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Abstract for I01090

The Assessment of the Ability of Trans-Resveratrol to Modulate Type 1 Diabetes in Female Non-Obese Diabetic (NOD/MrkTac) Mice

CASRN: 501-36-0
Chemical Formula: C14H12O3
Molecular Weight: 228.246
Report Date: October 2012

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.

trans-Resveratrol is a polyphenol that is found naturally in grapes, peanuts, and a number of other plants (Cottart et al., 2010). Human exposure to resveratrol compounds occurs mainly through the diet. RES was nominated for toxicology studies by the National Institute of Environmental Health Sciences based on the widespread human exposure to resveratrol through natural dietary sources and dietary supplement use, and also based on concern that RES has not been sufficiently evaluated for potential toxicological effects. Type 1 diabetes, or insulin-dependent diabetes mellitus, is an immune-mediated disease that represents a significant public health concern, as the global incidence is increasing approximately 3% per year. T1D is among the most common chronic diseases with onset in childhood. In addition to genetic susceptibility, environmental triggers (such as drugs, chemicals, and diet) are also involved in the development of T1D.

The objective of this study was to determine if RES had the potential to modulate the progression of T1D in female non-obese diabetic/MrkTac mice when administered by gavage once daily for up to 21 weeks. Six groups of mice (approximately 32 animals/group; 6-7 weeks of age with normal blood glucose levels) were utilized: vehicle control (0.5% methylcellulose), and five RES treatment groups (125, 250, 500, 1000, and 2000 mg/kg body weight). Mice were fed a soy- and alfalfa-free diet (5K96) during the study, and were monitored for body weight and blood glucose changes every week. Approximately 8 animals per group were euthanized at 51 days for an interim histopathology analysis. The remaining animals (approximately 24/group) were maintained until the terminal sacrifice. RES-treated animals started to develop diabetes at week 2 during the study. At week 9, no mice in the vehicle group and the 500 mg/kg RES group were diabetic, while the incidences of diabetes (blood glucose ≥ 250 mg/dl) in other RES groups ranged from 4.2 to 16.7%. Vehicle mice started to develop diabetes at week 10. Significant decreases (60 - 63%) in the incidence of diabetes were observed from week 18 to the study termination in the 125 mg/kg dose group when compared to the vehicle control. In the 250 mg/kg dose group, a 31% decrease in the incidence of diabetes was observed at week 17. No other significant changes were observed for any other groups at any time during the study.

Overall, body weight was not significantly affected with the exception that a slight (< 6%), albeit significant, increase was observed at day 92 (week 13) in the 250 mg/kg RES group in Study 2. Similarly, significant increases in body weight gain in the 250 mg/kg RES group were observed at days 71, 78, 85, and 92 during the study. There were significant decreases in liver weight in terminally euthanized mice at the 500 mg/kg dose level when compared to the vehicle control in both Study 1 (absolute and relative) and Study 2 (relative). In Study 2, both absolute and relative liver weights were increased at the 2000 mg/kg dose level. Furthermore, in Study 2, decreases (approximately 12%) in relative kidney weights were observed at the 125 mg/kg dose level when compared to the vehicle control in mice exposed to RES for 147 days. Among animals that died or were euthanized prematurely, differences in spleen, pancreas, and adrenal gland weights were observed. In addition, some toxicity was noted (including impaction of the gavage suspension in the gastrointestinal tract) at doses ≥ 250 mg/kg as demonstrated by significant decreases in the percentages of total living mice starting at week 11 in the 2000 mg/kg dose group and at week 12 in the 1000 mg/kg dose group.

Taken together, these results indicate that oral exposure to RES at 125 mg/kg dose level delayed the development of type 1 diabetes in female NOD mice fed a soy- and alfalfa-free diet. At higher dose levels, the effect of RES was inconclusive due to the toxicity observed.

Reference

Cottart, C. H., Nivet-Antoine, V., Laguillier-Morizot, C., & Beaudeux, J. L. (2010). Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res 54, 7-16.