Wyeth-14,643 (WY) and ammonium perfluorooctanoate (C8) belong to a diverse class of compounds which have been shown to produce hepatic peroxisome proliferation in rodents. From previous work, WY, but not C8, has been shown to produce hepatocellular carcinoma in rats, while C8 has been shown to produce Leydig cell adenomas. In addition, based on a review of bioassay data a relationship appears to exist between peroxisome-proliferating compounds and Leydig cell adenoma and pancreatic acinar cell hyperplasia/adenocarcinoma formation. To further investigate the relationship between peroxisome-proliferating compounds and hepatic, Leydig cell, and pancreatic acinar cell tumorigenesis, a 2-year feeding study in male CD rats was initiated to test the hypothesis that peroxisome proliferating compounds induce a tumor triad (liver, Leydig cell, pancreatic acinar cell), and to examine the potential mechanism for the Leydig cell tumors. The study was conducted using 50 ppm WY and 300 ppm C8. The concentration of WY in the diet was decreased to 25 ppm on test day 301 due to increased mortality. In addition to the ad libitum control, a second control was pair-fed to the C8 group. Interim sacrifices were performed at 1- or 3-month intervals. Peroxisome proliferation measured by beta-oxidation activity and cell proliferation were measured in the liver and testis at all time points and in the pancreas beginning at the 9-month time point (cell proliferation only). Serum hormone concentrations (estradiol, testosterone, LH, FSH, and prolactin) were also measured at each time point. Increased relative liver weights and hepatic beta-oxidation activity were observed in both the WY- and C8-treated rats at all time points. In contrast, hepatic cell proliferation was significantly increased only in the WY-treated group. Neither WY nor C8 significantly altered the rate of Leydig cell beta-oxidation or Leydig cell proliferation when compared to the control groups. Moreover, the basal rate of beta-oxidation in Leydig cells was approximately 20 times less than the rate of hepatic beta-oxidation. There were no biologically meaningful differences in serum testosterone, FSH, prolactin, or LH concentrations in the WY- and C8-treated rats when compared to their respective controls. There were, however, significant increases in serum estradiol concentrations in the WY- and C8-treated rats at 1, 3, 6, 9, 15, 18, and 21 months. At 12 months, only the C8-treated rats had elevated serum estradiol concentrations when compared to the pair-fed control. Histopathological evaluation revealed compound-related increases in liver, Leydig cell, and pancreatic acinar cell tumors in both WY- and C8-treated rats. The data support the hypothesis that the peroxisome-proliferating compounds induce the previously described tumor triad. In addition, both C8 and WY produced a sustained increase in serum estradiol concentrations that correlated with the potency of the 2 compounds to induce Leydig cell tumors (i.e., WY caused a more consistent sustained increase in serum e...
Administration of ammonium salts of perfluorooctanoate (PFOA) to rats results in peroxisome proliferation and benign liver tumors, events associated with activation of the nuclear receptor (NR) peroxisome proliferator-activated receptor-alpha (PPARalpha). Due to its fatty acid structure, PFOA may activate other NRs, such as PPARbeta, PPARgamma, liver X receptor (LXR), or retinoid X receptor (RXR). In this study, the activation of human, mouse, and rat PPARalpha, PPARbeta, PPARgamma, LXRbeta, and RXRalpha by PFOA (including its linear and branched isomers) and perfluorooctane sulfonate (PFOS) was investigated and compared to several structural classes of natural fatty acids and appropriate positive control ligands. An NR ligand-binding domain/Gal4 DNA-binding domain chimeric reporter system was used. Human, mouse, and rat PPARalpha were activated by PFOA isomers and PFOS. PPARbeta was less sensitive to the agents tested, with only PFOA affecting the mouse receptor. PFOA and PFOS also activated human, mouse, and rat PPARgamma, although the maximum induction of PPARgamma was much less than that seen with rosiglitazone, suggesting that PFOA and PFOS are partial agonists of this receptor. Neither LXRbeta nor the common heterodimerization partner RXRalpha was activated by PFOA in any species examined. Taken together, these data show that of the NRs studied, PPARalpha is the most likely target of PFOA and PFOS, although PPARgamma is also activated to some extent. Compared to naturally occurring long-chain fatty acids, e.g. linoleic and alpha-linolenic acids, these perfluorinated fatty acid analogs were more selective and less potent in their activation of the NRs.
An in vivo screening assay using intact adult male rats has been evaluated for its ability to detect six antiandrogenic compounds via oral administration. The test compounds included cyproterone acetate (CPA), flutamide (FLUT), p,p'-DDE (DDE), di-n-butyl phthalate (DBP), linuron (LIN), and vinclozolin (VCZ). Two of the test compounds (DDE and FLUT) have been previously evaluated in the 15-day intact male assay with compound administration via intraperitoneal injection (ip). For the current studies, male rats were dosed for 15 days via oral gavage and euthanized on the morning of test day 15. The endpoints evaluated included final body and organ weights (liver, thyroid gland, testes, epididymides, prostate, seminal vesicles with fluid, accessory sex gland unit [ASG]), serum hormone concentrations (testosterone [T], estradiol [E2], dihydrotestosterone [DHT], luteinizing hormone [LH], follicle stimulating hormone [FSH], prolactin [PRL], T(3), T(4), and thyroid stimulating hormone[TSH]), and histopathology of the testis, epididymis, and thyroid gland; positive results for each endpoint are described below. In addition, an evaluation of immune system endpoints (humoral immune function, spleen and thymus weights, and spleen cell number) was conducted on a subset of animals dosed with either DDE or FLUT. All six endocrine-active compounds (EACs) increased relative liver weight. FLUT and VCZ caused the typical pattern for an androgen receptor (AR) antagonist, although not all endpoints were statistically significant for VCZ: decreased ASG weights, hormonal alterations (increased T, DHT, LH, and FSH), and induced Leydig cell hypertrophy and/or hyperplasia. CPA caused effects consistent with its mixed AR antagonist/progesterone receptor agonist activity: it decreased ASG weights, caused hormonal alterations (increased T and E2; decreased FSH), and caused spermatid retention. DBP, a compound with antiandrogen-like activity via a nonreceptor mediated mechanism, caused hormonal alterations (decreased T, DHT, and E2; increased LH, FSH, and PRL) and induced general testicular degeneration. LIN, a weak AR antagonist, decreased ASG weights, caused hormonal alterations (decreased T, DHT, and LH; increased E2), and caused spermatid retention. Unlike the other AR antagonists evaluated, DDE, a weak AR antagonist, did not alter reproductive parameters. All six antiandrogens caused some effects on thyroid parameters, although only CPA, DDE, and VCZ caused results consistent with a potential thyroid-modulator. FLUT and DDE did not alter the primary humoral immune response to SRBC, spleen or thymus weights, or spleen cell number. In the current study, 5 of the six test substances were identified as endocrine-active substances consistent with their known/proposed mechanism(s) of action. The effects that were observed in the current study via oral (gavage) compound administration were similar to the responses that were observed by the ip route in previous studies for DDE and FLUT. This report, in addition to the > 20 compounds that have al...
A subchronic inhalation toxicity study of inhaled vapor grown carbon nanofibers (CNF) (VGCF-H) was conducted in male and female Sprague Dawley rats. The CNF test sample was composed of > 99.5% carbon with virtually no catalyst metals; Brunauer, Emmett, and Teller (BET) surface area measurements of 13.8 m2/g; and mean lengths and diameters of 5.8 µm and 158 nm, respectively.Four groups of rats per sex were exposed nose-only, 6 h/day, for 5 days/week to target concentrations of 0, 0.50, 2.5, or 25 mg/m3 VGCF-H over a 90-day period and evaluated 1 day later. Assessments included conventional clinical and histopathological methods, bronchoalveolar lavage fluid (BALF) analysis, and cell proliferation (CP) studies of the terminal bronchiole (TB), alveolar duct (AD), and subpleural regions of the respiratory tract. In addition, groups of 0 and 25 mg/m3 exposed rats were evaluated at 3 months postexposure (PE). Aerosol exposures of rats to 0.54 (4.9 f/cc), 2.5 (56 f/cc), and 25 (252 f/cc) mg/m(3) of VGCF-H CNFs produced concentration-related small, detectable accumulation of extrapulmonary fibers with no adverse tissue effects. At the two highest concentrations, inflammation of the TB and AD regions of the respiratory tract was noted wherein fiber-laden alveolar macrophages had accumulated. This finding was characterized by minimal infiltrates of inflammatory cells in rats exposed to 2.5mg/m(3) CNF, inflammation along with some thickening of interstitial walls, and hypertrophy/hyperplasia of type II epithelial cells, graded as slight for the 25mg/m(3) concentration. At 3 months PE, the inflammation in the high dose was reduced. No adverse effects were observed at 0.54mg/m(3). BALF and CP endpoint increases versus controls were noted at 25mg/m(3) VGCF-H but not different from control values at 0.54 or 2.5mg/m(3). After 90 days PE, BALF biomarkers were still increased at 25mg/m(3), indicating that the inflammatory response was not fully resolved. Greater than 90% of CNF-exposed, BALF-recovered alveolar macrophages from the 25 and 2.5mg/m(3) exposure groups contained nanofibers (> 60% for 0.5mg/m(3)). A nonspecific inflammatory response was also noted in the nasal passages. The no-observed-adverse-effect level for VGCF-H nanofibers was considered to be 0.54mg/m(3) (4.9 fibers/cc) for male and female rats, based on the minimal inflammation in the terminal bronchiole and alveolar duct areas of the lungs at 2.5mg/m(3) exposures. It is noteworthy that the histopathology observations at the 2.5mg/m(3) exposure level did not correlate with the CP or BALF data at that exposure concentration. In addition, the results with CNF are compared with published findings of 90-day inhalation studies in rats with carbon nanotubes, and hypotheses are presented for potency differences based on CNT physicochemical characteristics. Finally, the (lack of) relevance of CNF for the high aspect ratio nanomaterials/fiber paradigm is discussed.
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