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PubMed1999

Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis.

This study sought to determine the relative roles of glycolic acid (GA), a toxicologically important metabolite of ethylene glycol (EG), and metabolic acidosis in causing developmental toxicity in Sprague-Dawley rats. To tease apart these two interrelated factors, we developed an experimental approach in which high blood glycolate levels could be achieved, in either the presence or absence of metabolic acidosis. Initially, rats previously implanted with a carotid artery cannula were given, on gestation day (gd) 10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4) via subcutaneous (sc) injection, or distilled water via gavage (control). Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and NaG groups and, as expected, EG and GA caused a metabolic acidosis, but acid base balance was normal with NaG. Subsequently, these treatments were given on gd 6-15 to groups of 25 time-mated rats, followed by fetal evaluation on gd 21. EG and GA decreased fetal body weights and caused a similar spectrum of developmental effects, including numerous axial skeleton malformations. NaG treatment also caused slight decreases in fetal body weight, increases in skeletal variations, and totally malformed fetuses. These results indicate that glycolate, in the absence of metabolic acidosis, can cause the most sensitive of EG's developmental effects, whereas metabolic acidosis appears to interact with glycolate at very high doses to markedly enhance teratogenesis. These results support previous studies, which indicated that glycolate is the proximate developmental toxicant for EG, and that GA toxicokinetic parameters can be used to define a quantitative, physiologically based threshold for EG-induced developmental effects.

Acidosis↗
PubMedDate not supplied

Prevention by chelating agents of metal-induced developmental toxicity.

Chelating agents such as calcium disodium ethylenediaminetetraacetate (EDTA), 2,3-dimercaptopropanol (BAL), or D-penicillamine (D-PA) have been widely used for the past 4 decades as antidotes for the treatment of acute and chronic metal poisoning. In recent years, meso-2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercapto-1-propanesulfonate (DMPS) and sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron) have also shown to be effective to prevent against toxicity induced by a number of heavy metals. The purpose of the present article was to review the protective activity of various chelating agents against the embryotoxic and teratogenic effects of well-known developmental toxicants (arsenic, cadmium, lead, mercury, uranium, and vanadium). DMSA and DMPS were found to be effective in alleviating arsenate- and arsenite-induced teratogenesis, whereas BAL afforded only some protection against arsenic-induced embryo/fetal toxicity. Also, DMSA, DMPS, and Tiopronin were effective in ameliorating methyl mercury-induced developmental toxicity. Although the embryotoxic and teratogenic effects of vanadate were significantly reduced by Tiron, no significant amelioration of uranium-induced embryotoxicity was observed after treatment with this chelator.

Abnormalities, Drug-Induced↗
PubMed1989

Determination of the developmental toxicity potential of butoxypropanol in rabbits after topical administration.

The developmental toxicity (embryofetotoxicity or teratogenicity) and maternal toxicity of butoxypropanol, a propylene glycol ether, was evaluated in New Zealand White rabbits. Dosages of 0 (water), 10, 40 or 100 mg/kg/day, selected on the basis of the water solubility of butoxypropanol and the results of a pilot study, were administered percutaneously to groups of artificially inseminated (Day 0) female rabbits on Days 7 through 18 of gestation. The dosage volume was 2 ml/kg. The control group contained 17 does and each test group contained 19 does. Does were observed for signs of test substance effect on abortion or premature delivery, body weight, and feed consumption. On Day 29, they were euthanized and examined for pregnancy, number and placement of implantations, early and late resorptions, and live fetuses. Pregnancy occurred in 15 control does (88%) and in 16 does in each test group (84%). There were no statistically significant differences between test and control groups for maternal body weight gain, feed consumption, number of corpora lutea per ovary, implantations, live fetuses, early and late resorptions, fetal body weights, gender, or gross external changes. There were no visceral or skeletal fetal alterations at any dose tested. No signs of maternal toxicity were observed; however, mild erythema occurred at the site of application at the 100 mg/kg/day dose level. The developmental no-effect level was greater than 100 mg/kg/day.

Administration, Topical↗
PubMed2001

Toward a biologically based dose-response model for developmental toxicity of 5-fluorouracil in the rat: a mathematical construct.

Biologically based dose-response (BBDR) models comprise one way to incorporate mechanistic information into a dose-response assessment to be used for risk assessments. The chemotherapeutic drug 5-fluorouracil (5-FU) has been used as a prototypic compound for the construction of a BBDR model for developmental toxicity. Previous work has provided data and a general mechanistic framework for the developmental toxicity of 5-FU when it was administered to pregnant rats subcutaneously on gestation day 14. In this paper, a mathematical model relating maternally administered treatment with 5-FU to embryonal thymidylate synthetase inhibition and thymidylate synthetase inhibition to various measures of deoxyribonucleotide triphosphate (dNTP) pool perturbation is developed, and parameters are estimated using the data collected. The strategy used was to develop semi-empirical submodels for each of the intervening steps, and to estimate model parameters from previously described data. The models developed predict that there is no practical threshold for dNTP pool perturbation; that is, even minimal doses of 5-FU should result in some perturbation of dNTP pools. In particular, the relationship between dNTP pool perturbation and fetal weight deficit suggests that if there is a biological threshold for the effect of 5-FU on fetal weight, the responsible repair or compensation mechanism must be downstream of dNTP pool perturbation, and saturable at 5-FU doses lower than 10 mg/kg (the lowest dose examined for developmental effects in these studies).

Abnormalities, Drug-Induced↗
PubMed1993

Developmental toxicity of methanol in whole embryo culture: a comparative study with mouse and rat embryos.

Methanol (MeOH), a widely used industrial solvent, has been proposed as an alternative motor vehicle fuel. Inhaled MeOH is developmentally toxic in both rats and mice but the mouse is more sensitive than is the rat. The contribution of the embryo to this differential sensitivity was studied in whole embryo culture (WEC) using equivalent stage rat (day 9) and mouse (day 8) embryos (plug day = day 0). Rat embryos were explanted and cultured in 0, 2, 4, 8, 12 or 16 mg MeOH/ml rat serum for 24 h and then transferred to rat serum alone for 24 h. Embryonic development of the 2 and 4 mg MeOH/ml groups was not significantly different from the controls whereas the higher concentrations resulted in a concentration related decrease in somite number, head length and developmental score. The 12 mg/ml dose resulted in some embryolethality as well as dysmorphogenesis, while the highest dose was embryolethal. MeOH was dysmorphogenic in vitro in rat embryos at a MeOH concentration comparable to that reported in maternal serum following teratogenic in vivo exposures. Day 8 mouse embryos were explanted and cultured in 0, 2, 4, 6 or 8 mg MeOH/ml culture medium (75% rat serum, 25% Tyrode's salt solution) for 24 h. Embryonic development in the 2 mg/ml MeOH group was not significantly different from the controls but all higher concentration groups had a significant decrease in developmental score and crown-rump length. The high concentration group also suffered 80% embryolethality. Thus, mouse embryos were affected at MeOH concentrations which were not dysmorphogenic or embryotoxic in the rat, suggesting that the higher sensitivity of the mouse to the developmental toxicity of inhaled methanol is due, at least in part, to greater intrinsic embryonal sensitivity of this species to methanol.

Animals↗
PubMed1996

Developmental toxicity evaluation of sodium fluoride administered to rats and rabbits in drinking water.

Sodium fluoride (NaF; Cas No. 7681-49-4) is used in fluoridating municipal water supplies, resulting in chronic exposure of millions of people worldwide. Because of a lack of pertinent developmental toxicity studies in the literature, sodium fluoride was administered ad libitum in deionized/filtered drinking water (to mimic human exposure) to Sprague-Dawley-derived rats (26/group) on Gestation Days (GD) 6 through 15 at levels of 0, 50, 150, or 300 ppm and New Zealand White rabbits (26/group) on GD 6 through 19 at levels of 0, 100, 200, or 400 ppm. Higher concentrations via drinking water were not practicable due to the poor palatability of sodium fluoride. Drinking water (vehicle) contained less than 0.6 ppm sodium fluoride (limit of detection) and sodium fluoride content of the feed was 12.4 ppm fluoride (rats) and 15.6 ppm fluoride (rabbits). Maternal food, water, body weights, and clinical signs were recorded at regular intervals throughout these studies. Animals were killed on GD 20 (rats) or 30 (rabbits) and examined for implant status, fetal weight, sex, and morphological development. In the high-dose group of both studies there was an initial decreased maternal body weight gain which recovered over time and a decreased water consumption--attributed to decreased palatability. No clear clinical signs of toxicity were observed. Maternal exposure to sodium fluoride during organogenesis did not significantly affect the frequency of postimplantation loss, mean fetal body weight/litter, or external, visceral or skeletal malformations in either the rat or the rabbit. The NOAEL for maternal toxicity was 150 ppm sodium fluoride in drinking water (approximately 18 mg/kg/day) for rats, and 200 ppm (approximately 18/mg/kg/day rabbits. The NOAEL for developmental toxicity was > or = 300 ppm sodium fluoride (approximately 27 mg/kg/day) for rats and > or = 400 ppm (approximately 29 mg/kg/day) for rabbits administered during organogenesis in drinking water. The total exposure to fluoride (mg F/kg body weight/day from food and drinking water combined) in the mid- and high-dose groups for both species was > 100-fold higher than the range at 0.014-0.08 mg F/kg/day estimated for a 70-kg person from food and fluoridated (1 ppm) drinking water.

Animals↗
PubMed2006

Developmental toxicity evaluation of triclopyr butoxyethyl ester and triclopyr triethylamine salt in the CD rat.

Triclopyr (3,5,6-trichloro-2-pyridyloxyacetic acid) is an herbicide used extensively in the control of woody plants and broadleaf weeds, and is often formulated as a triethylamine salt (T-TEA) or butoxyethyl ester (T-BEE). This study evaluated the developmental toxicity of T-TEA or T-BEE in time-mated CD rats gavaged on gestation days 6-15 with 0, 30, 100 or 300 mg/kg body weight(bw)/day. The doses of each compound were equimolar and equivalent to 22, 76, 216 mg/kg bw/day of triclopyr, based on prior studies indicating rapid cleavage of the salt or ester and equivalent pharmacokinetics for the active ingredient. T-TEA caused maternal toxicity, evidenced by the death of one high-dose dam, reduced body weight gain, increased relative liver and kidney weights (300 mg/kg bw/day), reduced feed consumption, and increased water consumption (100 and 300 mg/kg bw/day). Developmental effects were limited to slightly decreased fetal body weight and reduced skeletal ossification at the high dose level. T-BEE caused similar, albeit slightly more severe, maternal toxicity, with three maternal deaths at 300 mg/kg bw/day, and slight maternal effects at 30 mg/kg bw/day. Due to an equivocal increase in malformations, which were mainly clustered in litters from three high dose dams with marked maternal toxicity, the T-BEE study was repeated using 30 dams/group, investigator-blind fetal evaluations, and an additional dose group (5 mg/kg bw/day). In the repeat study, the only reproducible fetal effect was an increased incidence of 14th thoracolumbar rib at 300 mg/kg bw/day. Overall analysis of the two T-BEE studies suggested that the fetal malformations unique to the initial study likely reflected a combination of spontaneous events, exacerbated by marked maternal toxicity. The combined weight of evidence from these developmental toxicity studies, coupled with their known pharmacokinetic equivalence, indicates that T-BEE and T-TEA are not selectively toxic to the fetus. The respective maternal toxicity no-observed effect levels (NOEL) for T-BEE and T-TEA were 5 and 30 mg/kg bw/day, while the NOEL for developmental toxicity was 100 mg/kg bw/day for both compounds.

Abnormalities, Drug-Induced↗
PubMed1993

Effectiveness of sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron) in protecting against uranium-induced developmental toxicity in mice.

The effect of Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate), a chelating agent used in the treatment of experimental poisoning by a number of heavy metals, on uranium-induced developmental toxicity was evaluated in Swiss mice. A series of four Tiron injections was administered intraperitoneally to pregnant mice immediately after a single subcutaneous injection of 4 mg/kg of uranyl acetate dihydrate given on day 10 of gestation and at 24, 48, and 72 h thereafter. Controls received 0.9% saline with or without uranyl acetate. Tiron effectiveness was assessed at 500, 1000 and 1500 mg/kg per day. Amelioration by Tiron of uranium-induced embryolethality was not noted at the two lower doses. The percentage of dead and resorbed fetuses in the Tiron-treated groups was not statistically different from that in the positive control group. However, treatment at 1500 mg/kg per day showed isolated protective effects against uranium fetotoxicity, such as that evidenced by the lack of differences in fetal body weight between this group and the uranium-untreated group, as well as by a decrease in the number of skeletal defects. According to these results, the ability of Tiron to protect the developing mouse fetus against uranium-induced developmental toxicity offers only modest encouragement with regard to its possible therapeutic potential for pregnant women exposed to this metal.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1995

Comparative developmental toxicity of n-butyl benzyl phthalate and di-n-butyl phthalate in rats.

n-Butyl benzyl phthalate (BBP) and di-n-butyl phthalate (DBP) were evaluated and compared for their developmental toxic potential. Pregnant rats were given either BBP or DBP by gastric intubation at a dose of 0.75, 1.0 and 1.25 g/kg on days 7-9, days 10-12 and days 13-15 of pregnancy. Regardless of the days of treatment, a significantly increased incidence of postimplantation loss was found at all doses of BBP and DBP. While treatment with BBP and DBP at doses of 0.75 g/kg and above on days 7-9 or days 13-15 resulted in a significant increase in the incidence of fetuses with malformations, no increase in the incidence of malformed fetuses was found after treatment with BBP and DBP on days 10-12. The incidences of postimplantation loss and malformed fetuses increased as the doses of BBP and DBP were increased. Deformity of the vertebral column and ribs commonly occurred after treatment with BBP and DBP on days 7-9. Cleft palate and fusion of the sternebrae were predominantly observed after treatment with BBP and DBP on days 13-15. The similarity in dependence of gestational days of treatment on the manifestation of developmental toxicity and on the spectrum of fetal malformations caused by BBP and DBP suggests that they may act by the same mechanism, possibly via a common metabolite of these two parent compounds.

Abnormalities, Drug-Induced↗
PubMed1991

Developmental toxicity evaluation of tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) in mice.

Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate), a chelating agent used in the treatment of experimental metal poisoning, was evaluated for developmental toxicity in pregnant Swiss mice. Tiron was administered intraperitoneally on gestational days 6 through 15 at doses of 0, 750, 1500, or 3000 mg/kg/day. Cesarean sections were performed on gestation day 18. All fetuses were examined for external, visceral, and skeletal malformations and variations. Treatment with Tiron resulted in maternal toxicity at 3000 mg/kg/day as evidenced by a high number of deaths, reduced body weight during gestation and increased relative liver and kidney weights. There were no significant differences between treated and control animals on the number of total implants, dead fetuses, or sex ratio. However, embryo fetotoxicity was evidenced at 3000 mg/kg/day by a significant increase in the number of resorptions per litter, and a significant decrease in the average fetal body weight. There were no significant changes in the incidence of abnormalities (expressed as total, individual, external, visceral, or skeletal). The no observable adverse effect level (NOAEL) for maternal and developmental toxicity was 1500 mg Tiron/kg/day.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1989

Preparation and developmental toxicity of monoclonal antibodies against rat visceral yolk sac antigens.

Thirty clones producing monoclonal antibodies (MCAs) to rat visceral yolk sac (VYS) antigens have been prepared. These MCAs localized by immunofluorescence in the VYS endoderm in vitro and were tested for developmental toxicity by intraperitioneal injection of ascites fluid into pregnant rats on day 9 of gestation. Five of the hybridomas produced MCAs that induced embryonic death, malformation, and growth retardation; the other MCAs had no developmental toxicity. Five MCAs, three teratogenic and two nonteratogenic, were tested for their ability to inhibit pinocytosis in the isolated day 17-VYS. Only the teratogenic MCAs were inhibitory, providing further evidence for the hypothesis that teratogenic antibodies interfere with the nutritional supply to the embryo.

Animals↗
PubMed1996

A simulation study of the influence of study design on the estimation of benchmark doses for developmental toxicity.

The benchmark dose (BMD)4 approach is emerging as replacement to determination of the No Observed Adverse Effect Level (NOAEL) in noncancer risk assessment. This possibility raises the issue as to whether current study designs for endpoints such as developmental toxicity, optimized for detecting pair wise comparisons, could be improved for the purpose of calculating BMDs. In this paper, we examine various aspects of study design (number of dose groups, dose spacing, dose placement, and sample size per dose group) on BMDs for two endpoints of developmental toxicity (the incidence of abnormalities and of reduced fetal weight). Design performance was judged by the mean-squared error (reflective of the variance and bias) of the maximum likelihood estimate (MLE) from the log-logistic model of the 5% added risk level (the likely target risk for a benchmark calculation), as well as by the length of its 95% confidence interval (the lower value of which is the (BMD). We found that of the designs evaluated, the best results were obtained when two dose levels had response rates above the background level, one of which was near the ED05, were present. This situation is more likely to occur with more, rather than fewer dose levels per experiment. In this instance, there was virtually no advantage in increasing the sample size from 10 to 20 litters per dose group. If neither of the two dose groups with response rates above the background level was near the ED05, satisfactory results were also obtained, but the BMDs tended to be more conservative (i.e., lower). If only one dose level with a response rate above the background level was present, and it was near the ED05, reasonable results for the MLE and BMD were obtained, but here we observed benefits of larger dose group sizes. The poorest results were obtained when only a single group with an elevated response rate was present, and the response rate was much greater than the ED05. The results indicate that while the benchmark dose approach is readily applicable to the standard study designs and generally observed dose-responses in developmental assays, some minor design modifications would increase the accuracy and precision of the BMD.

Abnormalities, Drug-Induced↗
PubMed1990

The developmental toxicity of orally administered theophylline in rats and mice.

Theophylline (THEO), a widely prescribed anti-asthmatic, was evaluated for developmental toxicity. It was administered continuously on Gestational Days 6 through 15 to pregnant Sprague-Dawley (CD) rats in the feed (0, 0.15, 0.30, or 0.40%) and to pregnant Swiss (CD-1) mice in the drinking water (0, 0.075, 0.15, or 0.20%). Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day, while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats, maternal weight gain parameters (weight gain during gestation and treatment, as well as corrected weight gain) decreased at 0.40%. While food consumption was lower only in the 0.40% treatment group, water consumption was higher in all treated groups. There was a dose-related decreasing trend in gravid uterine weight. The number of live fetuses per litter decreased at 0.40% and the average male and female fetal weight per litter decreased at 0.30 and 0.40%. There was no increase in malformations. In mice, maternal corrected body weight and weight gain during gestation decreased at 0.15 and 0.20%, and weight gain during treatment and gravid uterine weight decreased at 0.20%. Water consumption was reduced by as much as 30-45% of controls at 0.15 and 0.20%, respectively, while food consumption did not change with THEO treatment. There was an increase in percentage resorptions per litter and a decrease in the average male and female fetal weight per litter at 0.15 and 0.20%. An increasing trend was noted for percentage malformed fetuses per litter, and percentage litters with externally malformed fetuses were slightly increased in the mid- and high-dose groups. However, these increases were not statistically significant. In summary, there were developmental effects seen in rats at a dose (0.30%) that did not produce overt maternal toxicity, but the adverse developmental effects in mice were observed at doses that caused reduced maternal water consumption and body weight gain. It is possible that water deprivation contributed to the effects seen in mice after THEO treatment. For maternal toxicity, no observable adverse effect levels (NOAELs) were 218 mg/kg for rats and 282 mg/kg for mice. NOAELs for developmental toxicity were 124 mg/kg for rats and 282 mg/kg for mice. These NOAELs are approximately 10- to 30-fold greater than doses required to maintain humans on serum THEO concentrations that are clinically useful.

Abnormalities, Drug-Induced↗
PubMed2005

Predicting the risk of developmental toxicity from in vitro assays.

Reproductive toxicity refers to the adverse effects of a substance on any aspect of the reproductive cycle, including the impairment of reproductive function, the induction of adverse effects in the embryo, such as growth retardation, malformations, and death. Due to the complexity of the mammalian reproductive cycle, it is impossible to model the whole cycle in a single in vitro system in order to detect chemical effects on mammalian reproduction. However, the cycle can be broken down in its biological components which may be studied individually or in combination. This approach has the advantage that the target tissue/organ of a developmental toxicant can be identified. In specific areas of developmental toxicity, a number of useful and promising in vitro models are already available. The individual tests may be used as building blocks of a tiered testing strategy. So far, research has focused on developing and validating tests covering only a few components of the reproductive cycle, in particular organogenesis of the embryo, reflecting important concerns for teratogenic chemicals. During the last three decades, a number of established models and promising new developments have emerged that will be discussed, e.g. culture of mammalian embryos and embryonic cells and tissues and the use of embryonic stem cells.

Animals↗
PubMed1996

Developmental toxicity study of mangafodipir trisodium injection (MnDPDP) in New Zealand white rabbits.

Mangafodipir trisodium injection (MnDPDP) is an intravenously administered manganese chelate undergoing clinical evaluation for magnetic resonance imaging contrast enhancement of the hepatobiliary system. The anticipated single clinical dose for adults is 5 micromol/kg body wt. MnDPDP, as well as the inorganic salt, MnCl2, was previously shown to induce a specific syndrome of skeletal abnormalities in rats. The syndrome malformations included angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. The objective of the present study was to assess the developmental toxicity of MnDPDP in a second mammalian species, the New Zealand White rabbit. MnDPDP was intravenously administered daily to groups of rabbits (22 per group) on Days 6 through 18 of pregnancy at doses of 0 (saline), 5, 20, 40, and 60 micromol/kg MnDPDP. Fetuses were examined on Day 29 of pregnancy for external, visceral, and skeletal abnormalities. Treatment with MnDPDP did not result in overt symptoms of maternal toxicity, and there were no significant effects on maternal body weight gains or feed consumption. The maternal no-observed-adverse-effect level (NOAEL), therefore, was 60 micromol/kg MnDPDP. Treatment with MnDPDP resulted in a significant increase in postimplantation loss at 60 micromol/kg, but there was no significant increase in external, visceral, or skeletal abnormalities at any dose. The developmental NOAEL for MnDPDP, therefore, was 40 micromol/kg. These results indicate that the developmental toxicity profile of MnDPDP differs considerably in the rat and rabbit. In the rat, this compound induces specific skeletal abnormalities, whereas in the rabbit, embryo/fetal toxicity is the most sensitive developmental endpoint with no evidence for the induction of specific skeletal abnormalities.

Abnormalities, Drug-Induced↗
PubMed1987

Developmental toxicity of ethanol in Drosophila melanogaster.

Ethanol was tested for teratogenicity in Drosophila melanogaster. Treatment consisted of rearing the fly larvae in media containing initial ethanol concentrations of 0%, 4%, 8%, or 14% by weight. Emerging flies were inspected for gross malformations. A low frequency of malformations was seen among controls (0.82%), increasing to 10.36% of emerging adults at the highest ethanol dose. The most common malformation involved the legs (segments missing or distorted or complete absence) and wings (uninflated, distorted, or absent). Less frequent defects included fused or missing mouth parts and missing halteres. Also, by exposing staged larvae to ethanol and examining the emerging flies, developmental stage sensitivity of Drosophila was investigated in terms of timing of treatment initiation. The results suggested that the incidence of defects increased with length of exposure. These results support the assumption that ethanol itself is the causative agent in ethanol-induced developmental toxicity and further support the use of Drosophila for developmental toxicity screening.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Lack of maternal and developmental toxicity in mice given high doses of aluminium hydroxide and ascorbic acid during gestation.

The present study was conducted to assess if the concurrent ingestion of high doses of aluminium hydroxide and ascorbic acid might result in maternal and developmental toxicity in mice. Three groups of pregnant Swiss mice were given by gavage daily doses of aluminium hydroxide (300 mg/kg), ascorbic acid (85 mg/kg), or aluminium hydroxide (300 mg/kg) concurrent with ascorbic acid 85 (mg/kg) on gestational days 6-15. A fourth group of animals received distilled water and served as control group. Dams were killed on gestation day 18 and foetuses were examined for external, internal, and skeletal abnormalities. The reproductive data did not show embryotoxic or foetotoxic effects in any group. No gross, internal, or skeletal malformations or variations related to the different treatments were found. There were no significant differences between control and treated groups on the aluminium levels in maternal liver and bone as well as in whole body foetuses, whereas aluminium concentrations were significantly higher in placenta and kidney of dams receiving aluminium hydroxide and aluminium hydroxide plus ascorbic acid than in those from the control group. Although in this study aluminium hydroxide was given at doses higher than those usually consumed by pregnant women, no signs of maternal or developmental toxicity were observed when the compound was given alone or concurrently with high doses of ascorbic acid.

Aluminum Hydroxide↗
PubMedDate not supplied

Influence of dietary folic acid on the developmental toxicity of methanol and the frequency of chromosomal breakage in the CD-1 mouse.

The proposed increased use of methanol (MeOH)-based fuels raises the concern for an increased risk for MeOH toxicity. MeOH, which is detoxified in part via a folate-dependent pathway, is known to be teratogenic in rodents. Previous observations have implicated maternal folate status as a critical modulator for the developmental toxicity of MeOH. The current study extends these findings, examining the effect of maternal dietary folate intake on fetal folate stores, as well as identifying a possible marker for the prediction of the developmental toxicity of MeOH. Virgin female CD-1 mice were assigned to diets containing either 400 (marginal) or 1200 (control) nmol folic acid (FA)/kg, and and 1% succinylsulfathiazole for 5 weeks prior to mating and throughout breeding and gestation. From gestation day (GD) 6 through 10 dams were given by gavage deionized, distilled water (dH2O) or MeOH at 2.5 g/kg body weight, twice daily. On GD 18, mice were weighed and killed and the liver, kidneys, and gravid uteri removed and weighed. Implantation sites, live and dead fetuses, and resorptions were counted; fetuses were weighed individually and examined for cleft palate and exencephaly. The marginal FA dietary treatment resulted in low maternal liver (50% reduction) and red cell folate (30% reduction) concentrations, as well as low fetal tissue folate concentrations (60 to 70% reduction) relative to the adequate FA dietary groups. Marginal FA treatment alone resulted in cleft palate in 13% of the litters; there were no litters affected with cleft palate in the adequate FA-control group. Marginal FA-MeOH treatment resulted in a further increase in the litters affected by cleft palate (72% of litters affected). The percent of litters affected by exencephaly was highest in the marginal FA-MeOH group. The frequency of micronuclei in maternal and fetal reticulocytes, a marker for chromosomal abnormalities, was not influenced by either the marginal FA diet or by MeOH treatment. These results show that marginal folate deficiency in pregnant dams significantly increases the teratogenicity of MeOH.

Abnormalities, Drug-Induced↗