Risks of genetic damage in offspring conceived using spermatozoa produced during chemotherapy or radiotherapy

Abstract

Background: Men who have just started cytotoxic therapy for cancer are uncertain and concerned about whether spermatozoa collected or pregnancies occurring during therapy might be transmitting genetic damage to offspring. There are no comprehensive guidelines on the risks of different doses of the various cytotoxic, and usually genotoxic, antineoplastic agents. Objectives:To develop a schema showing the risks of mutagenic damage when spermatozoa, exposed to various genotoxic agents during spermatogenesis, are collected or used to produce a pregnancy. Materials and methods:A comprehensive literature review was performed updating the data on genetic and epigenetic effects of genotoxic agents on animal and human spermatozoa exposed during spermatogenic development.Results: Relevant data on human spermatozoa and offspring are extremely limited, but there are extensive genetic studies in experimental animals that define sensitivities for specific drugs and times. The animal data were extrapolated to humans based on the stage when the cells were exposed and the relative kinetics of spermatogenesis and were consistent with the limited human data. In humans, alkylating agents and radiation should already induce a high risk of mutations in spermatozoa produced within 1 or 2 weeks after initiation of therapy. Topoisomerase II inhibitors and possibly microtubule inhibitors produce the greatest risk at weeks 5-7 of therapy.Nucleoside analogs, antimetabolites, and bleomycin exert their mutagenic effects on spermatozoa collected at 7-10 weeks of therapy. Discussion and conclusions:A schema showing the time from initiation of therapy at which specific antineoplastic agents can cause significant levels of genetic damage in conceptuses and live offspring was developed. The estimates and methods for computing the level of such risk from an individual patient's treatment regimen will enable patients and counselors to make informed decisions on the use of spermatozoa or continuation of a pregnancy. K E Y W O R D Schemotherapy, radiotherapy, mutations, chromosome aberrations, human, animal models

Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility

“…Recent studies have raised awareness of the sensitivity of the immature testicular tissue to chemotherapy exposure and an increased risk of infertility in adult men treated during childhood compared with the overall population. This review highlighted the limited data available on the impact of chemotherapy exposure before puberty, especially with regard to the impact on somatic cells, interstitial tissue, and sperm quality in both human (Figure 1 [8,10,11,22,23,[31][32][33][34]40,42,58,61,[64][65][66][67][68]71,72,75,78,88,[99][100][101][102][103][104][105][106]114,115,[117][118][119][120]123,124,133,134,141]) and animal models (Figure 2 [24-30,43,46-48,52,53,55,56,62,77,81,83,89,96-98,108-111, 121,125,126,129-131,135,136,143-149,151]...…”

“…Indeed, a significant level of sperm DNA and chromatin damages has been observed in the semen samples of cancer patients, even after a 24-month recovery period [89,116]. Nuclear abnormalities observed in ejaculated sperm appeared to vary according to the stage of differentiation (spermatogonia, spermatocytes, or spermatids) at the time of chemotherapy exposure and the anticancer agent used [117].…”

Multidisciplinary consensus on the criteria for fertility preservation in cancer patients

“…In the case of radiotherapy, the maximum risk occurs one week after the start of the doses, but it persists for up to 2 months. Topoisomerase II inhibitors act mainly on meiosis; consequently, the greatest damage occurs between 30 and 50 days after administration [ 30 ]. These circumstances, as well as the inevitable effect of the underlying disease (hormonal or paracrine dysregulation in testicular tumours, fever in lymphomas or leukaemia, radiation exposure from diagnostic tests) are individual risk factors that should be included in the consent form.…”

Meiotic susceptibility for induction of sperm with chromosomal aberrations in patients receiving combination chemotherapy for Hodgkin lymphoma

“…https://doi.org/10.1371/journal.pone.0242218.t001 The days noted for exposure of cells as spermatogonia, spermatocytes, spermatids, and mature sperm are based on the timing of cells exposed to an administered agent at these stages to appear as sperm in the ejaculate (see S1 Fig in [42]). This timing is based on the kinetics of spermatogenesis in the testis [59], an updated system for staging cells in human spermatogenesis [60], and the appearance of labeled sperm in the ejaculate [61].…”

“…The differentiation stages of spermatogenesis from stem cells to mature sperm vary substantially in their susceptibilities to transmittable genomic damage from cancer drugs, depending on the mechanisms of action of the exposure agents, dosing regimen, type of genomic damage and other factors [3,42]. We analyzed semen samples collected at different times relative to the patients' anticancer treatment, to identify the windows of spermatogenesis that were most susceptible for the induction of chromosomal rearrangements versus aneuploidies and to compare kinetics of recovery for both categories of genomic damage after the end of therapy.…”