Toxic genetics: chemotherapy may increase disease susceptibility in offspring

Chemotherapy is a cancer treatment
that uses powerful drugs to kill cancer cells.
Chemotherapy can be used to treat cancer, shrink tumors, or slow the progression of
the disease.
It can be used alone or in combination with other treatments, such as surgery or radiation therapy
.
Chemotherapy may cause side effects such as nausea, vomiting, hair loss, and fatigue, but these are usually temporary and can be controlled
with medication.

A new study led by Washington State University has found that a common chemotherapy drug called ifosfamide may have toxic effects that may be passed on to the children and grandchildren of adolescent cancer survivors
.

The study, published in the journal iScience, found that male rats treated with ifosfamide during adolescence had a higher
chance of the disease in their offspring and grandchildren.
This is the first known study to show that susceptibility to disease resulting from cancer treatment can be passed on to the third generation of offspring
who have not been exposed to cancer.

Previous studies have shown that cancer treatment increases a patient's risk of developing the disease later in life, but this study expands that understanding
by demonstrating that the effects of chemotherapy can be passed on to future generations.

Michael Skinner, a biologist at Washington State University and corresponding author of the study, said: "The findings suggest that if a patient receives chemotherapy and then has children, their grandchildren, or even great-grandchildren, may increase susceptibility
to disease because of their ancestral chemotherapy exposure.
"

Skinner stressed that the findings should not prevent cancer patients from receiving chemotherapy, which can be a very effective treatment
.
Chemotherapy drugs can kill cancer cells and stop them from multiplying, but there are many side effects
because they affect the entire body, including the reproductive system.

Given the significance of this study, the researchers recommend that cancer patients who plan to have children later take precautions, such as using cryopreserved frozen sperm or eggs
before chemotherapy.

In the study, the researchers exposed a group of young male rats to ifosfamide for three days, mimicking the course
of treatment that adolescent human cancer patients might receive.
These rats then mate
with female rats who are not exposed to the drug.
The resulting offspring are again bred
with another group of unexposed rats.

Because the father's sperm of the first-generation offspring was exposed to chemotherapy drugs, they were exposed to some chemotherapy drugs, but the researchers found that not only did the first-generation offspring have a higher chance of getting the disease, but so did the second-generation offspring who were not directly exposed to the drug
.
While there are some differences between different generations and genders, associated problems include higher rates of kidney and testicular disease, as well as delayed onset of puberty and abnormally low anxiety, suggesting a lower
ability to assess risk.

The researchers also analyzed the rats' epigenomes, which are molecular processes independent of DNA sequences but affect gene expression, including turning genes
on or off.
Previous studies have shown that exposure to toxic substances, especially during development, produces epigenetic changes that are passed on
through sperm and eggs.

The researchers' analysis showed epigenetic changes
in rats initially exposed to chemotherapy over two generations.
In fact, these changes can be seen in grandchildren who are not directly exposed to chemotherapy drugs, suggesting that negative effects are passed on epigenetically
.

Skinner and colleagues at the Seattle Children's Research Institute are currently conducting a human study in pre-teenage cancer patients to learn more about the effects
of chemotherapy exposure on fertility and susceptibility to disease later in life.

A better understanding of the epigenetic changes in chemotherapy could also help patients understand how likely they are to develop certain diseases, creating possibilities for early prevention and treatment strategies
, Skinner said.

"We might determine whether a person's exposure produces these epigenetic changes that determine what disease they will develop and what they might pass on to their grandchildren
," he said.
"We can use epigenetics to help diagnose whether they will be susceptible to disease
.
"