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Results for “developmental toxicity”

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PubMed1978

Oxidative metabolism of dimethylnitrosamine: correlation with toxicity.

The relationship between oxidative metabolism and acute toxicity of dimethylnitrosamine (DMN) was examined in neonatal and adult rats to take advantage of developmental changes in activity of the metabolizing enzymes. The objective was to determine the extent to which CO2 production from DMN is correlated with toxicity. Neonatal rat liver and kidney demonstrated the ability to metabolize DMN. This ability progressed to a maximum activity in liver between the 5th and 21st d of age and in kidney between the 15th and 21st d of age. After weaning, the activity of DMN oxidation decreased with age in both tissues. Evidence is also presented to suggest that more than one enzyme may be responsible for the oxidation of DMN to CO2 and that the predominance of individual enzymes varies as the neonate develops. Estimates of LD50 values, used to quantitate the acute toxicity of DMN at various ages, suggest that the rat is most sensitive to DMN toxicity at 5 d of age; however, conversion of DMN to CO2, both in vitro and in vivo, was not well correlated with acute toxicity.

Age Factors↗

PubMed1979

Toxicity of selenium to developing Xenopus laevis embryos.

Se in the form of sodium selenite is toxic to Xenopus laevis embryos and tadpoles continuously exposed to concentrations above 1 ppm. Concentrations of 2 ppm and above result in severe developmental abnormalities and increased mortality. Uptake and loss of radioactive Se from water are rapid, but depuration is not complete indicating that some Se can remain bound by the organism. The facts that Se is toxic at low levels to Xenopus embryos and tadpoles, can cause developmental abnormalities, and accumulates in tissues suggest that increased release of Se compounds into the environment poses a potential threat to aquatic organisms.

Abnormalities, Drug-Induced↗

PubMed1977

Variation in the direction of selection applied by pentenol to the alcohol dehydrogenase locus in Drosophila melanogaster.

This paper describes selective effects of pentenol-impregnated media on six genotypes at the alcohol dehydrogenase (Adh) locus in D. melanogaster. In the laboratory population studied, developmental times of pre-adults homozygous for an alcohol dehydrogenase "null" allele increased with increasing pentenol concentrations. The developmental times of the other five genotypes, which produced active alcohol dehydrogenases, increased slightly at pentenol concentrations up to 0-0033%, but above this concentration they decreased markedly. In fact on 0-067% pentenol, the highest concentration tested, developmental times of these five genotypes were between 9 and 24 h less than their developmental times on media lacking pentenol. The magnitude of the reduction in developmental time differed significantly between genotypes and was positively correlated with alcohol dehydrogenase activity. Pentenol had toxic effects on adults and significant differences were found between survival percentages of adults of different genotypes on pentenol-impregnated media. These survival percentages were negatively correlated with alcohol dehydrogenase activities. Therefore selective differences between genotypes in adult survival were negatively correlated with those in developmental times. The variations in the direction of selection are discussed in terms of their possible biochemical basis and their effects on the maintenance of Adh polymorphisms.

Alcohol Oxidoreductases↗

PubMed1978

Influence of age on metal metabolism and toxicity.

The metabolism and toxicity of lead, cadmium, mercury, and manganese in the postnatal period was studied in rats. Absorption, whole body retention, and organ distribution of 203Pb, 115mCd, 203Hg, and 54Mn were determined after oral and parenteral administration of these radioisotopes. The acute oral toxicity (LD50) was determined after a single application of metal chlorides. The results obtained in sucklings show a very high intestinal absorption of all metals which is partly attributed to milk diet; a higher whole body retention, higher blood levels and a much higher accumulation in the brain; and a higher oral toxicity. These results indicate age specific differences in the pharmacokinetics of metals in sucklings. It seems reasonable to consider the early neonatal age as a critical period for metal accumulation and therefore for metal toxicity. The results are interpreted on the basis of current concepts of developmental physiology and pharmacology and suggestions for future research trends are made.

Aging↗

PubMed2026

Cloning of human DING: Developmental expression and downregulation by EtOH in-utero.

INTRODUCTION: An estimated 15-20% of women consume alcohol (EtOH) during pregnancy. Women with alcohol use in early pregnancy are likely to have a child with fetal alcohol spectrum disorders (FASD). Recently, we reported neuroprotective effects of human DING (a member of the DING family of phosphatases) against EtOH-mediated toxicity in rats and in human fetal cortical neurons in vitro. Now, we report the sequencing and developmental expression patterns of endogenous DING in human fetal brain. METHODS: DING cDNA was cloned from human U87MG astrocytoma cells with primers specific to the plant DING gene and known prokaryotic DING genes. This cDNA was used to prepare antibodies. The full-length human DING gene p38hu (1095 nucleotide bases) is flanked by the first initiating codon, ATG, and the last, stop codon, TAA. Post-mortem fetal tissues and maternal blood were collected during pregnancy between 8 and 37 weeks' gestation. The developmental, spatial, and temporal expression of DING protein in fetal brain tissue was analyzed by immunohistochemistry. Developmental expression of DING in fetal brain and placenta was quantified by qWestern blots. DING promoter expression was assayed by ddPCR. Statistical analysis included ANOVA. RESULTS: Sequencing revealed different-sized genomic DNA clones. The anti-DING antibody detected proteins ranging in size from 35 to 40 kDa, and high molecular weight precursor protein in fetal brain and placenta. DING protein was present in fetal brain at early stages and its level was increased at later gestational ages. The DING promoter was expressed in fetal brain, neurospheres, and fetal brain-derived exosomes. DING levels were reduced in samples exposed to maternally consumed alcohol. CONCLUSIONS: Because DING is neuroprotective, its reduced expression in fetuses exposed to alcohol may suggest a mechanism that contributes to the pathogenesis of FASD, which could lead to the development of therapeutic tools aimed at preventing, ameliorating or reversing this prevalent group of syndromes that are implicated in as many as 5% of births world-wide.

DING gene cloning↗

PubMed1977

Toxicity to bilirubin in neonates: infant development during first year in relation to maximum neonatal serum bilirubin concentration.

Neurologic and developmental performance during the first year of life was correlated with maximum neonatal serum bilirubin levels for 27,000 infants in the Collaborative Perinatal Project. The infants were grouped by race and by five birth weight/gestational age categories to control for the effect of these factors on hyperbilirubinemia and developmental outcome. Low mean eight-month motor scores and delayed one-year motor development were associated with serum bilirubin levels in the range of 10 to 14 mg/dl and above. This relationship was strongest for low-birth-weight/short-gestational-period infants. A persistent association of developmental outcome with hyperbilirubinemia was found over and above the variation of maturity within the birth weight/gestational age categories.

Bilirubin↗

PubMed1978

The behavioral toxicology of metals.

Many metals express their toxic actions through behavioral disturbances. Such disturbances most often reflect impairment of central nervous system function, but also may arise from deleterious effects in other systems. Numerous factors influence behavioral toxicity. Uptake into brain obviously is important; the chemical form of the metal (e.g., inorganic versus organic) and route of exposure are key determinants of brain penetration. Species differences in toxicity may arise from differences in kinetics (e.g., blood-brain ratio) and affinity to target brain structures. Developmental stage is still another crucial variable, but the young organism is not necessarily the most susceptible, and nutritional considerations confound the standard paradigms. Furthermore, parametric variations of behavioral functions can no more be ignored than dose-effect functions, a principle exemplified in research on methylmercury. Unwarranted loyalties to traditional psychological tests may be one source of the current dispute about safe levels of lead simply because parametric variations of clearly specified functions are beyond the scope of such instruments.

Aging↗

PubMed1979

Monosodium glutamate in the chick embryo: lack of obvious toxic or teratogenic effects when administered at 24 hours incubation.

The administration of monosodium glutamate (MSC) to chick embryos at 24 hours did neither produce gross developmental defects nor influence growth by 72 hours total incubation. The concentrations of MSG administered ranged from 0.3 to 46.6%, the volumes injected being 0.05, 0.1, or 0.2 ml. Several injection methods were evaluated. It is suggested that injection into the centre of the yolk is the most effective way to give water-soluble treatments during this period of development.

Animals↗

PubMed1977

Toxic effects of caffeine on growth and metamorphosis of the larvae of Musca domestica.

The somatic effects of caffeine were studied by using a rapidly proliferating insect developmental system. The results show that caffeine is a potent growth inhibitor of housefly larvae. Puparium formation is also severely affected, which sud when larvae are treated with higher concentrations of caffeine. The results indicate that caffeine may have several target sites of action; these are briefly discussed.

Animals↗

PubMed1978

Metal toxicity to embryos and larvae of eight species of freshwater fish-II: copper.

Fish larvae and early juveniles of all species tested (brook trout, rainbow trout, brown trout, lake trout, northern pike, white sucker, herring, and smallmouth bass) were more sensitive to copper than the embryos. Embryo survival was affected only at the higher concentrations tested, for all species except the rainbow trout. The concentrations of copper that caused significant effects on the larval standing crop were similar for all species (31.7-43.5 microgram Cu/1) except the northern pike, which seemed to be considerably more resistant (104.1 microgram Cu/1). Copper concentrations shown to have no significant effects on the early developmental stages of these species are considered close estimates of the copper concentrations that would have no measurable adverse effects during a complete life cycle toxicity test under similar test conditions.

Animals↗

PubMed2026

Neurodevelopmental toxicity of 2-(Methylthio)benzothiazole (MTBT) in zebrafish: Insights into PTGS2- associated dysregulation of the neuroactive ligand-receptor interaction pathway.

2-(Methylthio)benzothiazole (MTBT), an important derivative of benzothiazoles, has extensive applications in industrial processes, pharmaceuticals, and environmental monitoring. It can enter aquatic environments through surface runoff and has been detected at relatively high concentrations in various environmental systems. However, studies investigating the aquatic toxicity of MTBT remain limited. In this study, zebrafish embryos were exposed to MTBT at concentrations of 0, 10, 100, and 1000 μg/L for 144 h to evaluate its developmental and neurotoxic effects. MTBT exposure significantly reduced the survival rate, hatching rate, spontaneous movement, and body length of zebrafish larvae. MTBT also impaired locomotor behavior, reduced fluorescence of Tg(huc:eGFP) larvae in the central nervous system and inhibited motor neuron axonal development. Protein-protein interaction network and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that MTBT-induced neurotoxicity may be associated with disruption of the neuroactive ligand-receptor interaction pathway. Further validation experiments revealed that MTBT induced oxidative stress, inflammation, and apoptosis, suggesting that these adverse effects may underlie its neurodevelopmental toxicity. Collectively, these findings provide biological evidence that MTBT induces neurodevelopmental toxicity in zebrafish larvae and suggest that dysregulation of the PTGS2-related neuroactive ligand-receptor interaction pathway may be involved in this process.

2-(Methylthio)benzothiazole (MTBT)↗

PubMed1979

[Results of long-lasting drug intake on child development; clinical and electrophysiological study during drug withdrawal].

The case of a child under continuous anticonvulsant medication, especially barbiturate, since the age of 8 months for atypical seizures is reported. Medication was withdrawn when the child was 7.7 years old. The child was then under care in a Day Hospital with an autistic-like syndrome associated with important disturbances of sleep-waking regulation, complete learning incapability and major EEG abnormalities. The EEG paroxysmal discharges observed in the waking and all-night sleep records gradually decreased and then disappeared as the withdrawal was pursued over a period of several months. During the same period, the child's behaviour markedly improved and his sleep disturbances disappeared. The possibility of iatrogenic effects of early and continuous anti-convulsant therapies is discussed, even though the drug plasma levels remain within ranges generally considered as non-toxic.

Anticonvulsants↗

PubMed1979

Developmental abnormalities induced by 6-mercaptopurine in the hamster.

Pregnant hamsters were given varying doses of 6-mercaptopurine (6MP) at various times during gestation. The fetuses were examined for both gross and histological malformations which showed that the toxic and teratogenic effects of 6MP were dose and time dependent. The most severe gross malformations induced by 6MP were cleft palate, micrognathia and agnathia, microglossia, short limbs, and gut herniation. Grossly normal appearing fetuses, greated during late gestation, showed malformations at the tissue and cellular level. The effects of 6MP in hamster was compared with other species, and with other growth-supressive agents, and it was deduced that the teratogenicity of 6MP is species and tissue specific. Also, it was recommended that histological observations be made an integral part of the teratological safety analysis.

Abnormalities, Drug-Induced↗

PubMed1979

Physiological and neurobehavioral alterations during development in lead exposed rats.

Neonatal rats were exposed to lead (Pb) from parturition to weaning via the milk of dams which consumed 0 (tap water), 0.02% or 0.2% PbAc2 solutions. To determine if this regimen altered physiological and neurobehavioral development, responses to a battery of sensory-motor tests were evaluated during maturation and as adults. The tests were: visual evoked responses (VER), temperature regulation, maximal electroshock seizure patterns, reflex patterns, and neuromuscular performance. Overall results revealed that the Pb-exposed group compared to controls exhibited delayed maturation, altered developmental patterns and long-term CNS disturbances. Additionally, low-level strychnine administration during development caused additive interactions with both Pb groups, uncovering subtle effects of toxicant exposure. These sensitive and quantifiable techniques proved useful for assessing CNS functioning following perinatal insult, and except for the VER, are simple to conduct and cost efficient because they require a minimal amount of personnel training, equipment cost and time invested per animal. These screening tests also suggest further areas of study and may indicate the mechanism(s) responsible for the deficit.

Animals↗

PubMed1979

Influence of 6-mercaptopurine on the prenatal development of the rat cortex.

The prenatal cortex development after the application of 6-Mercaptopurine (6-MP) was studied in the rat embryo. 24 h after application of a single dose of 6-MP on day 12, 13, 14 or 15 of gestation first cell lesions occured in the form of necroses. 48 h after injection of the drug these necroses were most pronounced. Their extent and distribution pattern was, however, dependent on the developmental stage. In the early developmental phase, on days 12 and 13, massive necroses could be observed in the intermediate zone. At later stages of development (drug application on day 14 or 15) damaged cells could occasionally also be found scattered over the whole ventricular wall. The late toxic response to 6-MP treatment suggests that, after incorporation of metabolites of the agent into DNA during the S-phase, at least one additional S-phase is completed before the disturbance created in a cell is sufficient to cause necrosis. The necrosis may be a result of an action of 6-MP directly on DNA or via an affect on transcription. The different extent of the lesion during the various developmental phases suggests different growth dynamics of the cortex.

Animals↗

PubMed1977

The effect of two pesticides, Miedzian 50 and Gesagard 50, on the development of tadpoles of Rana temporaria.

Tadpoles of the frog, Rana temporaria, in two developmental stages were subjected to the action of aqueous suspensions of two pesticides--Miedzian 50 and Gesagard 50. The changes caused by these substances pertain chiefly to the alimentary canal, brain, and muscles, and are connected with the developmental stage of the animals. Miedzian 50 caused a partial sytolysis in the cells of the intestinal epithelium and the parenchyma of the liver. Gesagard 50 was more toxic; under its action strong degenerative changes were obtained in the alimentary canal and the brain. Also, disorders in the development of tadpoles were observed. These consisted in a partial inhibition of growth and a retardation of the process of completion of the operculum as compared with control animals.

Aging↗

PubMed1976

Perinatal development of conjugative enzyme systems.

The problems and priorities involved in studying the role of conjugagive enzymes in developmental pharmacology are discussed and evaluated. The relative rates of UDP glucuronyltransferase and beta-glucuronidase were studied during perinatal development in hepatic and extrahepatic tissues to determine the net balance of glucuronidation or deglucuronidation at different developmental stages. In general, deglucuronidation predominated over glucuronidation in fetal tissues whereas the converse was evident in adults. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an extremely toxic contaminant of some organochlorine compounds, was shown to be a potent inducer of some hepatic and extrahepatic drug-metabolizing enzymes. TCDD, administered during gestation, induced the postnatal activities of p-nitrophenol glucuronyltransferase and benzpyrene hydroxylase in rats. Foster mother experiments revealed that the postnatal induction was caused primarily by newborn exposure to TCDD in the mother's milk. Tissue distribution experiments with TCDD-14C confirmed these findings. Although TCDD induced non-steroid glucuronidation, no significant effects were evident on the postnatal development of steroid glucuronidation. The synthetic estrogen diethylstilbestrol (DES) is metabolized primarily by glucuronidation. The postnatal development of DES glucuronidation, like the steroid pathway, was not affected by gestational TCDD treatment. The fetal distribution of DES and DES-glucuronide, at different stages of development, correlated well with the perinatal development of steroid glucuronyltransferase activity.

Animals↗

PubMed1978

Effects of 3-trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332), a new enzyme inducer on the central nervous system of rats. Part II.

3-Trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332, Zixoryn) had been reported to induce the hepatic mixed function oxydase system similarly to phenobarbital [5]. CNS effects of both compounds were tested on immature rats, age 14 days, in the developmental phase of quick morphological and functional growth. A marked difference in total locomotor activity, exploratory behaviour and reaction to both compounds between immature and adult rats is reported. Toxicity of RGH-3332 is favourable in itself and in comparison to that of phenobarbital in both age groups. CNS effects are neglibile compared to the main effect, they can be observed only in 6--8fold doses eliciting maximum inductive response in case of RGH-3332, while CNS effects are caused by phenobarbital at lower doses than that required for maximum inductive response.

Animals↗