A repeated 28-day oral dose toxicity study of genistein in rats, based on the 'Enhanced OECD Test Guideline 407' for screening endocrine-disrupting chemicals

Abstract

In association with the international validation project to establish an OECD Enhanced Test Guideline 407, we performed a 28-day repeated-dose toxicity study of genistein, which is known as a phytoestrogen. Attention was paid to the sensitivity of certain additional parameters, such as histopathology observations and organ weights of endocrine related organs, sperm characteristics, serum hormone levels and estrous cycle, for detecting endocrine-related effects of endocrine-disrupting chemicals based on the existing TG 407. Seven-week-old Crj:CD(SD)IGS rats were assigned to one of four groups, each consisting of ten males and ten females, and genistein was administered once daily by gavage at doses of 0 (control), 120, 400 or 1000 mg/kg body weight per day. Male rats were killed on the day after the 28th administration. Female rats were killed on the day of the diestrus stage during the 4 days after the 28th administration. Endocrine-disrupting effects of genistein were detected in females by histopathology. The changes included vacuolation and mucinification of the vaginal epithelium in the 400 and 1000 mg/kg groups; however, the incidences of the lesion were very low. Although increased serum prolactin levels were recorded in the males of the 1000 mg/kg group, we could not determine whether this was indeed induced by genistein. General toxicological effects of genistein were detected in blood chemistry, such as increased triglycerides and total protein and a decreased albumin/globulin ratio, as well as increased liver weight and glycogen deposition in the periportal hepatocytes. Based on these results, the no-observed-adverse-effect level (NOAEL) in the present study was estimated to be 120 mg/kg per day. In particular, endocrine-related effects were most sensitively detected by histopathology examination of sexual organs. However, the findings indicate that chemicals with weak endocrine-disrupting potential like genistein must be evaluated taking into consideration the results of other test systems.

Phytoestrogens

“…This would equate to approximately 6 mg of genistein per day. In a study on potential toxicology of phytoestrogens, the no-observedadverse-effect level for genistein was estimated to be 120 mg/kg per day in rats (146). In rats, the hypocholesterolemic effect of a soy diet may involve interactions between the isoflavones and soy protein (149), whereas in cholesterol fed rabbits, attenuation of atherosclerosis by isoflavones does not require the presence of soy protein.…”

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

“…Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6,7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11)(12)(13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.…”

“…The benefits of using such a nutraceutical are many; it is possible that some patients may benefit simply from increasing their intake of soy products or adding a soy-based supplement to their diets, but further research is needed. The wealth of toxicity information on genistein suggests that it is safe for human consumption, even at the high concentrations used for cancer trials (11)(12)(13). This compound, however, is known to target multiple pathways (7,50) and, as such, must be used cautiously.…”

Assessing estrogenic activity of Nigella sativa in ovariectomized rats using vaginal cornification assay

“…Vaginal cytology assay is particularly used to determine the estrogenic activity of the synthetic estrogens, xenoestrogens (Ashby et al, 2000;Diel et al, 2000;Stroheker et al, 2003;Wuttke et al, 2003;Fusani et al, 2007) and phytoestrogens (Okazaki et al, 2002;Balk et al, 2002;Wuttke et al, 2003;Chiechi et al, 2003;Wang et al, 2003). It has been firstly used by Cook et al (1933).…”