Sublethal Dose Levels Research Articles

Effect of Heavy Metals on Protein Profile of Body Muscles of Cyprinus carpio

The study was carried out with commonly cultured C. carpio exposed to two sublethal dose levels of 0.025 and 0.05 ppm of arsenic, mercury, nickel and chromium individually and arsenic in combination with mercury, nickel and chromium. Protein quantity declined in all the heavy metal treatments except chromium, where it showed an increment in protein quantity. Gel electropherograms of muscle protein extracts of C. carpio on their exposure to different heavy metal treatments revealed a definite pattern of variations in their protein profile. It caused the synthesis of some additional protein fractions in almost all the treatments with subsequent deletion of some other protein fractions.

Postchronic Single-Walled Carbon Nanotube Exposure Causes Irreversible Malignant Transformation of Human Bronchial Epithelial Cells through DNA Methylation Changes.

As environmental pollutants and possible carcinogens, carbon nanotubes (CNTs) have recently been found to induce carcinogenesis and tumor metastasis after long-term pulmonary exposure. However, whether CNT-induced carcinogenesis can be inherited and last for generations remains unclear. Herein, postchronic single-walled carbon nanotubes (SWCNTs) exposed human lung cell model (BEAS-2B cells) are established to investigate SWCNT-induced carcinogenesis. At a tolerated sublethal dose level, postchronic SWCNT exposure significantly increases the migration and invasion abilities of BEAS-2B cells, leading to malignant cell transformation. Notably, the malignant transformation of BEAS-2B cells is irreversible within a 60 day recovery period after SWCNT exposure, and the malignant transformation activities of cells gradually increase during the recovery period. Moreover, these transformed cells promote carcinogenesis in vivo, accompanied by a raised level of biomarkers of lung adenocarcinoma. Further mechanism analyses reveal that postchronic exposure to SWCNTs causes substantial DNA methylation and transcriptome dysregulation of BEAS-2B cells. Subsequent enrichment and clinical database analyses reveal that differentially expressed/methylated genes of BEAS-2B cells are enriched in cancer-related biological pathways. These results not only demonstrate that postchronic SWCNT-exposure-induced carcinogenesis is heritable but also uncover a mechanism from the perspective of DNA methylation.

Changes in the neurotransmitter profile in the central nervous system of marine medaka (Oryzias melastigma) after exposure to brevetoxin PbTx-1 – A multivariate approach to establish exposure biomarkers

A strategy to construct multivariate biomarkers for exposure to algal neurotoxins via correlating changes to the profiles of a series of neurotransmitters and their metabolites in the central nervous system (CNS) of exposed test organism is reported. 3-Month-old marine medaka (Oryzais melastigma) were exposed to waterborne brevetoxin PbTx-1 at two sub-lethal dose levels (0.5 and 2.5 μg-PbTx-1 L−1) for a duration of 12 h before quantification of 43 selected neurotransmitters and metabolites in their CNS were measured via dansyl chloride derivatization and LC-MS/MS determination. The profiling data were analyzed by multivariate statistical analyses, including principle component analysis (PCA), projection on latent structure-discriminate analysis (PLS-DA) and orthogonal projection on latent structure-discriminate analysis (OPLS-DA). Neurotransmitters and metabolites related to activation of voltage-gated sodium channels (VGSCs), N-methyl-D-aspartic acid receptors (NMDARs) and cholinergic neurotransmission were found to contribute significantly to class separation in the corresponding OPLS-DA models. Those models obtained from different exposure dosages were correlated by the Shared and Unique Structures Plot (SUS-plot) to identify appropriate variables for the construction of exposure biomarkers in the form of multivariate predictive scores. The established biomarkers for male and female medaka fish were able to predict acute sub-lethal exposure to PbTx-1 with good sensitivity and specificity (male fish: sensitivity 94.7%, specificity 80.0%; female fish: sensitivity 91.4%, specificity 83.3%). Neurotransmitter profiles in the CNS of medaka fish that should have recovered from exposure to PbTx-1 have also been determined to reveal long-term impacts to the CNS of the affected organism even after the exposure has been interrupted.

Sublethal doses of neonicotinoid imidacloprid can interact with honey bee chemosensory protein 1 (CSP1) and inhibit its function

As a frequently used neonicotinoid insecticide, imidacloprid can impair the chemoreceptive behavior of honey bees even at sublethal doses, while the physiochemical mechanism has not been further revealed. Here, multiple fluorescence spectra, thermodynamic method, and molecular docking were used to study the interaction and the functional inhibition of imidacloprid to the recombinant CSP1 protein in Asian honey bee, Apis cerana. The results showed that the fluorescence intensity (λem = 332 nm) of CSP1 could be significantly quenched by imidacloprid in a dynamic mode. During the quenching process, ΔH > 0, ΔS > 0, indicating that the acting forces of imidacloprid with CSP1 are mainly hydrophobic interactions. Synchronous fluorescence showed that the fluorescence of CSP1 was mainly derived from tryptophan, and the hydrophobicity of tryptophan decreased with the increase of imidacloprid concentration. Molecular docking predicted the optimal pose and the amino acid composition of the binding process. Circular dichroism (CD) spectra showed that imidacloprid reduced the α-helix of CSP1 and caused the extension of the CSP1 peptide chain. In addition, the binding of CSP1 to floral scent β-ionone was inhibited by nearly 50% of the apparent association constant (KA) in the presence of 0.28–2.53 ng/bee of imidacloprid, and the inhibition rate of nearly 95% at 3.75 ng/bee of imidacloprid at sublethal dose level. This study initially revealed the molecular physiochemical mechanism that sublethal doses of neonicotinoid still interact and inhibit the physiological function of the honey bees' chemoreceptive system.

Synergistic Effects of the Alkaloids of Prosopis juliflora, Causing Multiple Organ Toxicity in Mouse Model

The present study was aimed to identify the role of Prosopis juliflora alkaloids in animal toxicity. Total alkaloids were extracted from the leaves of this plant and were separated into various fractions. Chemical characterization of the alkaloids and its separated fractions were done by DART-MS technique, which revealed the presence of piperidine group of alkaloids. They were subjected for acute toxicity analysis for the calculation of median lethal dose (LD50). LD50 value obtained was in the range of 27-100 mg/kg body weight and was lowest for the total alkaloid mixture, indicating a synergistic behavior. Subacute toxicity study of the total alkaloid extract was conducted for a period of 14 days at sub-lethal dose levels of 1, 2, 5 and 10 mg/ kg body weight. Physical parameters, biochemical parameters related to organ toxicity and hematological parameters were studied as end point of evaluation. Histopathological studies were also conducted to assess any organ specific toxicity. Results obtained showed toxic symptoms in multiple organs at high doses of 5 and 10 mg/kg body weight.

Antidiabetic and Antioxidant Effects of Newly Synthesized Pyrimido[1,6-A] Pyrimidine Derivatives in Neonatal Streptozotocin-Induced Diabetic Rats

Synthesis of some novel pyrimido[1,6-a]pyrimidine derivatives 4, 8 and 10 was described through the respective reactions of sodium salts of formyl ketones 1, 7 and 9 with 6-aminothiouracil. The characterization of the reaction products was confirmed by using the available elemental analysis and spectral data. One of these derivatives ( 4b), 1-thioxo-1,2,7,8,9,10-hexahydro-3H-pyrimido[1,6-a]quinazolin-3-one, was tested using sublethal dose level (10 mg/kg b. w./day for 3 weeks) and was found to have potent antihyperglycemic, antihyperlipidemic and antioxidant properties in neonatal streptozotocin-induced (n-STZ) diabetic male and female albino rats.

The antihyperlipidemic activities of 4(3H) quinazolinone and two halogenated derivatives in rats

In the present study, the effects of subchronic treatments (4 weeks) of hypercholesterolemic (single) and diabetic-hypercholesterolemic (combined) rats with 4 (3H) quinazolinone and 2 halogenated derivatives (6, 8-dibromo-2-methy-4 (3H) quinazolinone and 6-iodo-2-methyl-4(3H) quinazolinone) at a sublethal dose level (2 mg/Kg) on cholesterol metabolism were investigated. Bezafibrate, a hypolipidemic drug was used as a reference compound for data comparison. Treatment of rats with single and combined hypercholesterolemia with quinazolinone compounds gave rise to highly significant reductions in serum total cholesterol and cholesterol ester levels, whereas serum triacylglycerol level was significantly reduced only after treatment with halogen-substituted quinazolinones in single hyper-cholesterolemia, compared to the control group. The effects of different quinazolinones and bezafibrate on reduction of serum LDL-C level were comparable in single hypercholesterolemia but significantly different in combined hypercholesterolemia. Results obtained from this study suggest that the antihyperlipidemic effect of quinazolinone compounds was brought about by inhibition of dietary cholesterol absorption and / or intestinal ACAT activity.

Recovery from amiodarone-induced lipidosis in laboratory animals: A toxicological study

Numerous amphiphilic cationic drugs cause lipid-lysosomal storage in animal tissues; one of these drugs is amiodarone, a major antiarrhythmic agent. The toxicological effects of amiodarone were studied in three animal species (rats, dogs, and monkeys). It was shown that sublethal dose levels of amiodarone induced lipid storage in a great variety of tissues in rats (Fischer and Sprague-Dawley strains) and dogs. However, this change was not observed in baboons and Wistar rats. This storage, essentially characterized by lamellated inclusions, affected foamy macrophages, and at a later phase multiple cell types. Tissue biochemical analysis provided evidence of the phospholipidic nature of the storage. In addition, amiodarone induced an increased cholesterolemia and marked modifications of the lipoproteinogram. The kinetics of lipid storage was demonstrated following oral administration of amiodarone. After jejunal absorption, lipid storage occurred in the mesenteric lymph nodes followed by widespread deposition in the other lymph nodes and tissues, particularly in the lung. A complete recovery from lipid storage was observed in dogs and rats. Finally, an investigation of a correlation between animal and man by means of long-term experiments is proposed.

Evaluation of cytotoxic agents in human colonic tumor xenografts and mouse gastrointestinal tissues using a 3H-thymidine fractional incorporation assay

Drug induced changes in 3H -thymidine fractional incorporation (TFI) in 4 human colonic xenograft lines and mouse gastrointestinal tissues have been related to the growth inhibition and host toxicity respectively. Using the TFI assay, the combinations of actinomycin D with cyclophosphamide and methyl CCNU with pentamethyl-melamine have been examined. Both combinations showed greater than additive activity against only 1 of the 3 xenograft lines in which they were tested. The TFI assay allows more rapid evaluation of drug activity and is more sensitive than growth delay studies. It also allows quantitative measurement of cytotoxic activity in gastrointestinal tissues after sublethal dose levels.

A single oral treatment with mebendazole for the control of Taenia crassiceps larval infections in rats

A single oral treatment with mebendazole for the control of Taenia crassiceps larval infections in rats. International Journal for Parasitology 9: 73–76. Rats infected with Taenia crassiceps larvae were treated with mebendazole. At a sublethal dose level of 50 mg/kg, a single large oral treatment proved to be markedly more effective in killing cysts than the same amount of drug divided into 10 daily smaller doses. Levamisole promoted a vigorous host cellular response to the intraperitoneal cysts, but when incorporated with mebendazole, it did not enhance the action of the latter drug.

A study of the change in DNA synthesis of S phase cells treated with N-methyl-N-nitrosourethane: A study using Amoeba proteus as a single cell model

The present experiments using Amoeba proteus as a single cell model show that DNA synthesis continues during and after exposure of S phase cells to N-methyl-N'-nitrosourethane (MNU). At sublethal dose levels which caused long division delays, division and growth abnormalities and mutations, the amount of [3H] thymidine ([3H]Tdr) incorporated was decreased by 20–30%; at dose levels which killed all S phase cells it was inhibited by up to 90%. There was a direct correlation between the dose of MNU used and the degree of inhibition of [3H]Tdr incorporated. The effect was rapid, mainly taking place within 20 min of treatment.Amoeba heterokaryons (HKs) were used to examine the rate of DNA synthesis of treated and untreated nuclei in the same cytoplasm, i.e. where the nuclei would have the same [3H]Tdr intake, the same thymidine kinase (TK) activity and the same endogenous precursor pools. Direct comparison of the nuclear DNA synthetic activity in this way revealed less difference between treated and untreated nuclei than comparisons made using the nuclear grain counts from treated and untreated amoebae. This suggested that much of the decrease in [3H]Tdr incorporation by MNU-treatedS phase cells was due to a change in the cytoplasm and/or the cell membrane, rather than to nuclear damage. Thus MNU-treated nuclei were able to synthesize DNA at a near normal rate when they could draw on the resources of untreated cytoplasm, while the rate of DNA synthesis of control nuclei decreased when they occupied cytoplasm which had been exposed to high doses of MNU. These studies suggest that nuclear sites of damage were only involved when lethal doses of MNU had been used.

Effects of Antimetabolites upon the Renewal Patterns of Normal Cells.

Meeting Abstracts1 May 1970Effects of Antimetabolites upon the Renewal Patterns of Normal Cells.Joseph Post, M.D., F.A.C.P., Joseph Hoffman, M.D., (Associate)Joseph Post, M.D., F.A.C.P.Search for more papers by this author, Joseph Hoffman, M.D., (Associate)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-72-5-798_4 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptClinical experience has shown that the use of antimetabolites in the treatment of cancer and as immunosuppressants is limited by the tolerance of the host for the destruction of replicating hematopoietic and gut cells. Previous in vivo studies from this laboratory have correlated these effects with the more rapid multiplication of the normal populations vis-à-vis the coexistent autogenous tumor cells (New Eng J Med279:248, 1968; National Cancer Institute Monograph No. 30, p. 209, 1969). This report deals with the effects of nitrogen mustard and methotrexate, administered at sublethal dose levels, upon the renewal patterns of coexistent ileal cells and... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: Joseph Post, M.D., F.A.C.P.; Joseph Hoffman, M.D., (Associate)Affiliations: New York, N.Y. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1970Volume 72, Issue 5Page: 798-798KeywordsCancer immunotherapyCancer treatmentCellsImmunosuppressivesMethotrexatePopulation statisticsResearch laboratories ePublished: 1 December 2008 Issue Published: 1 May 1970 PDF downloadLoading ...

Pharmacologic and toxicologic studies of two new centrally acting skeletal muscle relaxants, chlormethazanone and dichlormethazanone

1. 1. 2-(4-Chlorophenyl)-3-methyl-4-metathiazanone-1-dioxide (Win 4692, chlormethazanone) and its 3,4-dichlorophenyl analog (Win 12,267, dichlormethazanone) produced an ascending type of paralysis associated with a marked ataxia in all species tested. At ataxic dose levels, Win 12,267 caused a marked hyperreflexia in the larger species (cat and monkey). Such effects were not seen with Win 4692 at sublethal dose levels. 2. 2. Both Win 4692 and Win 12,267 were found to be more active than meprobamate in various CNS effects as follows: Both Win 4692 and Win 12,267 intensified the depressant action of either pentobarbital or ethyl alcohol in mice. Both compounds inhibited the crossed extensor reflex of the spinal cat without affecting the monosynaptic (knee jerk) reflex. Both compounds produced EEG slowing and spindling, and blocked “EEG arousal” in the unanesthetized rabbit. 3. 3. Win 4692 was found to be devoid of analgesic properties in the rat at sublethal dose levels. No significant autonomic or smooth muscle effects could be demonstrated. 4. 4. The acute oral and intraperitoneal median lethal doses of Win 4692 and Win 12,267 in several species varied from about 400.0 to 1400.0 mg/kg and from about 300.0 to 1050.0 mg/kg, respectively. 5. 5. The daily administration of sublethal doses of either Win 4692 or Win 12,267 to albino rats for 5 consecutive days produced only an initial loss of weight. No significant hematologic alteration or macroscopic lesion of any of the viscera, attributable to medication with either drug, was observed. 6. 6. The results of a one-year chronic toxicity study in monkeys indicate that Win 4692, in doses of 10.0, 30.0, and 90.0 mg/kg per day, and Win 12,267, in doses of 5.0, 15.0, and 45.0 mg/kg per day, were well tolerated. The chief pharmacologic response observed was ataxia. The growth rates of all medicated groups were less than those of the controls, but these differences were not considered to be significant. Hematologic and histologic studies and urinalyses revealed no significant alteration or lesion attributable to medication.