Soy formula affects reproductive development in mice.

Jun 02, 2010

Cimafranca, MA, J Davila, GC Ekman, RN Andrews, SL Neese, J Peretz, KA Woodling, WG Helferich, J Sarkar, JA Flaws, SL Schantz, DR Doerge and PS Cooke. 2010. Acute and chronic effects of oral genistein administration in neonatal mice. Biology of Reproduction http://dx.doi.org/10.1095/biolreprod.109.080549.



Synopsis by Thea M. Edwards and Wendy Hessler

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A Hermida/flickr
 
Newborn mice fed genistein-enriched soy formula during the first five days of life developed abnormalities of the ovary, uterus and thymus gland that were estrogen related and persisted into adulthood. As adults, the mice had fewer reproductive cycles in a month than the untreated mice. The findings show that eating genistein right after birth causes short and long-term changes and raises concerns for health effects on human infants fed soy-based formula during their early months.
 
 
 

Context

In the United States, about 25 percent of formula-fed babies receive soy-based formula. The American Academy of Pediatrics (AAP) currently considers soy formulas acceptable for healthy term infants, although they are third choice after breastmilk and cow milk formulas.  "Acceptability" is based primarily on the fact that term infants fed soy formulas gain weight and appear to grow normally. 

The AAP only recommends soy formulas over cow milk formulas for vegan families or for infants with certain medical conditions that affect how the baby metabolizes lactose, such as diagnosed lactose intolerance or galactosemia, a rare genetic disease. The AAP does not recommend soy formulas for preterm or low birth-weight babies.

Soy-based formulas are made from soybeans. One concern with soy-based formulas is that they contain high levels of phytoestrogens like genistein. Phytoestrogens are molecules made by plants that mimic the actions of estrogen. Remarkably, genistein levels measured in the blood of soy-fed infants are roughly 10 times higher than phytoestrogen concentrations known to alter a woman’s menstrual cycle.

Estrogens are important in reproductive development and function. Although animal studies suggest effects, it is not definitive if the phytoestrogens in soy formulas can alter the reproductive development of infants.

Human studies have linked soy formula consumption with early breast development, abnormal menstrual cycles and a greater tendency to have twins. One study found reduced immune response to childhood vaccinations among children raised on soy formulas, although a follow-up study could not replicate the findings.

Rodent studies have shown that baby mice injected with genistein are more likely to have larger uterines, reduced fertility, altered estrous cycling, multioocytic follicles (MOFs), decreases in uterine progesterone receptor expression and other effects associated with excess estrogen exposure. When a female’s eggs develop in her ovary, they should occur as single cells contained in nests of nurse cells referred to as follicles. MOFs are an abnormal condition in which multiple egg cells develop within a follicle. MOFs in mice have been associated with reduced fertility. Progesterone receptors are important in the uterus because they regulate the maintenance of pregnancy, among other important reproductive functions. A loss of progesterone receptors could cause infertility and miscarriage.

Rodent studies that use injected mice have been criticized because the route of exposure is not the same as in humans. When genistein is injected into mice, it bypasses the gut, where it might be metabolized into less or more potent forms. In addition, many injection studies cause peak genistein concentrations in research mice that greatly exceed those measured in soy formula-fed infants.

What did they do?

Researchers fed baby mice a soy infant formula mix spiked with genistein once a day during the first five days after birth. The exposed pups suckled the treatment mixture from a plastic pipette tip and regularly nursed. Control animals received untreated formula and nursed.

The researchers fed the mice genistein 50 milligrams per kilogram per day rather than injecting it. They ensured – by measuring genistein levels in the blood – that the levels in the exposed mice were similar to concentrations measured in infants who are fed soy formula. Blood analysis also determined that the total genistein concentrations in control mice were minimal. Thus, the route of exposure and the dose were realistic relative to human exposure.

Effects of genistein on the uterus, ovary and thymus gland were determined for mice after the five days of exposure and at four months, after mice reached adulthood. At six months, the length of time between reproductive cycles was measured. Fertility was assessed by allowing the mice to mate and recording rates of pregnancy, birth, litter size and sex ratios of the offspring. The number of progesterone hormone receptors in the lining of the uterus was determined through tissue samples.

What did they find?

At the end of the five-day exposure period, thymus weights of the genistein-treated pups were reduced by 28 percent, uterine weights were increased by 41 percent and the number of progesterone receptors in the uterine lining was significantly decreased compared with unexposed control mice.

Moreover, in 5-day-old mice, the number of multioocytic follicles in genistein exposed mice was three times higher than controls. By adulthood, they were seven times higher in exposed mice than controls.

At six months, the number of reproductive cycles in the genistein-treated mice was less – due to longer times between estrous cycles – than the controls. As a consequence, they had fewer opportunities to become pregnant in a set period of time. However, fertility was normal when based on pregnancy rates and number of live births.

What does it mean?

Mice exposed to genistein for five days after birth develop reproductive and thymus gland abnormalities, as well as reproductive cycle changes, that are consistent with excess estrogen exposure. Some of the changes persist into adulthood.

The findings support the idea that plant-based phytoestrogens can alter estrogen-based development in mice. The results caution against the use of soy-based formulas for human babies.

This study is important because it is one of the first in which researchers dosed mouse pups by feeding them genistein rather than injecting them. This simulates human exposure more closely.

The animal model provides a way to determine if ingredients in soy foods may have short and long-term effects on development. The results can be compared to human studies, where it may take many years or be unethical to look for and determine reproductive, immune, fertility or other health problems from early life exposure to soy.

One difference between this study and human use of soy formulas is that pups were dosed with genistein once per day for the first five days after birth, with mother’s milk making up the rest of their diet until they were weaned 21 days after birth. Conversely, for human babies, soy formula may be the sole source of nutrition for the first six months of life and a large part of their diet until they turn one year old.

The genistein caused multioocytic follicles (MOFs) by 5 days of age. These multiple eggs per follicle then persist and increase in number into adulthood. The findings are consistent with other studies of rodents and some wildlife species exposed to estrogen or estrogenic contaminants.

MOFs have been found in humans too, but, as the authors note, a link to early estrogen exposure has not yet been established. One important difference between humans and rodents is that, in humans, eggs and follicles develop before birth, whereas in rodents, they develop after birth. If estrogen exposure causes MOFs in humans, then prenatal exposure is likely to be more important than postnatal formula consumption with regard to MOF development.

Other findings in this study relate more closely to humans. For instance, in this study, mice exposed to genistein had more time between reproductive cycles compared to controls. This relates to human data showing that women who were fed soy-based formula as infants are more likely to have menstrual abnormalities compared with women fed cows milk-based formula or breast milk.

The authors also note that these results complement new preliminary data showing that human baby girls given soy formula have changes in vaginal cell structure at six months and changes in breast development during their second year that are consistent with estrogenization.

The decrease in thymus weight is important because the thymus produces immune cells and is essential for immune function. Although immune effects in genistein treated mice remain to be determined, reduced thymus weight could cause either decreased immune function or hypersensitivity, which is associated with allergies and autoimmune disorders in adulthood. One study of adults who were fed soy formula as infants showed increased use of asthma or allergy medications, suggesting a link between soy formulas and immune function that requires further study.

Resources

Akingbemi, BT and W Hessler. 2009. Soy protein renders womb unsuitable for pregnancy. Environmental Health News Jan 26.

Bhatia, J, F Greer and the Committee on Nutrition. 2008. Use of soy protein-based formulas in infant feeding. Pediatrics 121(5): 1062-1068.

Harley, K and W Hessler. 2010. Soy formula associated with higher risk of fibroids in women. Environmental Health News, Feb 1.

Jefferson, W, R Newbold, E Padilla-Banks and M Pepling. 2006. Neonatal genistein treatment alters ovarian differentiation in the mouse: Inhibition of oocyte nest breakdown and increased oocyte survival. Biology of Reproduction 74(1):61-168.

Patisaul, H and W Hessler. 2009. Phytoestrogen in soy impedes egg, embryo growth, finds mouse study. Environmental Health News, July 28.

 

 

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