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, 116 (3), 322-8

Low Phytoestrogen Levels in Feed Increase Fetal Serum Estradiol Resulting in the "Fetal Estrogenization Syndrome" and Obesity in CD-1 Mice

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Low Phytoestrogen Levels in Feed Increase Fetal Serum Estradiol Resulting in the "Fetal Estrogenization Syndrome" and Obesity in CD-1 Mice

Rachel L Ruhlen et al. Environ Health Perspect.

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 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.

Keywords: casein; estradiol; fat; glucose tolerance; leptin; metabolic syndrome; obesity; puberty; reproductive organs; soy.

Figures

Figure 1
Figure 1
Mean (+ SE) serum estradiol (pg/mL) on GD18 in pregnant females and fetuses. Blood from males and from females within each PMI 5K96C litter (n = 13) and PMI 5008 litter (n = 10) was pooled. *p < 0.05.
Figure 2
Figure 2
Mean (+ SE) body weight of female pups (A,C,E; n = 18 PMI 5008/5001; n = 19 PMI 5K96C) and male pups (B,D,F; n = 18 PMI 5008/5001; n = 19 PMI 5K96C) at birth (PND1; E,F), weaning (PND20; C,D), and adulthood (PND90; A,B). *p < 0.01.
Figure 3
Figure 3
Mean (+ SE) weight of gonadal (A) and renal (B) fat pads from 3-month-old males and females (PMI 5008/5001, n = 10; PMI 5K96C, n = 9). *p < 0.01.
Figure 4
Figure 4
Mean (+ SE) serum leptin from 3-month-old males (n = 7/group) and females (PMI 5008/5001, n = 10; PMI 5K96C, n = 9). *p < 0.01.
Figure 5
Figure 5
Mean (± SE) blood glucose before (time 0) and 30, 60, and 90 min after an intraperitoneal injection of 2 mg/g glucose (in saline) in females (A) and males (B; n = 10/group) 1 week before sacrifice for examination of body fat and serum leptin on PND90. *p < 0.01.
Figure 6
Figure 6
Mean (+ SE) uterine weight on PND20 in response to a low dose of estradiol or oil vehicle via a subcutaneous Silastic implant (n = 10/group). *p < 0.05.
Figure 7
Figure 7
Mean (+ SE) body weight (A), uterine weight (B), height of the uterine luminal epithelium (C), and serum leptin (D) in females weaned on PND19 and examined on PND26. *p < 0.01.
Figure 8
Figure 8
Mean (+ SE) wet weight of testes (A), epidydimides (B), seminal vesicles (C), and prostates (D) collected from 3-month-old male mice fed PMI 5K96C (n = 24) or PMI 5008/5001 (n = 22). With the exception of the seminal vesicles, comparisons are based on ANCOVA, because for each organ measured, body weight accounted for a significant component of the variance. *p < 0.05. **p < 0.01.
Figure 9
Figure 9
Mean (+ SE) weight of reproductive organs in adult CF-1 male mice as a result of fetal exposure to 2 μg/kg/day BPA. BPA or oil vehicle (controls) was fed to pregnant females on GD11–GD17. All pregnant and lactating females were fed PMI 5008 and all males were fed 5001 after weaning. The effects of BPA on the reproductive organs in male mice maintained on the PMI 5008/5001 feed was identical to the effects of the PMI 5K96C feed compared with PMI 5008/5001 feed shown in Figure 8. This suggests that the elevation in fetal serum estradiol caused by the PMI 5K96C feed (Figure 1) produced a permanent effect on the reproductive organs in males, similar to the permanent effect caused by fetal exposure to BPA. Adapted from vom Saal et al. (1998). *p < 0.05. **p < 0.01. #p = 0.08.

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