Low amounts of soy during pregnancy lead to obesity in mice.

Sep 24, 2008

Ruhlen RL, KL Howdeshell, J Mao, JA Taylor, FH Bronson, RR Newbold, WV Welshons and FS vom Saal. 2008. Low phytoestrogen levels in feed increase fetal serum estradiol resulting in the “fetal estrogenization syndrome” and obesity in CD-1 mice. Environmental Health Perspectives, 116:322–328.


Mice exposed to low levels of soy proteins before and shortly after birth were obese as adults and had reproductive changes that differed between the sexes. The findings reinforce that hormonally active agents can act at low exposure levels and produce  effects different from those caused by high exposures.
The male mice born to mothers fed a low soy protein diet had underdeveloped testis and enlarged prostate glands compared to those born to mothers that were fed a high soy protein diet. The female pups from low exposure moms became sexually mature at an earlier age than expected. Male and female mice from mothers fed high soy diets did not have these effects.


Many plants contain compounds – called phytoestrogens – that can act like estrogen hormones in animals and humans. One type, the isoflavones, are found in soy products, including soy beans, soy milk and tofu. The major source of exposure to phytoestrogens is through food. The time and duration of exposure can influence how the phytoestrogens act in the body. During development, tissues have different sensitivities to the phytoestrogens depending on the estrogen levels present. Thus, phytoestrogens may cause both immediate and long-term effects on health. More information about how phytoestrogens influence fetal and adult tissues and systems is needed to determine if they are safe to use as non-dairy protein sources or as nutritional supplements.

Considerable evidence suggests that environmental exposures during pre-birth development set the stage for disease later in life.  This has become known as the ‘fetal basis of adult disease.’ This evidence suggests that health problems later in life, including throughout adulthood, are caused through effects on in the way genes are programmed to switch on and off as an individual ages. For example, testicular cancer in male and ovarian cancer in female adolescents is associated with pre-birth exposures to the synthetic estrogen diethylstilbestrol (DES). Malnutrition and other factors that affect fetal growth rate have been linked to adult obesity, diabetes and other metabolic syndromes. Overweight and obese people have increased risks of cardiovascular diseases such as heart attacks and stroke. It may be that phytoestrogens and other environmental estrogens target fat cells and alter the mechanisms involved in weight control. Some are also known to increase the rate of conversion of stem cells to fat cells. An individual with more fat cells is at greater risk to obesity.

What did they do?

Researchers fed mice two different soy-based diets - one with low and the other with high protein levels - during pregnancy and nursing to determine if soy levels in food affect how mouse reproductive and metabolic systems develop and function. Hormone levels, body weight and sexual organ sizes from male and female offspring exposed to the low soy protein diet were compared to animals exposed to the high soy protein diet.

The female sex hormone estradiol was measured in mothers' blood collected on day 18 of pregnancy from all groups. After birth, male and female offspring were weighed at 1, 20 and 90 days of age, and body fat was assessed by measurement of fat pads around the testes and kidneys at 90 days of age. The authors performed the glucose tolerance test and measured leptin, a hormone produced by body fat, in the blood of adult males and females to test whether differences in body weights at 90 days of age were associated with metabolic syndrome. Male sexual development was determined by measuring the size of sex organs, including the testis, epidydymis, seminal vesicles and prostate glands at 3 months of age. Uterine response to estrogen administration and the time of sexual maturity were used to define reproductive capacity in females.

What did they find?

Important developmental differences were found in mice born to mothers that ate the low soy protein diet versus those from mothers that ate the high soy protein diet. The observed reproductive organ changes also differed between the sexes. Both male and female mice exposed to the low soy protein diet had excessive weight gains as adults but only male offspring suffered from impaired glucose tolerance. However, body fat and the levels of the hormone leptin were elevated in both sexes. None of these conditions were found in mice exposed to high soy protein levels in their mother’s diet.

Both male and female pups from mothers fed the low soy protein diet had profound elevations in the blood concentrations of the sex hormone estradiol. Sexual organs (testis and epididymis) were smaller, whereas the prostate gland was enlarged in adult male mice exposed to low soy protein levels when compared to males born to mothers fed the high soy protein diet. In contrast, female pups from mothers fed the low soy protein diet reached puberty earlier, ovulated and became pregnant at a younger age than female offspring of mothers fed the high soy protein diet.

What does it mean?

This study provides evidence supporting previous reports that exposure to hormonally active agents, which increase levels of the sex hormone estradiol during development, result in permanent effects in adulthood. The effects associated with a low soy protein diet in this study are similar to those previously reported for several estrogenic compounds, for example, DES and the industrial chemical bisphenol A.

Importantly, the adverse effects seen in mice exposed to the low soy protein diet were absent or less often observed in animals exposed to high soy protein levels. This represents yet another example of how effects at low doses can be very different than those visible at high doses. 

Results from this study also add to a growing body of information indicating that early-life exposures to estrogen-active ingredients in food, air or water affect body metabolism in adulthood. The finding that exposure of the fetus to estradiol results in excessive body weight gains in the adult adds a new dimension to the ‘estrogenization syndrome’, which is a group of estrogen related reproductive problems in males and females that has been associated with exposure to several endocrine disrupting compounds.

Given the increasing incidence of obesity in the population, the study's results raise the question of whether exposure to endocrine-active agents is a major factor in obesity and more broadly to 'metabolic syndrome'.  Recent epidemiological studies with phthalates and bisphenol A reinforce this concern.

The early-life exposure to elevated blood levels of estradiol caused opposite effects in male and female offspring. Although there was no information on their ability to mate and achieve pregnancy in female partners, adult male mice exposed to low soy protein levels had underdeveloped reproductive organs, although the prostate gland was enlarged. On the other hand, female mice were fertile and became pregnant at an earlier age. However, other studies suggest that such increased uterine sensitivity to the sex hormone estradiol may predispose to uterine cancer later in life.

The authors describe a common disease pattern of adult obesity and reproductive organ disorders stemming from fetal and early life exposures to soy phytoestrogens. The results raise new questions about potential adverse effects of hormonally active compounds in the environment and point to the need for additional research "to determine whether all of these outcomes are caused by elevated estradiol levels during fetal life." A greater understanding of how the changes occur - whether through a decrease in the enzyme aromatase or, as the authors suggest, lower levels of estrogen carrying proteins in the blood - is also warranted.


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Health effects of soy phytoestrogens



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