Trans-resveratrol (RES) is a polyphenol found in various fruits and plants. Numerous in vitro studies have shown its clear antioxidant and anti-inflammatory effects, which has led to additional in vivo and clinical studies evaluating the use of RES to treat diseases such as cancer, cardiometabolic disease, and neurodegenerative disease. Despite growing interest in and use of RES, limited studies have assessed the safety of RES exposure, especially perinatally. The National Toxicology Program conducted toxicity studies to provide these data.
In the 3-month studies, RES (in 0.5% aqueous methylcellulose) was administered via gavage to time-mated Wistar Han rats from gestation day (GD) 6 through lactation day (LD) 21 at doses of 0, 78, 156, 312.5, 625, or 1,250 mg RES/kg body weight/day (mg/kg/day). Doses were selected based on the lack of observed toxicity in 2-week studies in Fischer 344 (F344/NTac) rats. Offspring were administered the same dose as respective dams from postnatal day (PND) 12 through PND 21 and then for 3 months after weaning. In addition, male and female B6C3F1/N mice at 5–6 weeks of age were administered 0, 156, 312, 625, 1,250, or 2,500 mg/kg/day of RES for 3 months.
In Wistar Han rats, no dose-related effects of RES on dam survival, gestation length, litter size, or pup weight on PND 1 were identified. Maternal mean body weights and body weight gains of RES-dosed dams were significantly decreased (4%–10% and 19%–35%, respectively) relative to the vehicle control group, especially during the later period of gestation (GD 15–21). The presence of RES and its metabolites in fetal tissue suggested low maternal transfer, and the presence of RES and its metabolites in PND 4 whole pups suggested lactational transfer. Pup mean body weights of RES-dosed groups (≥312.5 mg/kg/day) were lower starting on PND 4 through weaning. During the postweaning period, there was no dose-related effect on survival. Interim mean body weights of male and female rats in the 1,250 mg/kg/day groups during lactation were approximately 20% lower than those of the vehicle control groups. By study termination, mean body weights of all RES-dosed Wistar Han rats were within 10% of the vehicle control groups. There were no dose-related changes in sperm count or estrous cycling. Dose-related histological findings in the Wistar Han rat included nephropathy and renal pelvis and renal tubule dilatation in the kidney and lymphatic ectasia in the small intestine.
In B6C3F1/N mice, mean body weights were similar between RES-dosed and vehicle control groups throughout the study. After 3 months, there were no dose-related effects on survival. Minimal indications of decreased sperm count and impaired estrous cycling were observed, but these findings were not considered indicative of reproductive toxicity. The absolute and relative liver weights of 2,500 mg/kg/day male mice were significantly increased. Relative liver weights of ≥625 mg/kg/day female mice and relative kidney weights of ≥1,250 mg/kg/day female mice were significantly increased. These increased organ weights were not associated with microscopic findings. Respiratory metaplasia in the olfactory epithelium of the nose was observed in female mice. Increased incidences of this lesion were significant only at the highest dose (2,500 mg/kg/day).
No changes in the frequency of micronucleated reticulocytes and erythrocytes were considered biologically relevant in either species. RES was not mutagenic in the Salmonella typhimurium strains tested.
Under the conditions of this study, the lowest-observed-effect level (LOEL) was 312.5 mg/kg/day in rats as indicated by significantly decreased pup mean body weights of Wistar Han rats exposed perinatally. These body weight differences were resolved in the rat pups by the end of the 3‑month study. In B6C3F1/N mice, the LOEL was 625 mg/kg/day as indicated by significantly increased relative liver weights in females; however, these changes in liver weight were not associated with microscopic lesions. The no-observed-effect levels were 156 mg/kg/day in rats and 312 mg/kg/day in mice. Target organs included the kidney and small intestine in rats and the nose in female mice. There was no evidence of genetic toxicity in the micronucleus assay of RES at oral gavage doses up to 1,250 mg/kg/day in Wistar Han rats or up to 2,500 mg/kg/day in B6C3F1/N mice. No clear effects on reproductive parameters were observed. The presence of RES and its metabolites in fetal tissue suggested low maternal transfer, and the presence of RES and its metabolites in PND 4 whole pups suggested lactational transfer.
National Toxicology Program (NTP). 2021. NTP technical report on the toxicity studies of trans-resveratrol (CASRN 501-36-0) administered by gavage for two weeks or three months to F344/NTac rats, Wister Han [Crl:WI(Han)] rats, and B6C3F1/N mice. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 102. https://doi.org/10.22427/NTP-TOX-102