Toxicological Sciences, Vol 51, 236-244, Copyright © 1999 by Society of Toxicology
M Casanova, L You, KW Gaido, S Archibeque-Engle, DB Janszen and HA Heck
Estrogenic isoflavones, such as genistein and daidzein, are present in
virtually all natural-ingredient rodent diets that use soy as a source of
protein. Since these compounds are endocrine-active, it is important to
determine whether the amounts present in rodent diets are sufficient to
affect sexual development. The present study consisted of in vitro and in
vivo parts. In the in vitro portion, human hepatoma cells were transfected
with either rat estrogen receptor (ER) alpha or beta plus an
estrogen-responsive luciferase reporter gene. Genistein and daidzein were
complete agonists at both ERs, genistein being more potent than daidzein,
and both compounds were more potent at ER beta than ER 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.
ARTICLES
Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA. casaheck@beaufortco.com
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