Endocrine disrupting effects in rats perinatally exposed to a dietary relevant mixture of phytoestrogens.

Dietary phytoestrogens may prevent certain human diseases, but endocrine activity has been reported in animal studies. Sprague-Dawley rats were exposed perinatally to a 1-, 10- or 100-fold "high human dietary intake" mixture of 12 phytoestrogens consisting of mainly the lignan secoisolarici resinol and the isoflavones genistein and daidzein. This mixture induced persistent adverse effects, as adult male mammary glands showed hypertrophic growth. A reduced anogenital distance in newborn males indicated an anti-androgenic mode of action. Testosterone levels, testis and prostate weights, and expression of selected genes in testis and prostate were unaffected. Decreased serum estradiol was seen in genistein-exposed dams. This study indicated adverse effects at high intake levels in rats, but does not provide evidence for risk of phytoestrogen-mediated endocrine disruption at normal human dietary consumption levels. Further studies are warranted to increase the knowledge upon which risk assessment on dietary phytoestrogen exposure during pregnancy and infancy is based.

Effects of nutrition relevant mixtures of phytoestrogens on steroidogenesis, aromatase, estrogen, and androgen activity.

Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects on steroid hormone production, aromatase activity, estrogenic activity, and for interaction with the androgen receptor. The results show that a mixture of all tested PEs increased estradiol production and decreased testosterone production in H295R human adrenal corticocarcinoma cells, indicating an induced aromatase activity. Furthermore, exposure of the H295R cells to isoflavonoids caused a decrease in testosterone production, and various mixtures of PEs significantly stimulated MCF-7 human breast adenocarcinoma cell growth and induced aromatase activity in JEG-3 choriocarcinoma cells. The estrogenic effect in the MCF7 cells of the isoflavonoid mixture and coumestrol was supported by an observed increase in progesterone receptor protein expression as well as a decreased ERalpha expression. Overall, the results support that nutrition-relevant concentrations of PEs both alone and in mixtures possess various endocrine disrupting effects, all of which need to be considered when assessing the effects on human health.

Mixture toxicity of three toxicants with similar and dissimilar modes of action to Daphnia magna.

Mixture toxicity of similar- and dissimilar-acting toxicants can be predicted by the models concentration addition (CA) and independent action (IA) using single substance toxicity data. Knowledge of the toxicants mode of action is thus required in order to use the models. In order to test the predictive capability of the models, we conducted Daphnia magna 48 h immobilization experiments with three toxicants with known modes of action (dimethoate, pirimicarb and linear alkyl benzene sulfonate) singly, and in binary and ternary mixtures. Our results indicate that CA and IA predict binary mixtures of similar- and dissimilar-acting toxicants equally well. CA and IA also equally predicted the ternary mixture consisting of both similar- and dissimilar-acting chemicals. The paper discusses the concept of mode of action and the implications the definition of mode of action has on the choice of reference model for mixture toxicity studies.