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Rachel L. Ruhlen,¹ Kembra L. Howdeshell,^1,* Jiude Mao,¹ Julia A. Taylor,¹ Franklin H. Bronson,² Retha R. Newbold,³ Wade V. Welshons,⁴ and Frederick S. vom Saal¹

¹Division of Biological Sciences, University of Missouri-Columbia, Columbia, Missouri, USA; ²Department of Zoology, University of Texas at Austin, Austin, Texas, USA; ³Developmental Endocrinology and Endocrine Disruptor Section, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ⁴Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri, USA

Abstract
Background: Although estrogenic chemicals can disrupt development of the reproductive system, there is debate about whether phytoestrogens in soy are beneficial, benign, or harmful.

Objectives: 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 highphytoestrogen 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.

Key words: casein, estradiol, fat, glucose tolerance, leptin, metabolic syndrome, obesity, puberty, reproductive organs, soy. Environ Health Perspect 116:322–328 (2008) . doi:10.1289/ehp.10448 available via http://dx.doi.org/ [Online 26 November 2007]

Address correspondence to F.S. vom Saal, Division of Biological Sciences, 105 Lefevre Hall, University of Missouri-Columbia, Columbia, MO 65211 USA. Telephone: (573) 882-4367. Fax: (573) 884-5020. E-mail: vomsaalf@missouri.edu

*Current address: Reproductive Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 USA.

Support was provided by grants to F.S.vS. from the National Institute of Environmental Health Sciences (NIEHS ; ES11283) , the Kapor Foundation, and the W. Alton Jones Foundation. R.L.R. was supported by National Institutes of Health (NIH) training grant T32GM008396.

The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH, Public Health Service, or U.S. Environmental Protection Agency.

The authors declare they have no competing financial interests.

Received 8 May 2007 ; accepted 26 November 2007.