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Results for “developmental toxicity”

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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↗

PubMed1978

Methionine toxicity in chicks and poults.

In feeding experiments with poults, 2% DL-methionine caused a marked growth depression which could be alleviated by the addition of glycine. Homocystine at an equimolar level depressed growth to a lesser degree than methionine, and this growth depression could be alleviated by glycine. Betaine could alleviate the growth depression of homocystine but not that of methionine. Methionine-fed poults developed a cervical paralysis similar to that of a folic acid deficiency, but the addition of this vitamin at several times the requirement was ineffective in counteracting the toxicity of methionine in either chicks or poults.

Animals↗

PubMed2026

Genome-Wide Characterization of the ZIP Transporter Family in Sea Island Cotton (Gossypium barbadense L.) and Expression Profiling Under Heavy Metal and Pathogen Stresses.

G. barbadense represents an indispensable germplasm resource for high-quality textile fiber and disease resistance; nevertheless, systematic information regarding its ZRT/IRT-like protein (ZIP) gene family remains limited. Here, a total of 46 GbZIP genes were identified across the G. barbadense genome. Comprehensive bioinformatic investigations revealed uneven chromosomal distribution and confirmed that segmental/whole-genome duplications, supplemented by localized tandem duplications, drove family expansion. Members clustered within the same phylogenetic clades shared conserved motif organization and gene architecture, while promoter regions harbored abundant cis-acting elements associated with phytohormone and stress signaling. Transcriptome profiling indicated distinct expression patterns across vegetative/reproductive tissues, fiber and ovule developmental stages, and diverse abiotic stress conditions (cold, hot, drought, and salt). Quantitative Real-Time PCR (qRT-PCR) further validated that several GbZIP candidates exhibited temporal expression variations upon exposure to cadmium toxicity, V. dahliae infection, and combined Cd-V. dahliae stress. Specifically, GbZIP13, GbZIP18, GbZIP27, and GbZIP36 displayed prominent broad-spectrum responses to all three stress conditions, whereas GbZIP16, GbZIP29, and GbZIP30 showed stress-specific regulatory divergence. Overall, this study aims to systematically analyze the evolutionary characteristics and expression patterns of the GbZIP family, and to specifically evaluate the response differences under Cd stress, V. dahliae stress, and combined stress, in order to identify potential key candidate genes.

Gossypium barbadense↗

PubMed1979

Evaluation of teratogenicity and behavioral toxicity with inhalation exposure of maternal rats to trichloroethylene.

Female rats were exposed by inhalation to trichloroethylene (TCE) vapors at a concentration of 1800 +/- 200 ppm to determine whether exposure before mating and during pregnancy is more detrimental to reproductive outcome than exposure either before mating alone or during pregnancy alone. Four treatment groups were utilized in a two by two factorial design: exposure to TCE for 2 weeks before mating and during the first 20 days of pregnancy; TCE before mating and filtered air during pregnancy; filtered air before mating and TCE during pregnancy; and filtered air before and during pregnancy. Significant elevations in skeletal and soft tissue anomalies, indicative of developmental delay in maturation rather than teratogenesis, were observed in the group exposed during pregnancy alone. The mixed function oxidase enzymes, ethoxycoumarin and ethoxyresorufin, indicative of cytochrome P-450 and P-448 activities, respectively, were measured in maternal and fetal livers, as well as livers of non-pregnant females, and showed variable levels of activity not uniformly related to treatment or pregnancy. Behavioral evaluation of offspring indicated a lack of treatment effect in tests of general activity levels at 10, 20 and 100 days of age. However, a reduction in postnatal body weights was seen in offspring from mothers with pregestational exposure. No results indicative of treatment-related maternal toxicity, embryotoxicity, severe teratogenicity or significant behavioral deficits were obtained in any of the treatment groups.

Abnormalities, Drug-Induced↗

PubMed1977

L-Arginine kinase from tobacco hornworm, Manduca sexta (L.). Purification, properties, and interaction with L-canavanine.

Arginine kinase (adenosine 5'-triphosphate: L-arginine phosphotransferase, EC 2.7.3.3) was purified from the larvae of the tobacco hornworm, Manduca sexta (L). This enzyme catalyzes the production of L-phosphoarginine, which is the principal reserve of high energy phosphate compounds in insect muscle. The enzyme also phosphorylates L-canavanine, a guanidinooxy analogue of arginine which severely disrupts all developmental stages of this insect. Evaluations of certain kinetic and thermodynamic parameters of the reactions with arginine and canavanine suggest that reactions known to be much more sensitive to canavanine, such as protein synthesis or genome expression, rather than phosphagen formation and function account for the pronounced toxicity of canavanine in this insect. Sedimentation equilibrium and electrophoresis on polyacrylamide gels containing sodium dodecyl sulfate indicate that this insect enzyme has a molecular weight of about 40,000. This value is consistent with molecular weights of arginine kinases of non-insect arthropods. Its amino acid composition is also very similar to that of other arthropod arginine kinases. Km values for the enzyme are: L-arginine, 0.5 mM; Mg-ATP, 2.5 mM; L-canavanine, 22 mM; L-phosphoarginine, 0.7 mM; Mg-ADP, 0.45 mM; and L-phosphocanavanine, 27 mM. Turnover numbers (expressed as moles of product per min per mol of enzyme) are: L-arginine, 8,320; L-canavanine, 1,635; L-phosphoarginine, 25,875; and L-phosphocanavanine, 3,040. The apparent equilibrium constants at 37 degrees for phosphagen formation are 0.44 with arginine and 0.1 with canavanine. A procedure for L-phosphocanavanine synthesis is also presented.

Adenosine Triphosphate↗

PubMed1977

Development of bilirubin metabolism and transport in the neonate.

Comprehensive physiologic study of the developmental processes of bilirubin metabolism and transport reveal a complex interaction of various steps. Phase I Physiologic Jaundice results from the simultaneous increase in bilirubin load presented to the liver and decrease in bilirubin conjugating capacity. Phase II appears to result from a mild decrease in hepatic uptake capacity, coupled with the continuing increase in bilirubin load. Since these results are based upon studies of newborn rhesus monkeys, confirmatory studies in human neonates are required. Perhaps the most challenging aspect of these observations relates to the concept of a developmentally determined delicate imbalance between two functions. It is unlikely that pharmacologic agents could radically alter a single function. Therefore, it is perhaps more realistic to think that drug treatments which only slightly alter two functions simultaneously but in the appropriate directions could more effectively reduce the risk of toxicity. Thus, a mild increase in bilirubin conjugation coupled with a small but significant decrease in bilirubin load could markedly alleviate the severity of physiologic jaundice.

Bilirubin↗

PubMed1979

Developmental pharmacology and the Ah locus: regulatory and temporal genes affecting teratogenesis.

The "Ah cluster" is a group of regulatory, temporal, and structural genes associated with the inducibility of numerous monooxygenase activities by polycyclic aromatic compounds such as 3-methylcholanthrene. Age- and tissue-specific differences in temporal control of these enzymes are shown to exist. These differences could be important in the age- and tissue-specific differences in one's susceptibility to cancer, drug toxicity, and birth defects. Allelic differences at the Ah locus are shown in the mouse to be associated with benzo[a]-pyrene-produced in utero toxicity: increased stillborns, resorptions, and dysmorphogenesis, plus decreased fetal weight.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1979

Effects of fusion in pairs on the development of anurans Rana dalmatina and Rana esculenta.

Of 252 heterospecific, parabiotic pairs of Rana dalmatina and R. esculenta, fused during embryonic life, 87 died because the larva of R. dalmatina died at the beginning of its circulation. Later 89 pairs died when the R. esculenta larva died suddenly at the beginning of its independent feeding. Seventy-one pairs survived at the end of the metamorphic climax. Death in the first case is considered to result from some toxic effect, in the second from an immunological reaction. In the surviving pairs the duration of larval development in the rapidly developing species, i.e., R. dalmatina, was extended from two months to about four months, and in the more slowly developing species, i.e., R. esculenta, was reduced from about five months to about four. These changes in developmental rates are discussed in terms of changes in the concentration of the hormones controlling the rate of development due, in turn, to the parabiosis of embryos with different genetic constitution.

Animals↗

PubMedDate not supplied

Perinatal changes in the absorption of trace elements.

Fetal demands for many of the essential trace elements change markedly during the terminal stages of development. Susceptibility to deficiency during early postnatal life is influenced by the extent of fetal trace element reserves, by inadequacies in the supply of some elements in maternal milk and by postnatal changes in the efficiency of trace element absorption. The efficiency with which essential and some toxic trace elements are absorbed after birth is a function both of age and of diet. Homeostatic mechanisms for the control of iron absorption are poorly developed in the newborn. There are indications that pinocytotic absorption of iron, copper, lead and cadmium may occur at this stage and account for the high efficiency with which these elements are absorbed from a liquid diet. Evidence of developmental changes in the enterohepatic recirculation of such metals is considered and an account is given of our very inadequate understanding of the processes of trace metal absorption in the weaned animal.

Aging↗

PubMed2026

Sex and tissue resolved co-expression networks reveal a female placental-brain axis protective against prenatal PCB exposure.

BACKGROUND: Neurodevelopmental disorders have a strong male bias that is poorly understood. The placenta provides molecular information about environmental interactions with genetics (including biological sex) that shape developmental processes in the brain. We investigate placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). RESULTS: To understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta RNAseq data, we use weighted gene correlation network analysis (WGCNA) to create gene networks that could be compared across sex or tissue. WGCNA reveals that expression within most correlated gene networks is significantly and strongly associated with PCB exposure, but frequently in opposite directions between male-female and placenta-brain comparisons. In WGCNA and differentially expressed gene analyses, more transcriptional changes are observed in male brain than placenta, but the reverse is seen in females. Furthermore, female X-inactive specific transcript (Xist) levels correlate with sex-specific and non-monotonic PCB dose response, suggesting an X-linked protective epigenetic mechanism. The transcriptomic effects of low-dose PCB exposure are significantly opposed by dietary folic acid supplementation across both sexes but are strongest in female placentas. PCB and folic acid interacting gene networks are enriched in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipid, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. CONCLUSIONS: A female protective effect in response to prenatal PCB exposure appears to be mediated by dose-dependent sex differences in transcriptional modulation of placental metabolic pathways.

Female↗

PubMed1979

Chronic toxicity of sodium nitrite in mice, with reference to its tumorigenicity.

Sodium nitrite has been widely used as one of the most effective food additives to tinge color on cured meat. However, it has been elucidated that this chemical is not merely a precursor of N-nitroso compounds, many of which are strongly carcinogenic, but also a mutagenic substance in biological tests. In order to ascertain the possible tumorigenicity of sodium nitrite itself, chronic toxicity of the agent in mice, by means of daily oral administration as drinking water for more than 18 months, in the concentration of 0.5 (maximum tolerated dose), 0.25, and 0.125%, was tested. As a result, development of various tumors, including thymic lymphoma, nonthymic lymphoid leukemia, pulmonary adenoma and carcinoma, and benign and malignant tumors in soft tissue, was seen in these mice. However, as to the incidence of tumors as well as the developmental time of each histologically classified tumor, no apparent difference was detected between those in the experimental groups and the control group.

Animals↗

PubMed1976

Teratogenic and toxicological examination of 2,4,5-trichlorphenoxyacetic acid in developing chick embryos.

Practical grade 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), dissolved in dimethylsulfoxide (DMSO), was injected into the air space of fertilized chicken eggs prior to incubation. Doses of 2,4,5-T administered were 12.5, 25, 50, 75, 100, and 125 mg/kg to determine herbicide toxicity on the first day of incubation. A similar group was studied on day 5 of incubation with doses of 2,4,5-T at 50, 75, 100 and 250 mg/kg. LD50 was estimated to be 62 mg/kg on day zero and 68 mg/kg on day 5. Additionally, embryos were exposed to 2,4,5-T at 50 mg/kg on day zero of gestation and sacrificed after 48 h of incubation. Serial sections were examined for teratological and developmental anomalies. None were found.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed2026

Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease.

Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl-/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.

Chloride Channels↗

PubMed2026

Firemaster 550 differentially alters gene expression underlying synaptic function in amygdala of prairie voles after gestational or lactational exposure.

Neurodevelopmental disorders often share similar behavioral diagnostic criteria including socioemotional and cognitive deficits. The prairie vole is a uniquely suitable model to study these deficits because they demonstrate strong social affiliation, bi-parental care, and partner attachment. Previously, we have shown that developmental exposure to the flame-retardant mixture Firemaster 550 (FM 550) impairs socioemotional behavior in the prairie vole and alters underlying neuroanatomy and function. However, the mechanisms for impaired pair bonding in males and increased anxiety in females remain unknown, along with the specific critical window(s) of vulnerability. Herein, we exposed prairie vole dams to FM 550 during gestation or lactation, and performed bulk RNA-seq on the amygdala, a hub of socioemotional processing, in their adult offspring. Two mathematically orthogonal methods were utilized for analysis, a linear statistical method and an ensemble machine learning method, incorporating sex as a biological variable. Gene ontology (GO) pathway analysis was performed following both and results compared to identify potential mechanisms of toxicity. GO results indicated consistent expression changes in the Synapse cellular component in all conditions, and implicated glutamatergic signaling specifically. Additionally, gestational exposure (GE) altered genes underlying modulation of synaptic transmission and neural development, while lactational exposure (LE) impacted genes underlying synaptic plasticity, axon guidance, and mitophagy. Machine learning identified disruption of endocrine system development, regulation of biosynthetic processes in GE animals, and suppression of various neuroinflammatory genes across multiple groups. Finally, we performed RNA expression analysis using Nanostring and demonstrated stronger correlation with the differentially expressed genes (DEG) of interest in females than males. Overall, this study demonstrates both the intersecting and distinct impacts of FM 550 exposure on amygdalar gene expression depending on sex and timing of exposure.

Animals↗

PubMed1975

Retardation of development including immunogenic expression of histocompatibility antigens in mice--by postnatal administration of antiandrogenic steroid.

A specific antiandrogenic steroid cyproterone acetate was administered daily to mice of three different inbred strains starting from the day of birth until the age of 30 days. The total dose per mouse was 17.2 mg. This treatment resulted in developmental retardation which was manifested in a number of ways: at the age of 30 days, the weight of the body was well as spleen, testes and particularly thymus was significantly reduced; histologically, the normal proportion of the red and white pulp in the spleen was changes; spermatogenesis (but not oogenesis) was markedly retarded corresponding to the age of 12-15 days in normal males; also skin displayed a persisting immaturity as reflected by an abundance of mast cells. Minor signs of toxic changes were seen in the liver. Skin grafts from CA-pretreated donors had a subnormal immunogenicity; when transplanted across the MSA-barrier, they survived significantly longer than control grafts and about 23% took. Significantly prolonged survival was also observed with H-3 incompatible skin grafts from CA-pretreated donors, particularly from male donors. Across the barrier dicated, but did not reach a level of significance. The present study extends our previous observations concerning the androgen dependence of a normal immunogenic expression of H-antigens. The antiandrogenic effect of CA is comparable to the more complex effect of neonatal orchiectomy in terms of the subnormal immunogeneity of MSA-incompatible skin grafts from 30-day-old males which seems to be arrated at a stage typical for 1-2-day-old normal males.

Androgen Antagonists↗

PubMed1979

Effect of chronic developmental lead exposure on cell-mediated immune functions.

Studies were performed to investigate the effects of chronic, low level pre- and post-natal lead exposure on cell-mediated immune function in rats. Weanling female rats were exposed to lead (as lead acetate) in their drinking water at 0, 25, and 50 ppm for 7 weeks. At the end of 7 weeks they were mated with untreated males and continued on the same dosage throughout gestation and lactation. The offspring of these females were weaned at 21 days of age and continued on the same lead exposure regimen as their mothers. These offspring were used in immune surveillance procedures between 35 and 45 days of age. Lead exposure at the levels employed had no statistically significant effect on growth and did not result in overt signs of toxicity. Thymic weights were significantly decreased in both males and females of the two lead dosage groups. Furthermore, lead exposure resulted in suppression of responsiveness of lymphocytes to mitogen stimulation and in reduced delayed hypersensitivity responsiveness. Results indicate that chronic low-level lead exposure causes suppression of cell-mediated immune function.

Animals↗