A Toxic Inheritance: Chemotherapy Could Increase Disease Susceptibility in Future Generations

Ifosfamide Chemotherapy’s Multigenerational Effects

New research led by Washington State University has found that a common chemotherapy drug called ifosfamide may have toxic effects that can be passed down to the children and grandchildren of adolescent cancer survivors.

The study, published in the journal iScience, discovered that male rats who received ifosfamide during adolescence had an increased incidence of disease in their offspring and grand-offspring. This is the first known study to show that the susceptibility to disease resulting from cancer treatment can be passed down to the third generation of unexposed offspring.

Previous research has shown that cancer treatments can increase the risk of developing disease later in life for patients, but this study expands upon that understanding by demonstrating that the effects of chemotherapy can be passed down to future generations.

“The findings suggest that if a patient receives chemotherapy, and then later has children, that their grandchildren, and even great-grandchildren, may have an increased disease susceptibility due to their ancestors’ chemotherapy exposure,” said Michael Skinner, a WSU biologist and corresponding author on the study.

Recommendations for Cancer Patients

Skinner emphasized that the findings should not dissuade cancer patients from undertaking chemotherapy since it can be a very effective treatment. Chemotherapy drugs kill cancerous cells and prevent them from multiplying, but have many side effects since they impact the whole body, including the reproductive system.

Given this study’s implications, the researchers recommend that cancer patients who plan to have children later take precautions, such as using cryopreservation to freeze sperm or ova before having chemotherapy.

In the study, researchers exposed a set of young male rats to ifosfamide over three days, mimicking a course of treatment an adolescent human cancer patient might receive. Those rats were later bred with female rats who had not been exposed to the drug. The resulting offspring were bred again with another set of unexposed rats.

The first-generation offspring had some exposure to the chemotherapy drug since their fathers’ sperm was exposed, but researchers found a greater incidence of disease in not only the first- but also the second-generation, who had no direct exposure to the drug. While there were some differences by generation and sex, the associated problems included a greater incidence of kidney and testis diseases as well as delayed onset of puberty and abnormally low anxiety, indicating a lowered ability to assess risk.

Epigenetic Inheritance of Chemotherapy Effects

The researchers also analyzed the rats’ epigenomes, which are molecular processes that are independent of DNA sequence, but influence gene expression, including turning genes on or off. Previous research has shown that exposure to toxicants, particularly during development, can create epigenetic changes that can be passed down through sperm and ova.

The results of the researchers’ analysis showed epigenetic changes in two generations linked to the chemotherapy exposure of the originally exposed rats. The fact that these changes could be seen in the grand-offspring, who had no direct exposure to the chemotherapy drug, indicates that the negative effects were passed down through epigenetic inheritance.

Skinner and colleagues at Seattle Children’s Research Institute are currently working on a human study with former adolescent cancer patients to learn more about the effects chemotherapy exposure has on fertility and disease susceptibility later in life.

A better knowledge of chemotherapy’s epigenetic shifts could also help inform patients of their likelihood of developing certain diseases, creating the possibility of earlier prevention and treatment strategies, Skinner said.

“We could potentially determine if a person’s exposure had these epigenetic shifts that could direct what diseases they’re going to develop, and what they’re going to potentially pass on to their grandchildren,” he said. “We could use epigenetics to help diagnose whether they’re going to have a susceptibility to disease.”

Reference: “Examination of generational impacts of adolescent chemotherapy: Ifosfamide and potential for epigenetic transgenerational inheritance” by Ryan P. Thompson, Daniel Beck, Eric Nilsson, Millissia Ben Maamar, Margarett Shnorhavorian and Michael K. Skinner, 12 November 2022, iScience.
DOI: 10.1016/j.isci.2022.105570

The study was funded by The Templeton Foundation and the National Institutes of Health.

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