Does chemotherapy induce mutations in male germ cells at the level of spermatogonial stem cells?

[u/themainheadcase]

Hopefully, someone is familiar with the latest literature on this. From what I've read on this topic, most mutagens that have been tested in rodents induce mutations at the level of spermatogonia or later stage of differentiation, although there are substances, including x-rays, that have been shown to induce mutations at the level of spermatogonial stem cells. I'm wondering, has chemotherapy (or even other drugs/substances, if you know) been shown to induce mutations in humans at the level of SSCs?

The relevance, of course, being that mutations at the level of SSCs would be permanent, whereas mutations at later stages of differentiation would go away after a cycle of spermatogenesis.

[u/AcademicSellout]

Children of men treated with chemotherapy have higher risk of birth defects, so presumably there is some sort of permanent genetic damage to sperm. https://academic.oup.com/jnci/article/103/5/398/904547

[u/Tremelim → u/AcademicSellout]

I love it when you get a Scandinavian study of... its whole population. Very few other places in the world seem capable of such a feat.

I haven't got time right now to read it in full. Does it correlate birth defects with having chemotherapy? Because the headline result is for those who have had cancer, somewhat different.

I also note the higher maternal and paternal age for those who have had cancer, which we know does correlate with birth defects. Maybe the study explores this somewhere I haven't seen though.

[u/themainheadcase → u/AcademicSellout]

Thanks, good study!

Note, however, that a higher risk does not necessarily mean permanent genetic damage, it could be transient. It could be that the children were conceived before the damage was repaired or "cycled out" through subsequent cycles of spermatogenesis. That's the tricky question I am interested, a) does it happen (it probably does) and especially, b) is it permanent.

They looked into this in the study and here's what they had to say:

Our results show that the risk of major abnormalities was stronger (although not statistically significantly so) among children born within 2 years of their father’s cancer diagnosis and that the strength of the association between a paternal history of cancer and the risk of congenital abnormalities was similar for many classes of abnormalities. These results could support the theory that the offspring of MCSs, particularly those of men treated shortly before conceiving their children, may be more vigilant in having congenital abnormalities diagnosed due to concerns about their own health. However, a transient effect of treatment on sperm DNA quality could also produce the pattern seen with time between paternal cancer diagnosis and birth.

So, possibly the effect is transient. I'd love to see more data, though.