Analysis of DNA Adducts and Mutagenic Potency and Specificity in Rats Exposed to Acrylonitrile.

Acrylonitrile (ACN), which is a widely used industrial chemical, induces cancers in multiple organs/tissues of rats by unresolved mechanisms. For this report, evidence for ACN-induced direct/indirect DNA damage and mutagenesis was investigated by assessing the ability of ACN, or its reactive metabolite, 2-cyanoethylene oxide (CEO), to bind to DNA in vitro, to form select DNA adducts [N7-(2'-oxoethyl)guanine, ,3-ethenoguanine, 1,-ethenodeoxyadenosine, and 3,-ethenodeoxycytidine] in vitro and/or in vivo, and to perturb the frequency and spectra of mutations in the hypoxanthine-guanine phosphoribosyltransferase () gene in rats exposed to ACN in drinking water. Adducts and frequencies and spectra of mutations were analyzed using published methods.

Development and use of a single-animal whole-body system for inhalation exposure.

Inhalation exposure studies, in which test subjects are fully or partially immersed in an atmosphere containing a compound of interest, are usually carried out using one of two possible exposure systems: large whole-body chambers or systems that expose only the animal's nose or head. Whole-body chambers may require large quantities of test compound, which can pose a problem if the chemical is expensive or available in limited quantities. Nose- or head-only systems can help conserve test compound but may cause stress or injury to animals.

Respiratory tract toxicity in rats exposed to Mexico City air.

The rat has been used extensively as a health sentinel, indicator, or monitor of environmental health hazards, but this model has not been directly validated against human exposures. Humans in Mexico City show upper respiratory tract lesions and evidence of pulmonary damage related to their environmental inhalation exposure. In this study, male and female F344 rats were exposed (23 hr/day) in Mexico City to local Mexico City air (MCA)* for up to seven weeks.

Mutational spectrum of 1,3-butadiene and metabolites 1,2-epoxybutene and 1,2,3,4-diepoxybutane to assess mutagenic mechanisms.

1,3-Butadiene (BD) is a multisite carcinogen and is mutagenic in multiple tissues of B6C3F1 mice. BD is bioactivated to at least three directly mutagenic metabolites: 1,2-epoxybutene (EB), 1,2-epoxy-3,4-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB). However, the contribution of these individual metabolites to the carcinogenicity and in vivo mutatidnal spectrum of BD is uncertain.

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring.

Lung-specific mutagenicity and mutational spectrum in B6C3F1 lacI transgenic mice following inhalation exposure to 1,2-epoxybutene.

1,3-Butadiene (BD) is carcinogenic and mutagenic in B6C3F1 mice. BD inhalation induces an increased frequency of specific base substitution mutations in the bone marrow and spleen of B6C3F1 lacI transgenic mice. BD is bioactivated to at least three mutagenic metabolites: 1,2-epoxybutene (EB), 1,2-epoxy-3,4-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB), however, the contribution of these individual metabolites to the in vivo mutational spectrum of BD is uncertain.

A comparison of the roles of p53 mutation and AraC inhibition in the enhancement of bleomycin-induced chromatid aberrations in mouse and human cells.

Previous studies have shown that p53 is involved in the repair of bleomycin-induced DNA damage, and that the frequency of bleomycin-induced chromatid aberrations is elevated in G(2)-treated p53 null transgenic mouse embryo fibroblasts (MEF) as compared to isogenic controls. To further characterize p53-mediated DNA repair, we studied the effect of p53 status on the ability of the DNA repair inhibitor 1-ss-D-arabinofuranosylcytosine (AraC) to sensitize MEF to bleomycin-induced chromatid aberrations. Both p53+/+ and p53-/- MEF were treated in G(2) with 0 to 7.

Direct olfactory transport of inhaled manganese ((54)MnCl(2)) to the rat brain: toxicokinetic investigations in a unilateral nasal occlusion model.

Inhalation exposure of humans to high concentrations of manganese (Mn) is associated with elevated Mn levels in the basal ganglia and an extrapyramidal movement disorder. In the rat, direct olfactory transport of Mn from the nose to the brain has been demonstrated following intranasal instillation of (54)MnCl(2). However, the contribution this route makes to brain Mn delivery following inhalation is unknown and was the subject of our study.

Identification of metabolites of [1,2,3-(13)C]Propargyl alcohol in mouse urine by (13)C NMR and mass spectrometry and comparison to rat.

Species differences in the metabolism of acetylenic compounds commonly used in the formulation of pharmaceuticals and pesticides have not been investigated. To better understand the in vivo reactivity of this bond, the metabolism of propargyl alcohol (PA), 2-propyn-1-ol, was examined in rats and mice. An earlier study (Banijamali, A.

Metabolism and disposition of bisphenol A in female rats.

Bisphenol A (BPA), which is used in the manufacture of polycarbonates, elicits weak estrogenic activity in in vitro and in vivo test systems. The objectives of this study were to compare the patterns of disposition of radioactivity in adult female F-344 and CD rats after oral administration of (14)C BPA (100 mg/kg), to isolate the glucuronide of BPA and to assess its estrogenic activity in vitro, and to evaluate the transfer of radioactivity to pups from lactating dams administered (14)C BPA. Over 6 days, F-344 rats excreted more radioactivity in urine than CD rats.

Simulation modeling of the tissue disposition of formaldehyde to predict nasal DNA-protein cross-links in Fischer 344 rats, rhesus monkeys, and humans.

Formaldehyde inhalation causes formation of DNA-protein cross-links (DPX) in the nasal mucosa of Fischer 344 (F344) rats and rhesus monkeys. DPX are considered to be part of the mechanism by which cytotoxic and carcinogenic effects of formaldehyde in laboratory animals are exerted, and DPX data have been used as a measure of tissue dose in cancer risk assessments for formaldehyde. Accurate prediction of DPX concentrations in humans is therefore desirable.

Oestrogen receptor alpha and beta in rat prostate and epididymis.

The cellular localization of two oestrogen receptor (ER) subtypes, ER alpha and ER beta, was investigated in neonatal, postnatal, immature and adult male rats to determine whether these receptor subtypes are differentially expressed in prostate and epididymis. A monoclonal antibody against ER alpha and two polyclonal ER beta antibodies were used. Paraffin sections revealed a specific nuclear immunoreaction product in certain cells but not in others.

Increased sensitivity to chromatid aberration induction by bleomycin and neocarzinostatin results from alterations in a DNA damage response pathway.

DNA damage response pathways coordinate the cellular response to DNA damage. To investigate the roles of tumor suppressor genes in these pathways, human lymphoblastoid cells (wild-type, p53-/-, ATM-/-) were treated for 1 h with 0-3 microg/ml of the radiomimetic compound bleomycin (BLM), and cells treated in G(2) were analyzed for chromatid aberrations. BLM-induced aberration frequencies were significantly increased, to the greatest extent in the ATM-/- cells and, to a lesser extent, in the p53-/- cells compared to wild-type cells.

Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies.

We previously demonstrated differential interactions of the methoxychlor metabolite 2,2-bis(p-hydroxyphenyl)-1,1, 1-trichloroethane (HPTE) with estrogen receptor alpha (ERalpha), ERbeta, and the androgen receptor (AR). In this study, we characterize the ERalpha, ERbeta, and AR activity of structurally related methoxychlor metabolites. Human hepatoma cells (HepG2) were transiently transfected with human ERalpha, ERbeta, and AR plus an appropriate steroid-responsive luciferase reporter vector.

Pulmonary clearance of manganese phosphate, manganese sulfate, and manganese tetraoxide by CD rats following intratracheal instillation.

Manganese (Mn) is ubiquitous in ambient air due to both industrial and crustal sources. It is also a component of the octane-enhancing fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The combustion of MMT by the automobile engine results in the formation of Mn particulates including phosphate, sulfate, and oxide forms.

Induction of testosterone biotransformation enzymes following oral administration of methyl tert-butyl ether to male Sprague-Dawley rats.

Methyl tert-butyl ether (MTBE) is an oxygenated fuel additive used to decrease carbon monoxide emissions during gasoline combustion. In the current study, we investigated the hypothesis that the MTBE-induced decrease in serum testosterone levels in male rats may be due in part to the ability of MTBE to induce the metabolism of endogenous testosterone and hence enhance its clearance. Nine-week-old male Sprague-Dawley rats were gavaged with 250, 500, 1000, or 1500 mg MTBE/kg/day in corn oil or corn oil alone for 15 or 28 consecutive days.

Haber's rule: a special case in a family of curves relating concentration and duration of exposure to a fixed level of response for a given endpoint.

The concept that the product of the concentration (C) of a substance and the length of time (t) it is administered produces a fixed level of effect for a given endpoint has been ascribed to Fritz Haber, who was a German scientist in the early 1900s. He contended that the acute lethality of war gases could be assessed by the amount of the gas in a cubic meter of air (i.e.

1,3-butadiene: cancer, mutations, and adducts. Part II: Roles of two metabolites of 1,3-butadiene in mediating its in vivo genotoxicity.

1,3-Butadiene (BD) is carcinogenic in mice and rats, with mice being more susceptible than rats to its carcinogenic effects. 1,3-Butadiene is mutagenic in the bone marrow and spleen cells of B6C3F1 lacI transgenic mice. The goal of this research was to assess the roles of two BD metabolites, 1,2-epoxy-3-butene (BDO) and 1,2,3,4-diepoxybutane (BDO2), in the mutagenicity and mutational spectrum of the parent compound BD by determining the mutagenicity and mutational spectra of BDO and BDO2 in human and rodent cells in vitro and in vivo.

Hemoglobin adducts from acrylonitrile and ethylene oxide in cigarette smokers: effects of glutathione S-transferase T1-null and M1-null genotypes.

Acrylonitrile (ACN) is used to manufacture plastics and fibers. It is carcinogenic in rats and is found in cigarette smoke. Ethylene oxide (EO) is a metabolite of ethylene, also found in cigarette smoke, and is carcinogenic in rodents.

Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats.

Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model.