbits. On GD 12, maternal plasma, extra-embryonic tissue (placenta and amniotic fluid), and embryonic tissue were collected and analyzed for drug concentrations. RESULTS: In the IVL984 critical period study in pregnant rats, treatment on GD 10 and 11 resulted in increased post-implantation loss, skeletal variations, and spiral septal defects similar to those observed in standard embryo-fetal development studies with treatment throughout organogenesis. There were no embryo-fetal effects after treatment on GD 4 and 5, GD 6 and 7, or GD 8 and 9. There was a single aorta malformation after treatment on GD 12 and 13. In the TK studies, IVL745, HMR1031, and IVL984 were all detectable in embryonic tissue and there was no evidence for accumulation. Rat and rabbit embryo exposures (AUC or dose-adjusted AUC) on GD 12 could not explain the observed teratology (IVL984

Abstract: The potential for reproductive toxicity of an antisense oligonucleotide designed to inhibit ICAM-1 was evaluated as part of the safety assessment for this compound. The human active ICAM-1 inhibitor (ISIS 2302) is not pharmacologically active in rabbits. Female rabbits were treated once daily on Day 6 through 18 of gestation. Rabbits were treated with 0, 1, 3, and 9 mg/kg ISIS 2302 by daily i.v. injection. Reproductive indices evaluated included estrus cycling, litter parameters, fetal development, and fetal body weight. Concentrations of oligonucleotide in plasma following the last dose, and in selected maternal target organs, placenta, and fetal tissues at scheduled necropsy were also measured. Maternal toxicity was evident as a decreased maternal body weight gain, decreased food consumption, and scant feces at doses ≥3 mg/kg. Increased spleen to body weight ratio and increased mononuclear cell infiltrates were indicative of a proinflammatory effect of ISIS 2302 at the 9 mg/kg dose level. Despite the maternal toxicity, there were no changes in litter parameters or fetal development in rabbits treated with ISIS 2302. The only change was a decrease in fetal body weight at the 9 mg/kg dose level, which was attributed to the maternal toxicity observed. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no oligonucleotide measured in placenta or fetal tissues. Thus, there was no dose-dependent exposure and maternal toxicity to ISIS 2302, but no reproductive toxicity in rabbits, and exposure of fetus or pups is negligible. Birth Defects Res B 71:368–373, 2004. © 2004 Wiley-Liss, Inc.

Abstract: Using in vitro organ culture of the fetal mouse palate in a chemically defined serumless medium, the toxicity of 24 chemical compounds was investigated. Explanted palates of day-12.5 mouse fetuses were exposed for 72 h in vitro to various concentrations of each chemical, and the fusion rate and growth parameters were compared between the experimental group and respective controls. The average rate of palate fusion was 84% in vehicle controls. For compounds that are teratogenic in experimental animals in vivo, the fusion rates of palatal shelves decreased as the concentration of the test chemicals increased, showing a dose-dependent relationship. Palate fusion was inhibited by 11 of the 15 in vivo teratogens, and the predictability of in vivo developmental toxicity in this culture system was 73%. Cyclophosphamide itself did not inhibit the growth and fusion of explanted palates, but supplementation of hepatic S-9 fraction and cofactors for a monooxygenase system converted it to a toxic substance, as was shown in other in vitro systems. The 50% inhibitory concentration (IC50) value calculated based on the fusion rate was also found to be a useful parameter for evaluating the developmental toxicity of drugs. The teratogenic risk in the human fetus could be assessed by comparing the minimal toxic concentrations of the test compound on cultured palates with the maximal plasma level in pregnant women under therapeutic conditions and with the plasma concentrations when its minimal teratogenic dose is given to pregnant mice. This organ culture system of the fetal palate should be useful for screening the developmental toxicity of drugs and other environmental agents, and its value should increase when it is used in combination with other battery test systems.

Abstract: Teratology is the science of congenital malformations. The incidence of birth defects amounts to 2-3%, but it doubles postnatal owing to the fact that many dysfunctions are not discernible at birth. Congenital malformations were already known in ancient cultures, records from Assyrian and Babylonian astrologists as well as from physicians and philosophers of the Hippocratic era are testifying it. In medieval times they were recognized as supernatural phenomenons, terata, from what the term TERATOLOGY derived. In the eyes of the superstitious people affected stillborns were regarded as monster, symbol of devil or miracle. The foundation of anatomy as a science by Vesalius marked the beginning of a reorientation. In the 17th century, when the age of enlightenment began, ideas concerning the origin of birth defects became more objective. Original studies dealing with congenital malformations became common in the 18th century. Fundamental discoveries made by microscopy placed Teratology on a truly scientific basis. Significant impetus was grown to teratological research with the discovery of Gregg (1941) that German measles (rubella virus) of pregnant women caused birth defects in the embryo and the contergan disaster (1959--1962). Congenital malformations originate from genetic factors (single gene defects and chromosomal aberrations) and environmental factors, such as radiation, drugs, chemicals, and infectious agents. The susceptibility of teratogen depends on the period of embryonal development, which is classified into gametogenesis, blastogenesis, embryogenesis and fetogenesis. The Food and Drug Administration of the USA published guidelines for teratogenetic testing (1966). There are in-vivo and in-vitro-test programmes, the latter became of increasing importance owing to the large number of chemicals to be tested and the activities of opponents against animal experiments. Although great advances were made, the problem remained to transfer results from in-vivo and in-vitro tests to the constitution of man without risk.

Abstract: This study was performed to evaluate the effects of prenatal development of rats were exposed to Polnoks R and its monomer 2,2,4-trimethyl-1,2-dihydroquinoline (TMDHQ) by gavage every day on days 6-15 of gestation at doses equivalent 6%, 13% and 25% of LD50. Polnoks R and TMDHQ administered per os associated with significant maternal toxicity, embryonal lethality, retarded fetal development and congenital defects. Polnoks R induced skeletal malformations, internal hydrocephalus, and hydronephrosis. 2,2,4-trimethyl-1,2-dihydroquinoline produced internal malformations (exencephale, hydrocephalus, anophthalmia, hydronephrosis and renal hypoplasia) and skeletal malformations of ribs and vertebrae. Polnoks R monomer--2,2,4-trimethyl-1,2-dihydroquinoline is used as an antioxidant in elastomer and rubber productions. Polnoks R and its monomer 2,2,4-trimethyl-1,2-dihydroquinoline are teratogenic to rats and induces CNS, kidneys and skeletal defects.

Abstract: In earlier work we have reported that garlic and cabbage extracts can protect laboratory animals from the toxic effects of different mycotoxins. Previous research demonstrated that fumonisin (FB) induced developmental effects in mice, rats and hamsters. The objectives of the present study were to utilize the pregnant rat as an in vivo model to compare the potential of garlic and cabbage seed extracts to prevent the developmental toxicity of FB and the effects of these extracts on sphingolipid metabolism in dam and foetus livers. Six treatment groups included a control group, a group fed on an FB-containing diet (150 mg kg−1 feed) and groups treated orally with garlic or cabbage extracts (5 mg kg−1 body wt.) with or without FB during gestation days 6–15. Evaluations of toxicity were performed on day 20. These include: maternal (mortality, body weight, feed intake and litter weight), developmental (embryonic resorption, foetal body weight, foetal soft-tissue anomalies and foetal skeletal examinations) and maternal and foetal sphingolipid metabolism. Fumonisin alone resulted in significant decreases in feed intake, body weight gain, litter weight, number of live foetuses and foetal body weight, whereas it increased significantly the number of resorbed foetuses and the number of skeletal malformations (30.4% for skull and 26.08% for sternebrae) and also increased the sphinganine/sphingosine (Sa/So) ratio in dam but not fetus livers. Garlic alone or plus FB was comparable to the control regarding all the tested parameters. On the other hand, cabbage seed extract alone or plus FB resulted in 10% maternal mortality and a decrease in maternal body weight and litter weight. It resulted in 4.65% skull malformations in foetuses but it was comparable to the control with regard to the other tested parameters. It could be concluded that both garlic and cabbage seed extracts have protective effects in pregnant rats. Moreover, garlic extract was found to have a greater protective effect than cabbage seed extract. Copyright © 2004 John Wiley & Sons, Ltd.

Abstract: BACKGROUND: VLA-4 (Very late antigen 4, integrin α4β1) plays an important role in cell-cell interactions that are critical for development. Homozygous null knockouts of the α4subunit of VLA-4 or VCAM-1 (cell surface ligand to VLA-4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA-4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo-fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo-fetal effects consisted of slightly lower body weight and crown-rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo-fetal effects consisted of increased total post-implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo-fetal effects at maternally-toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species. Birth Defects Res B 71:55–68, 2004. © 2004 Wiley-Liss, Inc.

Abstract: BACKGROUND: The classic clinical criteria for the diagnosis of fetal alcohol syndrome (FAS) include a “characteristic” facial appearance, pre- and postnatal growth deficiency, microcephaly, mental retardation, and occasional major malformations. However, diagnostic constraints, especially in the newborn period, lead to an underestimate of their prevalence. We report an epidemiological study of the potential risk of congenital defects in the offspring of mothers who ingested different sporadic and daily amounts of alcohol during pregnancy. METHODS: The study was based on the data from the ECEMC hospital-based case– control study and surveillance system, with a methodology aimed not only at the surveillance of congenital anomalies, but also at investigating their characteristics, clustering, and causes. For the purposes of this study, we considered as exposed those infants whose mothers reported the ingestion of any amount of alcohol during gestation (4705 mothers of cases and 4329 mothers of controls), and classified them into five groups according to their levels of alcohol consumption. Two groups consisted of mothers who consumed increasing sporadic levels and the other three consisted of mothers who consumed increasing daily levels of alcohol. RESULTS: Our study showed that even low sporadic doses of alcohol consumption during pregnancy may increase the risk of congenital anomalies in the offspring and that this risk increases with increasing levels of alcohol exposure. CONCLUSIONS: The results of our study suggest that it is necessary to generalize the preventive norm and recommend complete abstinence from alcohol during gestation. Birth Defects Research (Part A) 70:194 –200, 2004. © 2004 Wiley-Liss, Inc.

Abstract: There have been amazing advances in embryology, teratology, reproductive biology, genetics, and epidemiology in the past 50 years that have provided scientists and clinicians with a better perspective on the causes of congenital malformations. We still cannot provide the families of children with malformations a definitive diagnosis and cause in every instance. The purpose of this article is to inform pediatricians about environmental drugs, chemicals, and physical agents that have been documented to produce congenital malformations and reproductive effects and to indicate that the multitude of teratogenic agents account for only a small proportion of malformations. The most common known cause is genetic, but the largest group, unfortunately, There have been amazing advances in embryology, teratology, reproductive biology, genetics, and epidemiology in the past 50 years that have provided scientists and clinicians with a better perspective on the causes of congenital malformations. We still cannot provide the families of children with malformations a definitive diagnosis and cause in every instance. The purpose of this article is to inform pediatricians about environmental drugs, chemicals, and physical agents that have been documented to produce congenital malformations and reproductive effects and to indicate that the multitude of teratogenic agents account for only a small proportion of malformations. The most common known cause is genetic, but the largest group, unfortunately, is unknown. There are a number of important clinical rules that are important for clinicians to use when determining the cause of their patient's congenital malformations: 1. No teratogenic agent should be described qualitatively as a teratogen, because a teratogenic exposure includes not only the agent but also the dose and the time in pregnancy when the exposure has to occur. 2. Even agents that have been demonstrated to result in malformations cannot produce every type of malformation. Known teratogens may be presumptively implicated by the spectrum of malformations that they produce. It is easier to exclude an agent as a cause of birth defects than to conclude definitively that it was responsible for birth defects, because of the existence of genocopies of some teratogenic syndromes. 3. When evaluating the risk of exposures, the dose is a crucial component in determining the risk. Teratogenic agents follow a toxicologic dose-response curve. This means that each teratogen has a threshold dose below which there is no risk of teratogenesis, no matter when in pregnancy the exposure occurred. 4. The evaluation of a child with congenital malformations cannot be performed adequately unless it is approached with the same scholarship and intensity as the evaluation of any other complicated medical problem. 5. Each physician must recognize the consequences of providing erroneous reproductive risks to pregnant women who are exposed to drugs and chemicals during pregnancy or alleging that a child's malformations are attributable to an environmental agent without performing a complete and scholarly evaluation. 6. Unfortunately, clinical teratology and clinical genetics is not emphasized in medical school and residency education programs, but pediatricians have a multitude of educational aids to assist them in their evaluations, which includes consultations with clinical teratologists and geneticists, the medical literature, and the OMIM web site.

Abstract: The histopathological features of various abnormalities induced by different doses of ochratoxin A (OA), aflatoxin B1 (AFB1), and their combination in rat fetuses were studied. The pregnant Wistar rats were orally treated during 6–15 gestation days with different doses of OA (0.125, 0.25, 0.50, 0.75 mg/kg), AFB1 (0.125, 0.25, 0.50, 1.00 mg/kg), and their combination (0.125+0.125, 0.25+0.50, 0.50+0.25 mg/kg). The fetal sections passing through liver, kidney, brain, heart, and eyes were selected from the fetuses given visceral examination representing each litter. The selected sections were processed for paraffin embedding, stained with H and E, and examined by light microscopy. The histological examination of the fetal organs revealed that OA, AFB1, and their combination treatments caused variable changes in internal organs. In the case of OA, the incidence of pathological lesions liver, kidney, brain, and eye lesions was high, whereas in AFB1treatment, liver, brain, kidney, and heart were affected. The incidence of heart lesions, especially valvular defects, increased in the combination groups. Bile duct proliferation/new bile duct formation, defective ossification of cranial bones, exposure of the brain to the exterior, hypoplasia of cerebellum, and retinal defects observed in OA treatment and spinal cord defects in addition to liver, kidney, and brain changes observed in AFB1 were less severe in the combination groups. The present study indicates that the occurrence of brain, kidney, and liver lesions in combination treatment was less than in either individual treatment suggesting antagonism of OA-induced teratogenic effects by AFB1. The indication of subtle lesions due to an interference with normal development and arrest of differentiation in various internal organs observed in the present study suggests that microscopic examination of the tissues can provide additional useful information to a developmental toxicity study. Birth Defects Res B 71:352–358, 2004. © 2004 Wiley-Liss, Inc.

Abstract: Journal of Pediatric Gastroenterology and NutritionVolume 39, Issue S1 p. S34-S35 ABSTRACTS: Oral Presentation Abstracts O0071 GENETIC VARIABILITY OF MULTI-DRUG RESISTANCE PROTEIN 3: POSSIBLE IMPACT ON FUNCTION M. C. Stephens, M. C. Stephens Pediatric Gastroenterology and Nutrition, Clinical Pharmacology, Pharmacogenetics, and Teratology, Medical College of Wisconsin, Milwaukee, United StatesSearch for more papers by this authorA. Sommers, A. Sommers Pediatric Gastroenterology and Nutrition, Clinical Pharmacology, Pharmacogenetics, and Teratology, Medical College of Wisconsin, Milwaukee, United StatesSearch for more papers by this authorR. N. Hines, R. N. Hines Clinical Pharmacology, Pharmacogenetics, and Teratology, Medical College of Wisconsin, Milwaukee, United StatesSearch for more papers by this author M. C. Stephens, M. C. Stephens Pediatric Gastroenterology and Nutrition, Clinical Pharmacology, Pharmacogenetics, and Teratology, Medical College of Wisconsin, Milwaukee, United StatesSearch for more papers by this authorA. Sommers, A. Sommers Pediatric Gastroenterology and Nutrition, Clinical Pharmacology, Pharmacogenetics, and Teratology, Medical College of Wisconsin, Milwaukee, United StatesSearch for more papers by this authorR. N. Hines, R. N. Hines Clinical Pharmacology, Pharmacogenetics, and Teratology, Medical College of Wisconsin, Milwaukee, United StatesSearch for more papers by this author First published: 01 June 2004 https://doi.org/10.1002/j.1536-4801.2004.tb12379.x Submitted by: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Reference(S): 1.Collins, F. S., L. D. Brooks, et al. (1998). “A DNA polymorphism discovery resource for research on human genetic variation.” Genome Res 8 (12): 1229–31. 10.1101/gr.8.12.1229 CASPubMedWeb of Science®Google Scholar Volume39, IssueS1June 2004Pages S34-S35 ReferencesRelatedInformation