New research suggests that exposure of newborn female mice to a compound called genistein, which occurs naturally in soy products, may cause the animals to experience pregnancy failure later in life. The study found that the reproductive tracts of adult mice exhibited structural changes that did not allow embryos to implant properly.

The finding may have implications for the fertility of women who were fed soy-based formulas as infants. The study was published online March 18 in the journal Environmental Health Perspectives. Its findings highlight how exposure during a window of sensitivity in early life can lead to consequences later on.

Rodent versus human

'Several NIEHS scientists have studied the impact of genistein on fibroids and menstrual cycles, but ours is the first to examine it regarding pregnancy,' Jefferson said. (Photo courtesy of Steve McCaw)

Corresponding author Wendy Jefferson, Ph.D., a biologist in the NIEHS Reproductive Medicine Group, led a team that included collaborators from Michigan State University. She said that because it is a mouse study, it is not clear whether the same uterine developmental changes happen in humans. Her previous rodent studies also showed deficits in the uterine function of adult animals that were fed genistein as pups.

To date, no human studies have examined pregnancy failure in women who drank soy formula as infants.

'The amount of genistein we used with the mice produces a blood level similar to what human infants on soy formula have,' Jefferson said. 'Our new research confirms our hypothesis that developmental exposure to genistein results in pregnancy failures in adult mice.'

Each day during the first five days after birth, Jefferson and her colleagues injected corn oil under the skin of female mouse pups for the control group and genistein dissolved in corn oil for the experimental group. She said that in humans, this time period correlates with the third trimester through early adolescence. The reason the timespan is much longer in girls is the human female reproductive tract takes that long to differentiate, or fully develop. In mice it happens soon after birth.

Soybeans naturally contain genistein. (Photo courtesy of Lisa Banks)

Team members collected uterine tissue at three points: embryonic day five, four weeks after birth, and during pregnancy. They weighed the tissue, examined physical changes, and analyzed differences in gene expression. The scientists also looked at responses to pregnancy hormones in adult mice that had their ovaries removed.

Developmental changes

When stimulated with hormones involved in pregnancy, all of the genistein-exposed mice had smaller uteruses compared with unexposed mice, according to the authors. The gene expression changes in the exposed mice looked like those in mice that lacked expression of developmental genes required for proper female reproductive tract development, also referred to as differentiation.

The researchers concluded that this early exposure to genistein altered the differentiation of the reproductive tract so that it did not function properly later. The mechanism behind this changed differentiation has to do with genistein’s structural similarity to estrogen. The two molecules look so much alike that cells respond similarly to both.

Williams holds a secondary appointment in the NIEHS Epigenetics and Stem Cell Biology Laboratory. (Photo courtesy of Steve McCaw)

'As a result, genistein turns on estrogen receptor signaling in the uterus when it shouldn’t,' said Carmen Williams, M.D., Ph.D., deputy chief of the NIEHS Reproductive and Developmental Biology Laboratory and head of the research group where Jefferson works. 'Because lots of downstream signaling occurs based on the estrogen receptor, you end up turning on genes that should be off, and vice versa.'

Williams said proper uterine gland function is important for establishing pregnancy. In genistein-exposed mice, the gene is disrupted in these glands. Interestingly, other compounds that act on the estrogen receptor, such as diethylstilbestrol (DES) and bisphenol A, also result in altered uterine differentiation when exposure occurs during the first few days after birth.

'While we know that complex hormonal signaling and precise timing of uterine differentiation are crucial for successful embryo implantation and growth, we still don’t know exactly how genistein interferes with this process,' Jefferson said.

Citation: Jefferson WN, Padilla-Banks E, Suen AA, Royer LJ, Zeldin SM, Arora R, Williams CJ. 2020. Uterine patterning, endometrial gland development, and implantation failure in mice exposed neonatally to genistein. Environ Health Perspect 128(3):37001.