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Biomedical subjects

J A Bantle

Publications and source records attributed to J A Bantle.

At least 19 recordsLinked to original sources
PubMed2000

Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis assay-xenopus (FETAX): biotransformation and detoxification.

The developmental toxicity of thalidomide was evaluated using FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Young X. Laevis embryos were exposed to this compound in each of two concentration-response experiments with and without differently induced exogenous metabolic activation systems (MASs) and/or inhibited MASs. Young male Sprague-Dawley rats were treated with either isoniazid or Aroclor 1254 to induce cytochrome P-450. Several of the rats were subsequently treated with diethyl maleate (DM) to deplete glutathione reserves. Specific aliquots of rat liver microsomes were treated with 3-amino-1,2,4-triazole (ATZ) or alpha-napthoflavone (alpha-N) to selectively inhibit P-450 activity. Bioactivation was indicated by increased developmental toxicity observed in MAS tests. Results obtained indicated that thalidomide was predominantly activated by P-450 isozyne CYP2E1, although weak cross-specificity between CYP1A1/A2 may have existed. Detoxification pathways for thalidomide were investigated by treatment of the MAS with cyclohexene oxide (CHO) and DM to inhibit the epoxide hydrolase and glutathione conjugation pathways, respectively. Results indicated that epoxide hydrolase was primarily responsible for the detoxification of bioactivated thalidomide. Teratogenesis Carcinog. Mutagen. 20:35-47, 2000.

Amitrole↗
PubMed2000

The effect of cadmium on oogenesis in Xenopus laevis.

Reproductive toxicity studies have historically centered on post-fertilization events. A thorough assessment of reproductive hazards to an organism should include all aspects of its life cycle. Cadmium is a teratogenic and carcinogenic heavy metal that occurs naturally in the environment but is also released anthropogenically. The effect of cadmium administration on oocyte development in Xenopus laevis was studied. Adult female Xenopus were injected in the dorsal lymph sac with cadmium chloride (CdCl2) at doses of 0.5, 0.75, 1.0, 3.0 or 5.0 mg/kg every other day for 21 days. Significant adverse effects of Cd on oocyte development were observed. The percentage of oocytes at all stages of oogenesis was decreased while the population of atretic oocytes increased dramatically (P < 0.0001). Numerous oocytes exhibited a speckled or mottled appearance and the incidence of completely atretic oocyte follicles increased. The observations indicate that Cd has the potential to significantly disrupt oogenesis and that examination of developing gametes may be a useful parameter for assessing the influence of environmental contaminants on reproductive capacity.

Animals↗
PubMed1999

Lead inhibition of DNA-binding mechanism of Cys(2)His(2) zinc finger proteins.

The association of lead with chromatin in cells suggests that deleterious metal effects may in part be mediated through alterations in gene function. To elucidate if and how lead may alter DNA binding of cysteine-rich zinc finger proteins, lead ions were analyzed for their ability to alter the DNA binding mechanism of the Cys(2)His(2) zinc finger protein transcription factor IIIA (TFIIIA). As assayed by DNase I protection, the interaction of TFIIIA with the 50-bp internal control region of the 5S ribosomal gene was partially inhibited by 5 microM lead ions and completely inhibited by 10 to 20 microM lead ions. Preincubation of free TFIIIA with lead resulted in DNA-binding inhibition, whereas preincubation of a TFIIIA/5S RNA complex with lead did not result in DNA-binding inhibition. Because 5S RNA binds TFIIIA zinc fingers, this result is consistent with an inhibition mechanism via lead binding to zinc fingers. The complete loss of DNase I protection on the 5S gene indicates the mechanism of inhibition minimally involves the N-terminal fingers of TFIIIA. Inhibition was not readily reversible and occurred in the presence of an excess of beta-mercaptoethanol. Inhibition kinetics were fast, progressing to completion in approximately 5 min. Millimolar concentrations of sulfhydryl-specific arsenic ions were not inhibitory for TFIIIA binding. Micromolar concentrations of lead inhibited DNA binding by Sp1, another Cys(2)His(2) finger protein, but not by the nonfinger protein AP2. Inhibition of Cys(2)His(2) zinc finger transcription factors by lead ions at concentrations near those known to have deleterious physiological effects points to new molecular mechanisms for lead toxicity in promoting disease.

Animals↗
PubMed1999

Animals as sentinels of human health hazards of environmental chemicals.

A workshop titled "Using Sentinel Species Data to Address the Potential Human Health Effects of Chemicals in the Environment," sponsored by the U.S. Army Center for Environmental Health Research, the National Center for Environmental Assessment of the EPA, and the Agency for Toxic Substances and Disease Registry, was held to consider the use of sentinel and surrogate animal species data for evaluating the potential human health effects of chemicals in the environment. The workshop took a broad view of the sentinel species concept, and included mammalian and nonmammalian species, companion animals, food animals, fish, amphibians, and other wildlife. Sentinel species data included observations of wild animals in field situations as well as experimental animal data. Workshop participants identified potential applications for sentinel species data derived from monitoring programs or serendipitous observations and explored the potential use of such information in human health hazard and risk assessments and for evaluating causes or mechanisms of effect. Although it is unlikely that sentinel species data will be used as the sole determinative factor in evaluating human health concerns, such data can be useful as for additional weight of evidence in a risk assessment, for providing early warning of situations requiring further study, or for monitoring the course of remedial activities. Attention was given to the factors impeding the application of sentinel species approaches and their acceptance in the scientific and regulatory communities. Workshop participants identified a number of critical research needs and opportunities for interagency collaboration that could help advance the use of sentinel species approaches.

Animals↗
PubMed1998

Ground and surface water developmental toxicity at a municipal landfill: description and weather-related variation.

Contaminated groundwater poses a significant health hazard and may also impact wildlife such as amphibians when it surfaces. Using FETAX (Frog Embryo Teratogenesis Assay-Xenopus), the developmental toxicity of ground and surface water samples near a closed municipal landfill at Norman, OK, were evaluated. The groundwater samples were taken from a network of wells in a shallow, unconfined aquifer downgradient from the landfill. Surface water samples were obtained from a pond and small stream adjacent to the landfill. Surface water samples from a reference site in similar habitat were also analyzed. Groundwater samples were highly toxic in the area near the landfill, indicating a plume of toxicants. Surface water samples from the landfill site demonstrated elevated developmental toxicity. This toxicity was temporally variable and was significantly correlated with weather conditions during the 3 days prior to sampling. Mortality was negatively correlated with cumulative rain and relative humidity. Mortality was positively correlated with solar radiation and net radiation. No significant correlations were observed between mortality and weather parameters for days 4-7 preceding sampling.

Animals↗
PubMed1998

Phase III interlaboratory study of FETAX, Part 2: interlaboratory validation of an exogenous metabolic activation system for frog embryo teratogenesis assay--Xenopus (FETAX).

Interlaboratory validation of an exogenous metabolic activation system (MAS) developed for the alternative, short-term developmental toxicity bioassay, Frog Embryo Teratogenesis Assay-Xenopus (FETAX) was performed with cyclophosphamide and caffeine. Seven study groups within six separate laboratories participated in the study in which three definitive concentration-response experiments were performed with and without the MAS in a side-by-side format for each chemical. Since both chemicals had been previously tested in FETAX, the test concentrations were provided to each laboratory prior to testing. Interlaboratory coefficient of variation (CV) values for unactivated cyclophosphamide (no MAS) were 15%, 15%, 29%, and 25% for the 96-hr LC50, 96-hr EC50 (malformation), Minimum Concentration to Inhibit Growth (MCIG), and Teratogenic Index (TI) values, respectively. Addition of the MAS increased the CV values of each endpoint at least 3.9-fold. Interlaboratory CV values for unactivated caffeine were 31%, 18%, 31%, and 46% for the 96-hr LC50, 96-hr EC50 (malformation), MCIG, and TI values, respectively. Addition of the MAS decreased the CV values of each respective endpoint by at least 1.6-fold. Results indicated that bioactivated toxicants may be prone to greater variability in response amongst laboratories than compounds, which are detoxified. Even though more variability was noted with activated cyclophosphamide, results were within interlaboratory variation expected for other aquatic-based bioassays. Thus, results from these studies warrant the continued use and further refinement of FETAX for alternative developmental toxicity assessment.

Abnormalities, Drug-Induced↗
PubMed1998

Evaluation of the developmental toxicities of coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin using FETAX.

The developmental toxicities of coumarin and hydroxycoumarin metabolites were evaluated using FETAX. Young X. laevis embryos were exposed to coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS) and/or inhibited MAS. The MAS was treated with carbon monoxide (CO), cimetidine (CIM), or ellipticine (ELL) to selectively modulate cytochrome P-450 activity. The MAS was also treated with cyclohexene oxide (CHO) to selectively modulate epoxide hydrolase activity. Without the MAS or inhibited MAS, coumarin and 7-hydroxycoumarin were nearly equitoxic, whereas 4-hydroxycoumarin was nearly 2-fold less developmentally toxic than coumarin on an equimolar basis. Addition of the MAS and CIM-MAS increased the developmental toxicities of coumarin and, particularly, 4-hydroxycoumarin. Addition of the CHO-MAS greatly increased the developmental toxicity of coumarin and, especially, 4-hydroxycoumarin. Addition of the ELL- or CO-inhibited MAS did not increase the developmental toxicity of coumarin. However, addition of the intact MAS did not alter the developmental toxicity of 7-hydroxycoumarin. Results from these studies suggested that P-450; specifically ELL-inhibited P-450 (arylhydrocarbon hydroxylase) may have been responsible for increasing the developmental toxicity of coumarin. Furthermore, the increased toxicity of coumarin or 4-hydroxycoumarin following co-incubation with CHO-treated microsomes indicated that highly toxic epoxide intermediates may be produced from oxidative P-450 metabolism and that epoxide hydrolase may play a role in detoxification of the reactive intermediates.

4-Hydroxycoumarins↗
PubMed1996

Evaluation of the developmental toxicity of theophylline, dimethyluric acid, and methylxanthine metabolites using Xenopus.

The developmental toxicities of theophylline and theophylline metabolites were evaluated using FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Young X. laevis embryos were exposed to theophylline, 1-methylxanthine, 3-methylxanthine, or 1, 3-dimethyluric acid in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS) and/or inhibited MAS. The MAS was treated with carbon monoxide (CO), cimetidine (CIM), or ellipticine (ELL) to selectively modulate cytochrome P-450 activity. Addition of the MAS and CIM-MAS reduced the developmental toxicity of theophylline. Addition of the ELL- or CO-inhibited MAS did not reduce the developmental toxicity of theophylline. Addition of the intact MAS did not alter the developmental toxicity of 1-methyl- or 3-methylxanthine which were slightly more developmentally toxic on an equimolar basis than theophylline itself. 1, 3-dimethyluric acid was not developmentally toxic at maximum soluble concentrations in 1% (V/V) DMSO. Results from these studies suggested that P-450, specifically ELL-inhibited P-450 (aryl hydrocarbon hydroxylase) may have been responsible for detoxification of theophylline and that 1, 3 dimethyluric acid represented the primary detoxification metabolite of theophylline.

Abnormalities, Drug-Induced↗
PubMed1995

Protective effects of glucose-6-phosphate and NADP against alpha-chaconine-induced developmental toxicity in Xenopus embryos.

In previous studies a metabolic activation system (MAS) composed of Aroclor 1254-induced rat liver microsomes led to an apparent reduction of potato glycoalkaloid developmental toxicity in the frog embryo teratogenesis assay-Xenopus (FETAX). The reasons for this reduction were investigated in this study. The effect of the exogenous MAS on glycoalkaloid developmental toxicity was examined in two experiments in which a concentration series of alpha-chaconine was tested with a MAS with and without a reduced nicotinamide adenine dinucleotide (NADPH) generator system consisting of NADPH, oxidized nicotinamide adenine dinucleotide (NADP), glucose-6-phosphate (G6P) and glucose-6-phosphate dehydrogenase. The NADPH generator system and each of its individual components were tested at a single high concentration of alpha-chaconine to evaluate their potential effects on toxicity. The findings indicated that the protective effect of the MAS was not the result of detoxification by microsomal enzyme systems, but was caused by two components of the NADPH generator system, namely NADP and G6P. G6P was more protective of alpha-chaconine-induced toxicity than NADP at the concentrations tested. Thus, FETAX with a MAS must be performed with appropriate controls that take into account the possible interactions with individual components of the system.

Animals↗
PubMed1995

Synergistic interaction of glycoalkaloids alpha-chaconine and alpha-solanine on developmental toxicity in Xenopus embryos.

The embryo toxicities of two major potato glycoalkaloids, alpha-chaconine and alpha-solanine, were examined individually and in mixtures using the frog embryo teratogenesis assay-Xenopus. Calculations of toxic units (TUs) were used to assess possible antagonism, synergism or response addition of several mixtures ranging from approximately 3:1 to 1:20 TUs of alpha-chaconine to alpha-solanine. Some combinations exhibited strong synergism in the following measures of developmental toxicity: (a) 96-hr LC50, defined as the median concentration causing 50% embryo lethality; (b) 96-hr EC50 (malformation), defined as the concentration causing 50% malformation of the surviving embryos; and (c) teratogenic index which is equal to LC50/EC50 (malformation). The results indicated that each of the mixtures caused synergistic mortality or malformation. Furthermore, these studies suggested that the synergism observed for a specific mixture cannot be used to predict possible synergism of other mixtures with different ratios of the two glycoalkaloids; toxicities observed for individual glycoalkaloids may not be able to predict toxicities of mixtures; and specific combinations found in different potato varieties need to be tested to assess the safety of a particular cultivar.

Abnormalities, Drug-Induced↗
PubMed1994

Genome size and organization in the ixodid tick Amblyomma americanum (L.).

We used DNA reassociation kinetics to determine genome size and organization in the ixodid tick Amblyomma americanum. We calculated the genome size of A. americanum to be approximately 1.08 pg or 1.04 x 10(9) base pairs and to consist of 35.8% unique DNA, 4.2% foldback sequences, 17.9% highly repetitive sequences, and 42.1% moderately repetitive sequences. Comparison of the reassociation kinetics of long and short fragments revealed repetitive sequences to be distributed in a pattern of long period interspersion, a feature that, to date, has been associated with arthropod genomes that lack a high percentage of repetitive DNA.

Animals↗
PubMed1993

Evaluation of the developmental toxicity of trichloroethylene and detoxification metabolites using Xenopus.

Potential mechanisms of trichloroethylene-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay--Xenopus). Early Xenopus laevis embryos were exposed to trichloroethylene for 96 h in two separate definitive concentration-response assays with and without an exogenous metabolic activation system (MAS) and inhibited MAS. The MAS was treated with either carbon monoxide or cyclohexene oxide to modulate mixed-function oxidase (MFO) or epoxide hydrolase activity, respectively. Trichloroethylene metabolites: dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid were also evaluated in two separate definitive, static renewal tests. Addition of the MAS decreased the 96 h LC50 and EC50 (malformation) of trichloroethylene 1.8-fold and 3.8-fold, respectively. Addition of the carbon monoxide inhibited MAS decreased the developmental toxicity of activated trichloroethylene to levels approximating that of the parent compound. Cyclohexene oxide-inhibited MAS substantially increased the developmental toxicity of trichloroethylene. In addition, each of the metabolites tested were significantly less developmental toxic than the parent compound, trichloroethylene. Results indicate that a highly embryotoxic epoxide intermediate, trichloroethylene oxide, formed as the results of MFO mediated metabolism may play a significant role in the developmental toxicity of trichloroethylene in vitro.

Animals↗
PubMed1993

Detection of Anaplasma marginale (Rickettsiales: Anaplasmataceae) in hemolymph of Dermacentor andersoni (Acari: Ixodidae) with the polymerase chain reaction.

The polymerase chain reaction (PCR) was used to detect Anaplasma marginale in hemolymph collected from live Dermacentor andersoni Stiles ticks. Hemolymph was collected from severed legs of male and female ticks exposed to A. marginale as either nymphs or adults. Heat treatment was found to be the optimum method of hemolymph preparation for PCR. Hemolymph samples were collected and pooled from adult ticks exposed as nymphs on days 0-10 of feeding on a susceptible calf. For male and female ticks exposed as adults, samples were collected as ticks fed 7 d on an infected calf, while being held 9 d between feedings, and during a second feeding of 10 d (or to repletion) when they transmitted the parasite. Hemolymph samples were collected from uninfected ticks at the same times to serve as controls. Anaplasma marginale DNA was amplified with primers BAP-2 (5'-GTATGGCACGTAGTCTTGGGATCA-3') and AL34S (5'-CAGCAGCAGCAAGACCTTCA-3'), which flank a 409-bp fragment of the A. marginale Florida isolate msp1 beta gene. Infected tick hemolymph was PCR-positive for A. marginale at all collection times, including unfed adults infected as nymphs and previously unexposed adults that fed on infected calves for only 1 d. The PCR-based assay of tick hemolymph proved to be a sensitive method for identification of infected ticks, potentially without killing them; it would be well suited for identification of laboratory- or field-infected ticks that could then be used for further studies. The primers used in this assay were also found specific when tested with species of 18 different genera, and universal for 7 A. marginale isolates from diverse geographical areas of the United States.

Anaplasma↗
PubMed1993

Detection of Anaplasma marginale (Rickettsiales: Anaplasmataceae) in secretagogue-induced oral secretions of Dermacentor andersoni (Acari: Ixodidae) with the polymerase chain reaction.

The polymerase chain reaction (PCR) was used to detect Anaplasma marginale in secretagogue-induced oral secretions of male and female Dermacentor andersoni Stiles exposed as nymphs or adults by feeding on infected calves. A 409-bp DNA fragment derived from the A. marginale (Florida isolate) msp1 beta gene was amplified with oligonucleotide primers BAP-2 (5'-GTATGGCACGTAGTCTTGGGATCA-3') and AL34S (5'-CAGCAGCAGCAAGACCTTCA-3'). The target DNA was amplified in oral secretions of female ticks exposed to A. marginale as adults and stimulated to secrete by injection of dopamine. Conversely, A. marginale was detected in saliva from prefed female ticks exposed as nymphs only after stimulation with a combination of dopamine, gamma-aminobutyric acid, pilocarpine, and theophylline. Saliva from ticks exposed as nymphs and stimulated with ergot alkaloids did not contain the A. marginale target DNA. Saliva collected after 11 d of feeding from dopamine-stimulated male ticks contained A. marginale DNA. The results indicate that A. marginale is present in tick saliva and suggest that the parasite can be transmitted to cattle via saliva of feeding ixodid ticks. The variable appearance of A. marginale in saliva, regardless of the method used to induce salivation, suggests that transmission of A. marginale may be affected by the physiological state of the tick.

Anaplasma↗
PubMed1992

Amplification fragment length polymorphism in Brucella strains by use of polymerase chain reaction with arbitrary primers.

DNA heterogeneity among members of the genus Brucella was demonstrated with the arbitrarily primed polymerase chain reaction (AP-PCR). Simple, reproducible genomic fingerprints from DNA of 25 different Brucella strains were generated with five arbitrarily chosen primers, alone and in pairs, with the PCR. Reaction conditions were optimized for each primer. Several DNA segments were amplified in each sample with all of the primers. PCR products that are not shared among all strains act as polymorphic markers. Polymorphism was apparent for each primer. The Brucella strains can be distinguished according to the banding patterns of their amplified DNA on agarose gels, and the differences can be diagnostic of specific strains. To determine genetic relatedness among the Brucella strains, similarity coefficients were calculated. Statistical analysis of the similarity coefficients revealed the degrees of relatedness among strains of the genus Brucella.

Base Sequence↗
PubMed1992

Evaluation of acetaminophen-induced developmental toxicity using FETAX.

Potential mechanisms of acetaminophen-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay-Xenopus). Early Xenopus laevis embryos were exposed to acetaminophen for 96-h in two definitive concentrations-response assays with and without an exogenous metabolic activation system (MAS). Two static renewal tests of acetaminophen and the MAS treated with carbon monoxide, cimetidine, ellipticine, diethyl maleate, and supplemented with glutathione were also performed. Addition of the MAS decreased the 96-h LC50 and EC50 (malformation) values of unactivated acetaminophen 3.9-fold and 7.1-fold, respectively. Addition of the carbon monoxide- and ellipticine-inhibited MAS, as well as the glutathione-supplemented MAS decreased the developmental toxicity of activated acetaminophen to levels near that of the unactivated parent compound. Cimetidine-inhibited MAS also reduced the developmental toxicity of acetaminophen, but not to the extent observed with the carbon monoxide- and ellipticine-inhibited, or glutathione-supplemented MAS. Addition of the diethyl maleate-treated MAS substantially increased the developmental toxicity of acetaminophen. Results indicate that a highly reactive intermediate formed as the result of MFO-mediated metabolism (possibly P-448) significantly increased the developmental toxicity of acetaminophen. Glutathione was also found to play a major role in intermediate detoxification in vitro.

Abnormalities, Drug-Induced↗