Genistein Toxicity from Dietary Exposure from Early Pregnancy through Puberty

A dose range finding study was conducted by feeding genistein to Sprague-Dawley rats at 0, 5, 25, 100, 250, 625 and 1250 ppm in a soy-free diet, from gestation d 7 to postnatal d 50. Plasma levels ranged from ~l0 nmol/L to 10 [micro]mol/L. Adverse effects included hypertrophy and hyperplasia of the mammary ducts and acini in males at 25 ppm and in females at 625 ppm. Hypospermia at the head of the epididymis, inflammation of the dorsal prostate and asynchronous cycles of the uterus and vagina were observed at 625 ppm. Degeneration of the ovaries and seminiferous tubules was seen at 1250 ppm. There was a dose-dependent decrease in thyroid peroxidase activity at 25-1250 ppm. Thyroid peroxidase activity is known to be inhibited in vitro by genistein, and the prevalence of autoimmune thyroiditis was reported to be increased in children fed soy infant formula. In a separate study, genistein (1-100 [micro]g) was injected into neonatal mice daily on postnatal d 1-5 and the mice were killed at 18 mo. Polyovular multioocyte) follicles, uterine epithelial hyperplasia, hypoplastic uteri and uterine adenocarcinoma were observed. These were similar to the lesions reported earlier to be induced by diethylstilbestrol in mice by the use of the same treatment protocol. In addition to genistein, 45 other phyto- or mycoestrogens were assayed in a uterine estrogen receptor competitive binding assay. Twenty-nine of these competed and had a wide range of relative binding affinities. The number of naturally occurring chemicals that can bind to the estrogen receptor suggests that more intense or additional effects may be expected from exposures to multiple estrogenic chemicals from plants. These findings show a significant number of adverse effects from genistein in estrogen target organs, including malignancies. Some of these effects occur at low doses, consistent with findings from other estrogens. Additionally, genistein inhibition of thyroid peroxidase suggests the possibility that this mechanism may be responsible for goiter and autoimmune thyroiditis. The results of these studies have been used to design an ongoing multi-generation study with genistein that will examine reproductive fitness, among other endpoints. [Supported by USEPA #R825299-01-0.]