Παρασκευή, 17 Φεβρουαρίου 2017

EPIGENETIC CHAGES IN SPERM AFTER CHEMOTHERAPY IN PUBERTY

Young men who undergo chemotherapy during puberty may undergo permanent genetic changes in their sperm that could be passed on to the next generation, the results of a small-scale US study have demonstrated for the first time in humans.
The researchers found epigenetic changes in DNA methylation in the sperm of a group of male survivors of osteosarcoma, the most common cancer among males in their pubertal years. The changes were found 10 years after the individuals had undergone chemotherapy. Although most of the changes were typically small, half were associated with genes.
The study was published online in PLoS One on February 1.
Lead author, Michael K. Skinner, PhD, Eastlick Distinguished Professor, founding director, Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, said that these changes could influence the health of the patients' offspring.
"Now, we don't have evidence for that yet, but the potential's there because this [epigenetic change] is in a sperm," he told Medscape Medical News, adding that he and his colleagues intend to conduct studies to investigate that further.
For the present, Dr Skinner emphasized that the results do not mean that chemotherapy should be avoided, adding: "You should take the chemo, because that's going to allow you to survive.
"But what it does mean is there are some things you can do circumvent the problem, like if they were to collect sperm from the individuals and freeze before the chemo, then when that individual grew up and wanted to have children, he could use this cryopreserved sperm and then there wouldn't be any potential hazard of passing this [epigenetic change] to the next generation."
Dr Skinner pointed out that cryopreservation is already a well-established option for women undergoing chemotherapy, as they are more sensitive to drugs, which can kill all of their eggs and render them infertile.
"So they go in and they collect the eggs, freeze them and then later in life when they want to have children they can," he said. "That's going now, but we hadn't really thought about doing it for the male before."
Dr Skinner also noted that the issue of environmental exposures affecting the epigenetic programming of the germline and this being passed on to the next generation is not confined to chemotherapy.
"It'll probably be lots of environmental exposures; chemicals and things like that. There's animal studies now showing that if you have nutritional changes, or stress at a certain time, you can pass on your epigenetic differences to your offspring, and it becomes permanent."
He continued: "This nongenetic form of inheritance, called epigenetic transgenerational inheritance, is a real thing that we need to start thinking about. It's influenced by the environment, whereas genetics doesn't really change through environmental exposures like this."
Study Details
Building on previous research in animals suggesting that environmental exposures can cause epigenetic sperm changes, the researchers recruited 18 male survivors of osteosarcoma aged 19 to 30 years who had been treated with cisplatin-based chemotherapy regimens when they were aged 14 to 20 years.
They also recruited 18 adult male controls with no history of cancer. All the participants provided a semen sample via home collection. A sperm count was performed, as was methylated DNA immunoprecipitation sequencing analysis to assess for the presence of copy number variations (CNVs) and differential DNA methylation regions (DMRs). 
The cancer survivors had a mean sperm count of 77.8 million per individual, compared with 280 million per individual among controls, equating to patients having approximately 30% of normal sperm counts.
The team identified 2831 singe DMR sites and 135 multiple DMR sites that were present on all chromosomes, including the Y chromosome, although several regions on chromosomes 1, 9, 13, 14, and 15 did not have DMRs. This finding suggests that they may have elements that prevent DMR formation.
Most DMRs were in chromosomal regions with low-density CpG content, called CpG deserts, and were largely 1 kb in size, with only a few greater than 6 kb; there were no associations or overlaps with CNVs, indicating that this was not a cause of the DMRs.
The characteristics of the epigenetic changes were similar to those seen in different species with different environmental exposures, prompting the authors to note that "this conservation suggests a potential common mechanism, with broad impacts on medicine."
Further analysis indicated that approximately 50% of the DMRs had associations with genes, primarily in predicted promotor regions. Correction for known gene pathways indicated that no specific pathway or cellular process was associated with more than four associated genes.
The team writes: "The current study demonstrates for the first time the ability of chemotherapy to promote epigenetic reprogramming in the spermatogonial stem cell population that will lead to human sperm epimutations later in life. These DMRs have some gene associations that could influence genome activity. A set of epimutations (i.e. signature) was detected and may provide an epigenetic biomarker for chemotherapy exposures."
They add: "The potential biological impact of chemotherapy induced epimutations may be to transmit altered epigenetic information to the next generation and if imprinted-like to subsequent generations progeny."
Dr Skinner said that the results are likely to apply to other cancers and chemotherapy regimens but that further investigation is required.
"We haven't done enough studies to show whether different types of chemo cause different epigenetic programming at different epigenetic sites. That we don't know," he said. "But there's a lot of studies that need to be done now and one of them is: If you change the chemo, do you change the epigenetic pattern?"
The research was supported by National Institutes of Health (NIH) Male Reproductive Health Research Award K12 HD053984 and Childrens Oncology Group- AFLAC 2009-2010 Young Investigator Award grants to Margarett Shnorhavorian and NIH grant (ES012974-12) to Michael Skinner. The authors have disclosed no relevant financial relationships.
PLoS One. Published online February 1, 2017. Full text

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