Neoplastic pathology in male Sprague-Dawley rats fed AIN-93M diet ad libitum or at restricted intakes.

The primary purpose of this study was to evaluate the effects of age and long-term dietary reduction on neoplastic diseases in rats fed the AIN-93M purified diet. Second, pathologic profiles are critical to comprehensive dietary evaluation. Male Sprague-Dawley rats assigned to 2 groups, ad libitum (AL) and dietary restricted (DR), were fed the AIN-93M (casein protein) diet free choice and reduced in amount by 31%, respectively. At 58 weeks of age, the predominant types of lesions in AL and DR rats were pituitary and skin tumors. At 114 weeks of age, the most common lesions were pituitary, adrenal gland, skin, mammary, brain, and pancreatic tumors and mononuclear cell leukemia. However, DR had no significant effect on these lesions. Primary findings demonstrate that DR significantly reduced the total number of tumors per rat and incidence of benign and primary tumors (all organs) but did not reduce the incidence of malignant tumors (all organs). Dietary restriction increased the percentage of unknown deaths. These results may explain why survival rates for AL and DR rats were not significantly different at 114 weeks (43.3 vs 57.5%, respectively). These findings differ from previous studies using NIH-31 cereal diet (Aging Clin Exp Res 2001;13:263; J Nutr 2002;132:101; Aging Clin Exp Res 2003;16(6):68; Aging Clin Exp Res 2004;16:448) where neoplastic lesions rather than nonneoplastic lesions were linked to a significant increase in survival rate among cohorts of DR-fed rats (J Nutr 2002;132:101). Factors such as diet composition and digestibility, although not independent of body weight, may have contributed to differences in rat mortality and may affect humans in a similar manner.

Nonneoplastic pathology in male Sprague-Dawley rats fed the American Institute of Nutrition-93M purified diet at ad libitum and dietary-restricted intakes.

This study evaluates the effects of age and chronic dietary restriction (DR) on nonneoplastic diseases in rats that were fed the American Institute of Nutrition (AIN)-93M purified diet. Male Sprague-Dawley (SD) rats were divided into an ad libitum (AL) group and a DR group that was fed the AIN-93M diet with intake reduced by 31%. Nonneoplastic disease profiles were developed to clarify whether the AIN-93M diet fulfills long-term nutritional requirements of rats. Subsets of rats were killed at 58 and 114 weeks of age, and histopathology was performed. At 58 weeks of age, the 2 main types of nonneoplastic diseases in AL rats were liver vacuolization and cardiomyopathy. Dietary restriction reduced the severity and incidence of both lesions. At 114 weeks of age, the most common lesions in AL rats were cardiomyopathy, nephropathy, liver vacuolization, and degeneration with renal failure and genitourinary infections causing the greatest mortality. Dietary restriction reduced the incidence and severity of these lesions. Nonneoplastic diseases accounted for 28.9% and 0.0% of total mortalities in the AL and DR groups, respectively; however, there was a higher incidence of unknown deaths in the DR rats (52.6%) compared to AL rats (28.9%), which may have limited the success of DR to improve survival. Although the AIN-93M diet supported chronic rat growth, alterations in some dietary component concentrations may be required to lower body weight in chronic rodent and human studies. Factors such as diet composition and digestibility may alter nonneoplastic diseases and mortality in rats and humans in a similar fashion.

Modeling and assaying dioxin-like biological effects for both dioxin-like and certain non-dioxin-like compounds.

13C NMR data have been correlated to Toxic Equivalency Factors (TEFs) of the 29 PCDDs, PCDFs, or PCBs for which non-zero TEFs have been defined. Such correlations are called quantitative spectrometric data-activity relationship (QSDAR) models. An improved QSDAR model predicted TEFs of 0.037 and 0.004, respectively, for 1,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4,7-pentachlorodibenzo-p-dioxin (PeCDD), both among the 390 congeners for which zero value TEFs are assumed. A QSDAR model of Relative Potency (REP) values estimated the corresponding values as 0.115 and 0.020. Results from both models indicated that these two congeners may exhibit significant dioxin-like toxicity. If other such congeners have non-zero toxicity, TEF-based risk assessments of some dioxin-, furan-, or PCB-contaminated sites or foods may underestimate toxicity. Both models were extensively cross-validated and the TEF model was externally validated. We confirmed the predictions by an independent in vitro method, a luciferase gene expression assay based on mouse liver cells that found REPs of 0.027 and 0.013, respectively, for 1,3,7,8-TCDD and 1,2,3,4,7-PeCDD. The QSDAR-estimated and gene-expression assayed values agreed. The models were used to predict activity for an applicability domain including 108 non-2,3,7,8 dioxin, furan, or PCB congeners and 2,3,7,8-tetrachlorophenothiazine, a dioxin analog proposed as a drug candidate. This study showed that QSDAR prediction followed by a relatively inexpensive in vitro assay could be used to nominate a few candidates among hundreds for further investigation. It suggested that in silico and in vitro nomination protocols may facilitate practical risk assessment when chemical family members exhibit different degrees of toxicity operating via a common mechanism.

Phytoestrogens and mycoestrogens bind to the rat uterine estrogen receptor.

Consumption of phytoestrogens and mycoestrogens in food products or as dietary supplements is of interest because of both the potential beneficial and adverse effects of these compounds in estrogen-responsive target tissues. Although the hazards of exposure to potent estrogens such as diethylstilbestrol in developing male and female reproductive tracts are well characterized, less is known about the effects of weaker estrogens including phytoestrogens. With some exceptions, ligand binding to the estrogen receptor (ER) predicts uterotrophic activity. Using a well-established and rigorously validated ER-ligand binding assay, we assessed the relative binding affinity (RBA) for 46 chemicals from several chemical structure classes of potential phytoestrogens and mycoestrogens. Although none of the test compounds bound to ER with the affinity of the standard, 17beta-estradiol (E(2)), ER binding was found among all classes of chemical structures (flavones, isoflavones, flavanones, coumarins, chalcones and mycoestrogens). Estrogen receptor relative binding affinities were distributed across a wide range (from approximately 43 to 0.00008; E(2) = 100). These data can be utilized before animal testing to rank order estimates of the potential for in vivo estrogenic activity of a wide range of untested plant chemicals (as well as other chemicals) based on ER binding.