Molds of the genus Alternaria are common food pathogens responsible for the spoilage of fruits, vegetables, grains, and nuts. Although consumption of Alternaria alternata-contaminated foodstuffs has been implicated in an elevated incidence of esophageal carcinogenesis, the mutagenic potencies of several A. alternata toxins seem unable to account for the levels of activity found using crude mycelial extracts. In this study, the mutagenic effects of nitrosylation were examined with the major Alternaria metabolites Altenuene (ALT), Alternariol (AOH), Alternariol Monomethyl Ether (AME), Altertoxin I (ATX I), Tentoxin (TENT), Tenuazonic Acid (TA), and Radicinin (RAD) using the Ames Salmonella strains TA98 and TA100. In the absence of nitrosylation, ATX I was mutagenic when tested from 1 to 100 microg/plate in TA98 with rat liver S9 for activation, while AOH and ATX I were weakly mutagenic +/- S9 in TA100. Incubation with nitrite generally increased mutagenic potencies with ATX I strongly mutagenic +/- S9 in both TA98 and TA100, while ALT, AOH, AME, and RAD responses were enhanced in TA100 + S9. However, subsequent examination of three extracts made from A. alternata culture broth, acetone-washed mycelia, and the acetone washes showed a different mutagenic response with both broth and acetone washes directly mutagenic in TA98 and TA100 but with a reduced response + S9. The acetone-washed mycelial extract was found to have the lowest mutagenic activity of the three extracts tested. Nitrosylation had little effect on the mutagenicity of any of the extracts. Thus, while nitrosylation increases the mutagenicity of ATX I, and to a lesser extent that of several other Alternaria toxins, the results demonstrate that Alternaria produces a major mutagenic activity with a S. typhimurium response different from that found with the purified toxins. Efforts are currently underway to chemically identify this mutagenic species. Published 2001 Wiley-Liss, Inc.
In most thermally treated products, a series of alkylated furan derivatives have been found, in particular 2-substituted alkylfurans such as 2-methylfuran. These methyl analogs are metabolically activated in a similar fashion as the parent furan, yielding highly reactive unsaturated dialdehydes. There is currently limited toxicological data available for 2-methyl furan exposure by any route that makes conducting a risk assessment difficult. In this pilot study, we report the general toxicology findings affecting tissue morphology, histopathology, clinical biochemistry, and hematology in a 28-day gavage study. The liver was the primary target organ that developed dose-dependent toxicity. Relative liver weights were increased by 42% at 25.0 mg/kg/body weight (bw)/day. Histological changes in the liver were observed at 0.4, 1.5, 3.0, 6.0, 12.0, and 25.0 mg/kg bw/ day. These changes were not accompanied by clinical changes in the serum enzyme markers such as alanine transaminase, alkaline phosphatase, and aspartate transaminase. Clinical biochemistry markers for kidney were altered, but these were not accompanied by histological changes. The prostate was significantly decreased in size at the 25.0 mg/kg bw/day dose of 2-methyfuran. Some hematological parameters were also altered.
The effect of hepatic blood flow on the elimination of several highly cleared substrates was studied in the once-through perfused rat liver preparation. A constant and low input concentration of ethanol (2.0 mM), [14C]-phenacetin and [3H]-acetaminophen (0.36 and 0.14 microM, respectively), or meperidine (8.1 microM) was delivered once-through the rat liver preparation in five flow periods (greater than 35 min each); control flow periods at 12 ml/min were interrupted by flow changes to 8 or 16 ml/min. The steady-state hepatic availabilities (F or outflow survivals) at 12 ml/min were ethanol, 0.075 +/- 0.038; [14C]-phenacetin, 0.15 +/- 0.059; [3H]-acetaminophen, 0.34 +/- 0.051; meperidine, 0.047 +/- 0.017. Flow-induced changes were different among the compounds: with reduced flow (8 ml/min), F was decreased for ethanol (0.061 +/- 0.032) and [3H]-acetaminophen (0.28 +/- 0.051), as expected, but was increased for [14C]-phenacetin (0.20 +/- 0.068) and meperidine (0.05 +/- 0.03); with an elevation of flow (to 16 ml/min), F was increased for all compounds, as expected of shorter sojourn times: ethanol, 0.13 +/- 0.065; [14C]-phenacetin, 0.22 +/- 0.062; [3H]-acetaminophen, 0.43 +/- 0.063; meperidine, 0.055 +/- 0.022. A marked increase in F for ethanol had occurred when flow changed from 12 to 16 ml/min due to nonlinear metabolism; the latter was confirmed by a reduction in the extraction ratios at increasing concentrations (1.8 to 11.4 mM); this condition was not present for the other compounds. In order to explain the observations, we used the multiple indicator dilution technique to investigate the flow-induced behaviors of tissue distribution spaces of vascular and intracellular references in the perfused rat liver preparation.
Brominated diphenyl ethers (BDEs) are persistent environmental contaminants found in human blood, tissues, and milk. To assess the impact of the commercial BDE mixture DE-71 on the developing immune system in relation to hepatic and thyroid changes, adult (F0) rats were exposed to DE-71 by gavage at doses of 0, 0.5, 5, or 25 mg/kg body weight (bw)/d for 21 weeks. F0 rats were bred and exposure continued through gestation, lactation and postweaning. F1 pups were weaned and exposed to DE-71 by gavage from postnatal day (PND) 22 to 42. On PND 42, half of the F1 rats were assessed for toxicologic changes. The remaining F1 rats were challenged with the T-dependent antigen keyhole limpet hemocyanin (KLH) and immune function was assessed on PND 56. Dose-dependent increases in total BDE concentrations were detected in the liver and adipose of all F0 and F1 rats. In F0 rats, increased liver weight, hepatocellular hypertrophy, and decreased serum thyroxine (T4) were characteristic of DE-71 exposure. In F1 rats perinatal DE-71 exposure caused a nondose-dependent increase in body weight and dose-dependent increases in liver weight and hepatocellular hypertrophy. Serum T3 and T4 levels were decreased. In spleen from DE-71 exposed rats the area occupied by B cells declined while the area occupied by T cells increased; however, cellular and humoral immune responses to KLH challenge were not altered. Thus hepatic and thyroid changes in rats exposed perinatally to DE-71 were associated with altered splenic lymphocyte populations, an effect which has been linked to hypothyroidism.
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