Newbold, RR, EP Banks, B Bullock, and WN Jefferson 2001. Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Research 61: 4325-4328.

Newbold et al. report that when neonatal mice are exposed to genistein—a phytoestrogen present in soy—later in life they develop uterine cancer of the same form caused by diethylstilbestrol (DES). The levels of genistein used in these experiments are comparable to those found in infant formula based on soy.

This study makes two profoundly important points:

• It raises very large issues about the wisdom of basing infant formula on soy. Decades of research with DES showed time and again that effects first found in experiments with mice were then confirmed in studies of people.
• It confirms once again that estrogens at the wrong time in development can have extremely adverse effects, no matter whether they are from natural sources like soy or synthetic sources like DES. What matters is whether they penetrate the chemical defense systems of the developing organism at a vulnerable moment in development, one at which the developing organism would normally be using natural estrogen signals to guide development. At these moments, inappropriate estrogens can alter development by changing the intensity of the estrogen signal.

A key question that should be resolved as rapidly as possible is whether differences in the way that humans digest, metabolize and chemically partition genistein once ingested, compared to mice, make human infants less susceptible to this effect than the mice used in these experiments. Until this question is resolved, parents would be well-advised to minimize infant exposure to soy formula. It is plausible that cultural differences in exposure to soy would have led to systematic differences among populations of people in their sensitivity to genistein.

What did they do?

Newbold et al. exposed newborn female mice (days 1-5) to genistein by injection. Another group of newborn females was exposed to diethylstilbestrol, with the exposure level adjusted compared to genistein so that DES and genistein exposed pups received equal exposures in terms of estrogenic potency. The DES group was used as a positive control in the experiment. Another control group was exposed only to corn oil.

Some pups were sacrificed at the age of 5 days to allow examination of body and uterine weights. At the age of 18-months old the exposed mice were then examined to identify cases of uterine adenocarcinoma.

What did they find?

Newbold et al. report several significant findings:

• First, the uterine weights of the genistein-exposed pups increased comparably to the DES-exposed group (202% and 190%, respectively), and both groups differed significantly from the corn-oil exposed control group. This was to be expected as the dosage of DES and genistein were adjusted to yield exposures of equal potency.
• Second, noncancerous reproductive tract abnormalities were observed in both the DES and the genistein treated groups at high frequencies compared to the corn-oil controls. These included a variety of malformations and distortions typically found in mice after DES exposure.
• Third, uterine adenocarcinoma was detected in 35% of genistein-exposed and 31% of DES-exposed females. No uterine adenocarcinoma was detected in any of the corn-oil exposed controls. In fact, the authors of the study report that "similar malignant lesions have never been observed in control mice of this strain in our laboratory."

What does this mean?

From the authors: "Of particular significance in this study is the incidence of uterine adenocarcinoma after neonatal exposure to genistein. This compound is readily available to many infants during the first year of life as a component of soy-based formula... The amount of genistein used in our study is slightly higher than the amount consumed by infants, but it is certainly within one order of magnitude of the level of human exposure" (approximately 27 mg of genistein per day for infants feeding on formula vs. 50 mg/day in the experiment).

Newbold et al. also briefly summarize in the paper a variety of other impacts resulting in mice from genistein exposure, including reductions in fertility during adulthood following exposure as newborn.

"The findings of the present study raise concerns over the amount of phytoestrogens in soy-based infant formulas and other soy-based products that are fed to young children. Additional studies are needed to determine the potential effects in humans exposed to high quantities of phytoestrogens during critical stages of neonatal or early development."