Pregnancy Exposure to High-Fat and Estrogen Increases Breast Cancer Inheritance in Three Generations of Offspring

Connie K. Ho for — Your Universe Online

A study by researchers from Georgetown Lombardi Comprehensive Cancer Center and Virginia Tech shows that exposure to diets high in fat or a large amount of estrogen during pregnancy can heighten the risk of breast cancer for numerous subsequent generations of female offspring, including daughters, granddaughters and great-granddaughters.

The study´s results, recently featured in Nature Communications, highlighted the elevated risk of “familial” breast cancer due to biological causes that are linked to the mother´s diet during pregnancy. The effects, however, were not only inherited by the fetus but also by subsequent fetal germ cells, which are able to pass the mammary cancer risk on to following generations.

The research project also looked at the specific biological causes of the inheritable breast cancer cells, including high-fat diets and high levels of the hormone estrogen. Researchers found that these risk factors apparently lead to differences in DNA methylation patterns in future generations of offspring, making female descendants more susceptible to carcinogens.

DNA methylation plays an important part in the normal developmental and cell differentiation process, turning certain genes on or off, and helping specialized cells “remember” gene expression patterns. For this project, Virginia Tech researchers created mathematical models and machine-learning techniques to better understand the changes in the DNA methylation status.

“We know that maternal diet can have long lasting effects on an offspring’s health, but this study demonstrates, for the first time, that a high fat diet or excess estrogen can affect multiple generations of a rat’s offspring, resulting in an increase in breast cancer not only in their daughters, but granddaughters and great granddaughters,” commented senior investigator Leena Hilakivi-Clarke, a professor of oncology at Georgetown Lombardi, in a prepared statement.

The research project was a collaborative effort among scientists from Finland and the United States. The researchers examined three groups of pregnant rats and their offspring, two groups of which were exposed to cancer-inducing risk factors. The first group of rats was given a high fat diet before and during pregnancy. Compared to rats in the control group that consumed a normal diet during pregnancy, this group of rats experienced a heightened breast cancer risk of 55 to 60 percent in both the daughters and granddaughters.

“We also found that if the mother was fed a high fat diet before conception and throughout pregnancy, the risk of increased breast cancer was transmitted to granddaughters through either males or females exposed to the high fat diet in utero,” stated lead investigator Sonia de Assis, a postdoctoral researcher in Hilakivi-Clarke’s laboratory, in the statement.

During the last week of pregnancy, the second group of rats was given a diet that contained additional estrogen. The scientists discovered that the daughters, granddaughters and great-granddaughters of the rats exposed to excess estrogen had a 50 percent higher rate of breast cancer compared to the rats from the control group. They also found that there were epigenetic changes in the mammary glands of three generations of the rats who had been exposed to increased estrogen. Epigenetic changes involve modifications in the expression of genes from one generation to the next that do not involve a change in the underlying DNA sequence.

The researchers found that diets high in fat and diets with excess estrogen caused the later generations of female rats to have a high number of structures in the breast known as terminal end buds, which are often the targets of cancer-causing agents.

“Germ cells–cells involved in reproduction–first develop during the fetal period and in utero exposures, such as the ones in our study, could disrupt their normal epigenetic marks and affect how genes are turned on or turned off,” continued de Assis in the statement.

“Those alterations then can be passed on and affect the risk of disease, in this case breast cancer, in subsequent generations.”

The researchers believe that the findings from the study can help explain why some cases in human related to high-fat diets and excess estrogen could be connected to inherited epigenetic changes, a form of cellular differentiation.

“We know from human studies that daughters whose mothers took the synthetic estrogen diethylstilbestrol (DES) to reduce pregnancy complications, or who had a birth weight of more than 8.8 pounds are at an increased risk of developing breast cancer. Our study suggests their offspring may also be at risk,” said Hilakivi-Clarke in the statement.

The team also suggested that the epigenetic inheritance of breast cancer could possibly be diagnosed through blood testing.

“We have shown for the first time that altered DNA methylations modulated by specific diet in normal development are heritable and transgenerational,” commented Yue “Joseph” Wang, the Grant A. Dove Professor of Electrical and Computer Engineering at Virginia Tech Research Center, in the statement.

“We also identified key methylation alteration sites that may be involved or responsible for increased breast cancer risk, which may serve as novel biomarkers for scientists to develop novel and targeted prevention strategies.”

The scientists believe that the study could help researchers to better understand the impact of a mother´s diet on the development of breast cancer in subsequent generations.

“It’s easy to see how this study possibly has human health implications to be considered since fatty foods are endemic in our society, and low levels of chronic exposure to endocrine disruptors – substances that have hormonal activity such as estrogen – have been found in food and drinking water,” remarked de Assis in the statement.

The researchers also hope to utilize the study´s findings for future research projects.

“Ultimately, it may be possible to undo or prevent this harmful methylation and decrease the risk of breast cancer,” concluded Wang in the statement. “A next step will be to study the timing of the intervention and the impacts of the methylation as it occurs in the early, middle or end of the pregnancy. The promising news is pharmacologic or other interventions may be able to reverse the harmful exposure.”