Exposure of hematopoietic stem cells to benzene or 1,4-benzoquinone induces gender-specific gene expression.

Chronic exposure to benzene results in progressive decline of hematopoietic function and may lead to the onset of various disorders, including aplastic anemia, myelodysplastic syndrome, and leukemia. Damage to macromolecules resulting from benzene metabolites and misrepair of DNA lesions may lead to changes in hematopoietic stem cells (HSCs) that give rise to leukemic clones. We have shown previously that male mice exposed to benzene by inhalation were significantly more susceptible to benzene-induced toxicities than females.

Phytoestrogen genistein and its pharmacological interactions with synthetic endocrine-active compounds.

Phytoestrogens are plant-derived compounds with estrogen-like activities. Certain foods such as soy-derived products are known to have high levels of phytoestrogens, and about 25% of commercial infant formulas used in the United States are soy-based. One of the most important phytoestrogens is the isoflavone genistein.

Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset.

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The quantitative implications of the rat tumors for human cancer risk are of interest, since epidemiological studies have provided only equivocal evidence that formaldehyde is a human carcinogen. Conolly et al.

Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism.

The three beta AR (beta-adrenergic receptor) subtypes (beta(1)AR, beta(2)AR, and beta(3)AR) are members of the large family of G protein-coupled receptors, each of which is coupled to G alpha s and increases in intracellular cAMP levels. In white adipose tissues, catecholamine activation of the beta ARs leads to the mobilization of stored fatty acids and regulates release of several adipokines, whereas in brown adipose tissue they stimulate the specialized process of adaptive nonshivering thermogenesis. Noteworthy, in most models of obesity the beta AR system is dysfunctional, and its ability to stimulate lipolysis and thermogenesis are both impaired.

Respiratory tract toxicity of inhaled hydrogen sulfide in Fischer-344 rats, Sprague-Dawley rats, and B6C3F1 mice following subchronic (90-day) exposure.

The goal of this study was to characterize the toxicity of hydrogen sulfide (H2S), including nasal and pulmonary effects, in adult male and female Fischer-344 and Sprague-Dawley rats and B6C3F1 mice. Animals underwent whole-body exposure to 0, 10, 30, or 80 ppm H2S for 6 h/day for at least 90 days. Exposure to 80 ppm H2S was associated with reduced feed consumption during either the first exposure week (rats) or throughout the 90-day exposure (mice).

Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following subchronic (13-week) inhalation exposure.

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes.

Old age and gender influence the pharmacokinetics of inhaled manganese sulfate and manganese phosphate in rats.

In this study, we examined whether gender or age influences the pharmacokinetics of manganese sulfate (MnSO(4)) or manganese phosphate (as the mineral form hureaulite). Young male and female rats and aged male rats (16 months old) were exposed 6 h day(-1) for 5 days week(-1) to air, MnSO(4) (at 0.01, 0.

Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate.

Exposure to di (n-butyl) phthalate (DBP) in utero impairs the development of the male rat reproductive tract. The adverse effects are due in part to a coordinated decrease in expression of genes involved in cholesterol transport and steroidogenesis with a resultant reduction in testosterone production in the fetal testis. To determine the dose-response relationship for the effect of DBP on steroidogenesis in fetal rat testes, pregnant Sprague-Dawley rats received corn oil (vehicle control) or DBP (0.

The effect of ethylene exposure on ethylene oxide in blood and on hepatic cytochrome p450 in Fischer rats.

Ethylene (74-85-1) is an important petrochemical and is produced endogenously. It is metabolized to ethylene oxide (EO) by cytochrome P450. We studied the inhibition of cytochrome P450 activity during exposure to ethylene, and verified that this inhibition was reflected in the concentration of EO in the blood.

Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes.

Normal reproductive development depends on the interplay of steroid hormones with their receptors at specific tissue sites. The concentrations of hormone ligands in the circulation and at target sites are maintained through coordinated regulation on steroid biosynthesis and degradation. Changed bioavailability of steroids, through alteration of steroidogenesis or biotransformation rates, leads to changes in endocrine function.

In vivo mutagenicity and mutation spectrum in the bone marrow and testes of B6C3F1 lacI transgenic mice following inhalation exposure to ethylene oxide.

The lacI mutant frequency and mutation spectrum were determined in the bone marrow and testes of B6C3F1 lacI transgenic mice exposed by inhalation to ethylene oxide (EO). Groups of male transgenic lacI B6C3F1 mice were exposed to 0, 25, 50, 100 or 200 p.p.

Gene expression profile in bone marrow and hematopoietic stem cells in mice exposed to inhaled benzene.

Acute myeloid leukemia and chronic lymphocytic leukemia are associated with benzene exposure. In mice, benzene induces chromosomal breaks as a primary mode of genotoxicity in the bone marrow (BM). Benzene-induced DNA lesions can lead to changes in hematopoietic stem cells (HSC) that give rise to leukemic clones.

Mechanistic approaches for mixture risk assessments-present capabilities with simple mixtures and future directions.

Mechanistic studies with simple mixtures have provided insights into the nature of interactions among chemicals that lead to non-additive effects and have elucidated the exposure conditions under which interactions are likely to occur. This paper discusses studies on four mixtures: (1) 1,1-dichloroethylene and trichloroethylene, (2) carbon tetrachloride and Kepone, (3) hexane and methyl-n-butylketone, and (4) coplanar and non-coplanar polychlorinated biphenyls. These mechanistic studies show that interactions should be described at the level of target tissue dose and are best categorized as either pharmacokinetic (PK) or pharmacodynamic (PD) interactions.

Human CD34+ hematopoietic progenitor cells are sensitive targets for toxicity induced by 1,4-benzoquinone.

Chronic human exposure to benzene has been linked to several hematopoietic disorders, including leukemia and lymphomas. Certain benzene metabolites, including benzoquinone (BQ), are genotoxic and mutagenic. Bone marrow stem cells are targets for benzene-induced cytotoxicity and DNA damage that could result in changes to the genome of these progenitor cells, thereby leading to hematopoietic disorders and cancers.

Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl) phthalate.

In utero exposure of male rats to the antiandrogen di(n-butyl) phthalate (DBP) leads to decreased anogenital distance (AGD) on postnatal day (PND) 1, increased areolae retention on PND 13, malformations in the male reproductive tract, and histologic testicular lesions including marked seminiferous epithelial degeneration and a low incidence of Leydig cell (LC) adenomas on PND 90. One objective of this study was to determine the incidence and persistence of decreased AGD, increased areolae retention, and LC adenomas in adult rats following in utero DBP exposure. A second objective was to determine whether AGD and areolae retention during the early postnatal period are associated with lesions in the male reproductive tract.

A distributed-parameter model for formaldehyde uptake and disposition in the rat nasal lining.

DNA-protein cross-links (DPX) serve as a dosimeter for inhaled formaldehyde and are associated with tumor induction in rat nasal passages after chronic exposure to 6 ppm and above. To determine the role of epithelium-specific morphometry in formaldehyde-induced patterns of injury, we developed a mathematical model that links airflow-driven formaldehyde uptake with DPX formation in regions of the rat nose with high and low tumor incidence. A three-dimensional, anatomically accurate computational fluid dynamics model of rat nasal airflow and inhaled gas uptake was integrated with a physiologically based mathematical model incorporating tissue thickness, formaldehyde diffusion, its removal by enzymatic and nonenzymatic processes, and DNA distribution in the nasal mucosa to predict DPX formation.

Species and gender differences in the metabolism and distribution of tertiary amyl methyl ether in male and female rats and mice after inhalation exposure or gavage administration.

Tertiary amyl methyl ether (TAME) is a gasoline fuel additive used to reduce emissions. Understanding the metabolism and distribution of TAME is needed to assess potential human health issues. The effect of dose level, duration of exposure and route of administration on the metabolism and distribution of TAME were investigated in male and female F344 rats and CD-1 mice following inhalation or gavage administration.

Blood pharmacokinetics of tertiary amyl methyl ether in male and female F344 rats and CD-1 mice after nose-only inhalation exposure.

Interest in understanding the biological behavior of aliphatic ethers has increased owing to their use as gasoline additives. The purpose of this study was to investigate the blood pharmacokinetics of the oxygenate tertiary amyl methyl ether (TAME), its major metabolite tertiary amyl alcohol (TAA) and acetone in rats and mice following inhalation exposure to TAME. Species differences in the area under the curve (AUC) for TAME were significant at each exposure concentration.

Characterization of metabolites and disposition of tertiary amyl methyl ether in male F344 rats following inhalation exposure.

Tertiary amyl methyl ether (TAME) is a fuel additive used to reduce carbon monoxide in automobile emissions. Because of the potential for human exposure, this study was conducted to develop methods for the characterization and quantitation of metabolites in expired air and excreta of rats exposed to a mixture of [13C]- and [14C]TAME ([2,3,4-13C]- and [2-14C]2-methoxy-2-methylbutane). The distribution of TAME in rats was determined following inhalation exposure, and TAME-derived metabolites were characterized in expired air and urine.

Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats.

This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identification study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD(Sprague-Dawley) rats and CD-1 mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6-16 (mice) or 6-19 (rats).

Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism.

In utero exposure to di(n-butyl) phthalate (DBP) leads to a variety of male reproductive abnormalities similar to those caused by androgen receptor antagonists. DBP demonstrates no affinity for the androgen receptor, but rather leads to diminished testosterone production by the fetal testis. The purpose of this study was to determine the onset and reversibility of DBP effects on the fetal testis and to determine at a functional level the points in the cholesterol transport and steroidogenesis pathways affected by DBP.

Inhaled iron, unlike manganese, is not transported to the rat brain via the olfactory pathway.

Iron and manganese share structural, biochemical, and physiological similarities. The objective of this study was to determine whether iron, like manganese, is transported to the rat brain via the olfactory tract following inhalation exposure. Eight-week-old male CD rats were exposed to approximately 0.

Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice.

The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of renal cell carcinoma (RCC) in humans. VHL functions as a ubiquitin E3 ligase, controlling the stability of hypoxia inducible factor (HIF) and tumor angiogenesis. Alterations in this tumor suppressor gene are rarely observed in spontaneous or chemically induced RCC that arise in conventional strains of rodents and Vhl knockout mice (Vhl+/-) do not develop spontaneous RCC.

Nonmonotonic dose-response relationships: mechanistic basis, kinetic modeling, and implications for risk assessment.

Dose-response curves for the first interaction of a chemical with a biochemical target molecule are usually monotonic; i.e., they increase or decrease over the entire dose range.

Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles.

A multispecies, subchronic, inhalation study comparing pulmonary responses to ultrafine titanium dioxide (uf-TiO(2)) was performed. Female rats, mice, and hamsters were exposed to aerosol concentrations of 0.5, 2.