Central role of PPARalpha in the mechanism of action of hepatocarcinogenic peroxisome proliferators.

Peroxisome proliferators (PP) are a large class of structurally dissimilar chemicals. These chemicals have diverse effects in rodents and humans, including regulation of lipid metabolism, growth promotion, and induction of hepatocarcinogenesis. Most, if not all, effects of PP are mediated by three members of the nuclear receptor superfamily called PP-activated receptors (PPAR).

Epoxybutene-hemoglobin adducts in rats and mice: dose response for formation and persistence during and following long-term low-level exposure to butadiene.

Measurement of specific adducts to hemoglobin can be used to establish the dosimetry of electrophilic compounds and metabolites in experimental animals and in humans. The purpose of this study was to investigate the dose response for adduct formation and persistence in rats and mice during long-term low-level exposure to butadiene by inhalation. Adducts of 3,4-epoxy-1-butene, the primary metabolite of butadiene, with N-terminal valine in hemoglobin were determined in male B6C3F1 mice and male Sprague-Dawley rats following exposure to 0, 2, 10, or 100 ppm of 1,3-butadiene, 6 h/day, 5 days/week for 1, 2, 3, or 4 weeks.

Physiologically based pharmacokinetic modeling of blood and tissue epoxide measurements for butadiene.

In vitro and in vivo butadiene (BD) metabolism data from laboratory animals were integrated into a rodent physiologically based pharmacokinetic (PBPK) model with flow- and diffusion-limited compartments. The resulting model describes experimental data from multiple sources under scenarios such as closed chamber inhalation and nose-only flow-through inhalation exposures. Incorporation of diurnal glutathione (GSH) variation allows accurate simulation of GSH changes observed in air control nose-only exposures and BD exposures.

Region-specific DNA synthesis in brains of F344 rats following a six-day bromodeoxyuridine infusion.

Prolonged exposure to certain alkylating chemicals induces glial and meningeal tumours in rats, probably resulting from DNA damage to dividing neural cells. The present work evaluated DNA synthesis in the brains of untreated, young adult male F344 rats in order to define a BrdUrd infusion protocol to more adequately assess proliferation in slowly dividing neural cell populations. BrdUrd (2.

Health risk assessment of chemical mixtures from a research perspective.

Human exposures to chemicals in the environment and workplace typically involve chemical mixtures. One of the key risk assessment issues for mixtures is that of extrapolation from high to low dose. Observation of an interaction among chemicals in a mixture at high concentrations in animals does not necessarily mean that the same effect, in type or magnitude, will be significant in humans exposed to lower concentrations of the mixture.

Immunohistochemical localization of p53, PCNA, and TGF-alpha proteins in formaldehyde-induced rat nasal squamous cell carcinomas.

Mutation of the p53 tumor suppressor gene is a common event in many human cancers and has been specifically associated with invasive squamous cell carcinoma of the human skin and respiratory tract. Alterations in the p53 gene have also been identified in certain rodent tumors, including formaldehyde-induced nasal squamous cell carcinomas. Overexpression of transforming growth factor-alpha (TGF-alpha) is associated with carcinomas of the head and neck and respiratory tract in human patients and formaldehyde-induced rat nasal squamous cell carcinomas.

Peroxisome proliferators: potential role of altered hepatocyte growth and differentiation in tumor development.

Continued, exposure-dependent proliferation of hepatocytes in basophilic proliferative lesions appears to be critical to the mechanism of peroxisome proliferator carcinogenesis in rodents. Identification of the growth regulatory pathway(s) involved in the exaggerated hepatocellular proliferation observed in these lesions is proceeding. So far, regulatory pathways involving cyclophilin and IGFII/M6P receptor have been implicated, while no evidence for involvement of HGF-R, TGF alpha, or PPAR is available.

The toxicity of 1-week exposures to inhaled chloroform in female B6C3F1 mice and male F-344 rats.

Detailed quantitative descriptions of the toxicity of inhaled chloroform are lacking, despite the fact that the majority of environmental exposures occur by this route. We investigated the ability of chloroform vapors to produce toxicity and regenerative cell proliferation in the livers and kidneys, the principal target organs for carcinogenicity of female B6C3F1 mice and male F-344 rats, respectively. Nasal passages were also examined for toxic responses.

Nasal toxicity of chloroform in male F-344 rats and female B6C3F1 mice following a 1-week inhalation exposure.

Chloroform is an important environmental water and air pollutant. Inhalation exposure of female B6C3F1 mice and F-344 rats for 6 hr/day for 7 consecutive days to 0, 1, 3, 10, 30, 100, or 300 ppm of chloroform resulted in concentration-dependent lesions in the nasal passages. Chloroform-induced changes included increased epithelial mucosubstances in the respiratory epithelium of the nasopharyngeal meatus, primarily in the rats.

Computer-assisted semen analysis: results vary across technicians who prepare videotapes.

Automated semen analyses revealed differences of 21% to 30% in concentration-related parameters and 5% to 11% in motion-related parameters between means of groups of replicate specimens. Disparities among videotapes produced by two laboratory technicians accounted for the divergence in concentration-related parameters. This resulted partially from differences between the two technicians in propensity to dilute concentrated specimens.