How chemotherapy and radiation lead to intergenerational impact on fertility

On 31 October 2017, at the American Society for Reproductive Medicine in San Antonio, Patel and colleagues presented the first study to correlate chemotherapy-treated women with reduced fertility of their offspring[1]
.

Daughters born to chemotherapy-treated women had 71% fewer children of their own compared with the general population, while sons had 86% fewer children. On the other hand, children born to chemotherapy-treated men did not suffer much with respect to their fertility.

Two observations are deduced from this: (i) female parents, not male parents, pass their mutations to their offspring, and (ii) male offspring have a higher infertility rate compared with female offspring.

The first could be explained by the fact that male germ line (sperm) has a high turnover rate during a man’s life, whereas the female germ line (eggs) exists since birth and declines over time. As a result, eggs retain mutations.

The second could be explained by the discrepancy in the nature and frequency of mutations in sperm versus eggs, and those with respect to different treatment modalities. Radiation is region-specific, whereas, chemotherapy runs throughout the body, and leads to different forms of DNA mutations compared with ionising radiation.

The human mutation rate of sperm is six times higher than that of eggs[2]
. Specific regions of DNA in human sperm lacking methylation are more susceptible to mutations[3]
. Sperm tends to suffer from base pair change-related mutations, and eggs from nondisjunction mutations. Mutations in germ lines are linked to infertility.

This finding is not exclusive to chemotherapy. In 2000, Dubrova and colleagues came across an eye-popping observation. Radiation-treated parent mice had offspring with several times more mutations in their eggs and sperm[4]
. The researchers then exploited the effects of three commonly used chemotherapies (mitomycin C, procarbazine, and cyclophosphamide), with doses equivalent to those in the clinics, on male mice; this resulted in elevated mutation rates in sperm and bone marrow of offspring (sperm and the bone marrow are susceptible to chemotherapy-induced mutations owing to their high division rate)[5]
. Researchers hypothesised that this was the ‘bystander effect’, where mutations accumulate in the genome and manifest in later generations, long after exposure has ceased.

Patel and colleagues stressed that this study is preliminary and a follow-up in ten years with advanced reproductive age, and a study in a larger population, are needed to draw confident conclusions[1]
. Genetic and epigenetics changes in the germ line and gametes of offspring must be examined. Pre-chemotherapy fertility preservation services, such as freezing the eggs, must be provided. Guidelines from the National Institute for Health and Care Excellence recommend British women to freeze their eggs ahead of chemotherapy, but not all clinics provide this service. This study might reinforce the exigent need to do so.

Balkees Abderrahman,

Postdoctoral fellow 

University of Texas MD Anderson Cancer Center

References

[1] Patel B, Meeks H, Wan Y et al. Intergenerational effects of chemotherapy on fecundity: both male and female children born to women exposed to chemotherapy have fewer children. O-116. Presented at the American Society for Reproductive Medicine Scientific Congress and Expo on 31 October 2017. doi: 10.1016/j.fertnstert.2017.07.157

[2] Crow JF. Development. There’s something curious about paternal-age effects. Science 2003;301(5633):606–607. doi: 10.1126/science.1088552

[3] Gravtiz L. Lack of DNA modification creates hotspots for mutations. 28 June 2012. Spectrum. Available at: https://spectrumnews.org/news/lack-of-dna-modification-creates-hotspots-for-mutations (accessed November 2017)

[4] Dubrova YE, Plumb M, Gutierrez Bet al. Genome stability: transgenerational mutation by radiation. Nature 2000;405;37. doi: 10.1038/35011135

[5] Glen CD & Dubrova YE. Exposure to anticancer drugs can result in transgenerational genomic instability in mice. Proc Natl Acad Sci USA 2012;109(8):2984–2988. doi: 10.1073/pnas.1119396109

Last updated
Citation
Clinical Pharmacist, CP, December 2017, Vol 9, No 12;9(12):DOI:10.1211/PJ.2017.20203945