alpha. In combined studies with estradiol, genistein exerted additive effects with estradiol in vitro. In the
in vivo portion of the study, groups of six pregnant Sprague-Dawley females were fed one of the
following four diets, and the pups were maintained on the same diets until puberty: (1) a natural-
ingredient, open-formula rodent diet (NIH-07) containing 16 mg genistein and 14 mg daidzein per 100 g
of feed; (2) a soy- and alfalfa-free diet (SAFD) in which casein and corn oil were substituted for soy and
alfalfa meal and soy oil, respectively, that contained no detectable isoflavones; (3) SAFD containing
0.02% genistein (GE.02); or (4) SAFD containing 0.1% genistein (GE.1). In the GE.1 group, effects of
dietary genistein included a decreased rate of body-weight gain, a markedly increased (2.3-fold)
uterine/body weight (U/BW) ratio on postnatal day (pnd) 21, a significant acceleration of puberty
among females, and a marginal decrease in the ventral prostate weight on postnatal day (pnd) 56.
However, developmental differences among the groups fed SAFD, GE.02, or NIH-07 were small and
suggested minimal effects of phytoestrogens at normal dietary levels. In particular, on pnd 21, the U/BW
ratio of the GE.02 and NIH-07 groups did not differ significantly from that of the SAFD group. Only one
statistically significant difference was detected between groups fed SAFD and NIH-07: the anogenital
distance (AGD) of female neonates on pnd 1 whose dams were fed NIH-07 was 12% larger than that of
neonates whose dams were fed SAFD. The results suggest that normal amounts of phytoestrogens in
natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that
higher doses can affect several other parameters in both males and females. Based on these findings,
we do not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most
developmental toxicology studies. However, phytoestrogen-free diets are recommended for endocrine
toxicology studies at low doses, to determine whether interactive effects may occur between dietary
phytoestrogens and man-made chemicals.
Soy isoflavone supplements antagonize reproductive behavior and
estrogen receptor alpha- and beta-dependent gene expression in the
Endocrinology 2001 Jul;142(7):2946-52
Patisaul HB, Dindo M, Whitten PL, Young LJ.
Center for Behavioral Neuroscience, Emory University, Atlanta, Georgia 30329, USA.
Epidemiological evidence suggests that isoflavone phytoestrogens may reduce the risk of cancer,
osteoporosis, and heart disease, effects at least partially mediated by estrogen receptors alpha and beta
(ERalpha and ERbeta). Because isoflavone dietary supplements are becoming increasingly popular and
are frequently advertised as natural alternatives to estrogen replacement therapy, we have examined
the effects of one of these supplements on estrogen-dependent behavior and ERalpha- and ERbeta-
dependent gene expression in the brain. In the adult female rat brain, 17beta-estradiol treatment
decreased ERbeta messenger RNA signal in the paraventricular nucleus by 41%, but supplement
treatment resulted in a 27% increase. The regulation of ERbeta in the paraventricular nucleus is
probably via an ERbeta-dependent mechanism. Similarly, in the ventromedial nucleus of the
hypothalamus, supplement treatment diminished the estrogen-dependent up-regulation of oxytocin
receptor by 10.5%. The regulation of oxytocin receptor expression in the ventromedial nucleus of the
hypothalamus is via an ERalpha-dependent mechanism. Supplement treatment also resulted in a
significant decrease in receptive behavior in estrogen- and progesterone-primed females. The
observed disruption of sexual receptivity by the isoflavone supplement is probably due to
antiestrogenic effects observed in the brain. These results suggest that isoflavone phytoestrogens
are antiestrogenic on both ERalpha- and ERbeta-dependent gene expression in the brain and estrogen-
Effect of estradiol and soy phytoestrogens on choline acetyltransferase
and nerve growth factor mRNAs in the frontal cortex and hippocampus
of female rats.
Proc Soc Exp Biol Med 1999 Jun;221(2):118-25
Pan Y, Anthony M, Clarkson TB.