Low phytoestrogen levels in feed increase fetal serum estradiol resulting in the "fetal estrogenization syndrome" and obesity in CD-1 mice.
BACKGROUND
Although estrogenic chemicals can disrupt development of the reproductive system, there is debate about whether phytoestrogens in soy are beneficial, benign, or harmful.


OBJECTIVE
We compared reproductive and metabolic characteristics in male and female mice reared and maintained on non-soy low-phytoestrogen feed or soy-based high-phytoestrogen feed.


METHODS
The low-phytoestrogen diet was non-soy PMI 5K96 (verified casein diet), and the high-phytoestrogen diet consisted of soy-based PMI 5008 during pregnancy and lactation and soy-based PMI 5001 maintenance feed after weaning.


RESULTS
In fetuses whose mothers consumed the low-phytoestrogen PMI 5K96 feed, we found a paradoxical significant elevation in endogenous serum estradiol, which was associated postnatally with adverse reproductive outcomes referred to as the "fetal estrogenization syndrome (FES)". In females, this syndrome included early puberty and increased uterine responsiveness to estrogen, and in males, it included reduced testis, epididymis, and seminal vesicle size, but an enlarged prostate. The low-phytoestrogen-fed males and females were lighter at birth, but, between weaning and adulthood, they became obese and developed abnormally high serum leptin levels; these males, but not females, showed impaired glucose regulation.


CONCLUSIONS
Removing phytoestrogens from mouse feed produces an obese phenotype consistent with metabolic syndrome, and the associated reproductive system abnormalities are consistent with FES due to elevated endogenous fetal estradiol. Laboratory rodents may have become adapted to high-phytoestrogen intake over many generations of being fed soy-based commercial feed; removing all phytoestrogens from feed leads to alterations that could disrupt many types of biomedical research.
Ruhlen
Rachel L
RL
Division of Biological Sciences, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
Howdeshell
Kembra L
KL
Mao
Jiude
J
Taylor
Julia A
JA
Bronson
Franklin H
FH
Newbold
Retha R
RR
Welshons
Wade V
WV
vom Saal
Frederick S
FS
D000821:Animal Feed; D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000097:blood*; D005260:Female; D005836:Genitalia, Female / Q000033:anatomy & histology / Q000187:drug effects*; D005837:Genitalia, Male / Q000033:anatomy & histology / Q000187:drug effects*; D005951:Glucose Tolerance Test; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D051379:Mice; D009765:Obesity / Q000209:etiology*; D048789:Phytoestrogens / Q000008:administration & dosage / Q000494:pharmacology*; D011247:Pregnancy
D020738:Leptin; D048789:Phytoestrogens; D004958:Estradiol